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71.
Lior Rosenfeld Jason Shirian Yuval Zur Noam Levaot Julia M. Shifman Niv Papo 《The Journal of biological chemistry》2015,290(43):26180-26193
The molecular interactions between macrophage colony-stimulating factor (M-CSF) and the tyrosine kinase receptor c-FMS play a key role in the immune response, bone metabolism, and the development of some cancers. Because no x-ray structure is available for the human M-CSF·c-FMS complex, the binding epitope for this complex is largely unknown. Our goal was to identify the residues that are essential for binding of the human M-CSF to c-FMS. For this purpose, we used a yeast surface display (YSD) approach. We expressed a combinatorial library of monomeric M-CSF (M-CSFM) single mutants and screened this library to isolate variants with reduced affinity for c-FMS using FACS. Sequencing yielded a number of single M-CSFM variants with mutations both in the direct binding interface and distant from the binding site. In addition, we used computational modeling to map the identified mutations onto the M-CSFM structure and to classify the mutations into three groups as follows: those that significantly decrease protein stability; those that destroy favorable intermolecular interactions; and those that decrease affinity through allosteric effects. To validate the YSD and computational data, M-CSFM and three variants were produced as soluble proteins; their affinity and structure were analyzed; and very good correlations with both YSD data and computational predictions were obtained. By identifying the M-CSFM residues critical for M-CSF·c-FMS interactions, we have laid down the basis for a deeper understanding of the M-CSF·c-FMS signaling mechanism and for the development of target-specific therapeutic agents with the ability to sterically occlude the M-CSF·c-FMS binding interface. 相似文献
72.
Abstract: Recent immunohistochemical experiments revealed that specific anti-neurofilament monoclonal antibodies yield distinct patterns in different types of neurons. This led to the suggestion that neurofilaments are a family of heterogeneous molecules whose occurrence and distribution are a function of cell type. In the present study we examined the hypothesis that this heterogeneity is due to differences in the extent of phosphorylation of neurofilament proteins in distinct types of neurons. In view of the large number of potential phosphorylation sites on the heavy neurofilament protein (NF-H), we focused on this protein and examined its extent of phosphorylation in different types of neurons. This was performed using neurofilaments isolated from axons of the cholinergic bovine ventral root motor neurons and of the chemically heterogeneous bovine dorsal root neurons. Two-dimensional gel electrophoresis revealed that the isoelectric point of ventral root NF-H (pl 5.10) was ∼0.2 pl units more acidic than that of dorsal root NH-F. This difference was abolished by treating the neurofilaments with alkaline phosphatase, suggesting that the excess negative charge of ventral root NF-H is due to increased levels of phosphorylation. Amino acid analysis confirmed that the phosphoserine content of ventral root NF-H (27.2 ± 2.5% of the serines) is markedly higher than that of dorsal root NF-H (15.5 ± 6.2% of the serines). These findings provide a novel system for studying the biochemistry and function of distinctly phosphorylated neurofilaments in different types of neurons. 相似文献
73.
Isolation, characterization, and serotyping of Campylobacter jejuni and Campylobacter coli from slaughter cattle. 总被引:5,自引:0,他引:5 下载免费PDF全文
M M Garcia H Lior R B Stewart G M Ruckerbauer J R Trudel A Skljarevski 《Applied microbiology》1985,49(3):667-672
A total of 525 specimens from 100 slaughter beef cattle were examined for the presence of Campylobacter jejuni and Campylobacter coli by direct plating and enrichment techniques. Isolates were identified by cultural, biochemical, antibiotic sensitivity, and immunofluorescence tests and further characterized with the aid of recently developed biotyping and serotyping methods. Fifty animals were positive for C. jejuni; only one was positive for C. coli. The distribution pattern of C. jejuni-positive animals, in decreasing order, was steers (55%), bulls (40%), heifers (40%), and cows (22%). Significantly higher isolation rates were obtained from the gall bladders (33%), large intestines (35%), and small intestines (31%) than from the livers (12%) or the lymph nodes (1.4%). C. jejuni isolation by the enrichment technique was 40.2% more frequent than by direct plating; 24-h enrichment resulted in 24% more isolations than 48-h enrichment. Eighty-four of 105 C. jejuni cultures were typable serologically and represented 13 serogroups. Biotype I accounted for 71% of biotyped cultures. Serogroup 7 biotype I was the most commonly encountered (24%) isolate. About one in three positive animals had C. jejuni strains representing more than one serogroup. C. jejuni serogroups encountered in slaughter cattle were similar to those commonly isolated from human sources. 相似文献
74.
More than 2,000 confirmed cases of food poisoning occurred in the four Atlantic provinces of Canada and in Ontario during the second and third quarters of 1984. Salmonella typhimurium phage type 10 was identified as the etiologic agent, and cheddar cheese was implicated as the source of infection. Strains isolated from infected humans and from cheese were indistinguishable by biotyping, antibiotic resistance typing, and phage typing. Plasmid analysis confirmed cheese as the source of infection and revealed the presence of two molecular subgroups of bacteriophage type 10. Group I strains carried 57-, 22.3-, and 3.4-kilobase (kb) plasmids; group II strains carried 57-, 4.6-, and 3.4-kb plasmids. Digestion with endonucleases HaeIII, HpaII, and AvaIII indicated that the 3.4-kb plasmids were identical. This outbreak was, therefore, caused by a mixed infection with two distinct but related bacteria. Group I strains are fairly common among Canadian S. typhimurium phage type 10 isolates, whereas group II strains appeared to be unique to this outbreak. 相似文献
75.
Twenty O157:H7 enterohemorrhagic Escherichia coli strains from patients with different clinical conditions were tested for colicinogeny and the presence of Verotoxin (VT) genes. From bloody diarrhea cases, 7/8 isolates and from hemolytic uremic syndrome cases 3/5 isolates all synthesized what appeared to be colicin D. The remaining strains, which included 7 from asymptomatic sources, were noncolicinogenic. The plasmid determining the colicin was found to be 1.4 kb larger than the 5.2-kb pColD. The colicin D protein had a molecular weight of about 90,000, whereas the O157 colicin was 87,000. The plasmid was designated pColD157 to reflect these differences. Of O157:H7 isolates 17/20 had genes for both of the Verotoxins VT1 and VT2, and the remaining 3/20 for VT1 only. There was no correlation between the presence of VT determinants and colicinogeny or symptoms. The O157:H7 strains exhibited significant resistance to other colicins and bacteriophages. 相似文献
76.
Roberto Chertoff Lior Soussan Hanno Roder Daniel M. Michaelson 《Cellular and molecular neurobiology》1995,15(2):269-281
Summary 1. Previous immunohistochemical studies led to the suggestion that distinctly phosphorylated neurofilament isoforms exist in different types of neurons. We have recently examined this hypothesis by direct biochemical experiments, which revealed that the heavy neurofilament protein NF-H of bovine ventral root cholinergic neurons is more acidic and markedly more phosphorylated than that of bovine dorsal root neurons.2. In the present study we employed this system to study the degree to which distinctly phosphorylated NF-H isoforms differ in the extents to which they can be phosphorylated and dephosphorylatedin vitro. This was performed utilizing alkaline phosphatase and protein kinase PK40ERK, which is specific to serines of Lys-Ser-Pro (KSP) repeats. The results obtained reveal that:3. The more extensively phosphorylated ventral root NF-H is dephosphorylated more rapidly than dorsal root NF-H.4. Ventral root NF-H and dorsal root NF-H in their native form are both poor substrates of PK40ERK.5. Following dephosphorylation, ventral root and dorsal root NF-H are phosphorylated extensively and differentially by this kinase. Under these conditions, PK40ERK catalyzes the incorporation of, respectively, 4.2±1.3 and 2.8±0.6 mol of phosphate per molecule of ventral root NF-H and dorsal root NF-H. The ratio of phosphates incorporated into ventral root NF-H to those incorporated into dorsal root NF-H is 1.46±0.17.6. These findings support the hypothesis that different classes of neurons contain distinctly phosphorylated neurofilaments and show that ventral root and dorsal root neurons are a useful model system for studying the distinct characteristics of neurofilament phosphorylation in different types of neurons. 相似文献
77.
A selective medium for the isolation of Arcobacter from meats 总被引:4,自引:1,他引:3
E. de Boer J.J.H.C. Tilburg D.L. Woodward H. Lior W.M. Johnson 《Letters in applied microbiology》1996,23(1):64-66
A method, including enrichment in Arcobacter Selective Broth (ASB) and isolation on semisolid Arcobacter Selective Medium (ASM) under aerobic conditions at 24°C, is described for the isolation of Arcobacter from retail meat products. Selective agents used in ASB and ASM were cefoperazone, trimethoprim, piperacillin and cycloheximide. Arcobacters were isolated from 53 (24.1%) of 220 poultry meat products and also, at lower incidence from samples of beef and pork. The isolates were identified as A. butzleri or A. butzleri -like and belonged to a wide variety of serotypes and biotypes. 相似文献
78.
The Gibbs sampling method has been widely used for sequence analysis after it was successfully applied to the problem of identifying regulatory motif sequences upstream of genes. Since then, numerous variants of the original idea have emerged: however, in all cases the application has been to finding short motifs in collections of short sequences (typically less than 100 nucleotides long). In this paper, we introduce a Gibbs sampling approach for identifying genes in multiple large genomic sequences up to hundreds of kilobases long. This approach leverages the evolutionary relationships between the sequences to improve the gene predictions, without explicitly aligning the sequences. We have applied our method to the analysis of genomic sequence from 14 genomic regions, totaling roughly 1.8 Mb of sequence in each organism. We show that our approach compares favorably with existing ab initio approaches to gene finding, including pairwise comparison based gene prediction methods which make explicit use of alignments. Furthermore, excellent performance can be obtained with as little as four organisms, and the method overcomes a number of difficulties of previous comparison based gene finding approaches: it is robust with respect to genomic rearrangements, can work with draft sequence, and is fast (linear in the number and length of the sequences). It can also be seamlessly integrated with Gibbs sampling motif detection methods. 相似文献
79.
Daniel Yasur-Landau Charles L. Jaffe Lior David Gad Baneth 《PLoS neglected tropical diseases》2016,10(1)
Background
Visceral leishmaniasis caused by the protozoan Leishmania infantum is a zoonotic, life threatening parasitic disease. Domestic dogs are the main peridomestic reservoir, and allopurinol is the most frequently used drug for the control of infection, alone or in combination with other drugs. Resistance of Leishmania strains from dogs to allopurinol has not been described before in clinical studies.Methodology/Principal Findings
Following our observation of clinical disease relapse in dogs under allopurinol treatment, we tested susceptibility to allopurinol of L. infantum isolated from groups of dogs pre-treatment, treated in remission, and with disease relapse during treatment. Promastigote isolates obtained from four treated relapsed dogs (TR group) showed an average half maximal inhibitory concentration (IC50) of 996 μg/mL. A significantly lower IC50 (P = 0.01) was found for isolates from ten dogs before treatment (NT group, 200 μg/mL), as well as for five isolates obtained from treated dogs in remission (TA group, 268 μg/mL). Axenic amastigotes produced from isolates of the TR group also showed significantly higher (P = 0.002) IC50 compared to the NT group (1678 and 671 μg/mL, respectively). The lower sensitivity of intracellular amastigotes from the TR group relative to those from the NT group (P = 0.002) was confirmed using an infected macrophage model (6.3% and 20% growth inhibition, respectively at 300 μg/mL allopurinol).Conclusions
This is the first study to demonstrate allopurinol resistance in L. infantum and to associate it with disease relapse in the canine host. These findings are of concern as allopurinol is the main drug used for long term control of the disease in dogs, and resistant L. infantum strains may enhance uncontrolled transmission to humans and to other dogs. 相似文献80.
The palindromic LTR-LTR junction of Moloney murine leukemia virus is not an efficient substrate for proviral integration. 总被引:17,自引:13,他引:4 下载免费PDF全文
We generated viral constructs to test the hypothesis that the major substrate on retroviral DNA that is utilized for proviral DNA integration is the palindromic sequence, termed the LTR-LTR junction, normally present in circular molecules formed by joining the two termini of linear proviral DNA. Recombinant viral genomes were built which carried a selectable marker and an extra copy of the LTR-LTR junction from a cloned circular provirus. The junction sequence in each case was positioned such that its use during integration would lead to an easily detected, aberrantly integrated proviral DNA. Analysis of DNA from cells infected with the virus constructs showed that the introduced junction sequence is used at least 1,000-fold less efficiently than the natural sequences at the ends of the genome. This suggests that a linear or more exotic DNA intermediate is most likely the true precursor for the integration reaction. 相似文献