Optimizing potentials for the inverse protein folding problem

Inverse protein folding, which seeks to identify sequences that fold into a given structure, has been approached by threading candidate sequences onto the structure and scoring them with database-derived potentials. The sequences with the lowest energies are predicted to fold into that structure. It has been argued that the limited success of this type of approach is not due to the discrepancy between the scoring potential and the true potential but is rather due to the fact that sequences choose their lowest-energy structure rather than structures choosing the lowest-energy sequences. Here we develop a non- physical potential scheme optimized for the inverse folding problem. We maximize the average probability of success for a set of lattice proteins to obtain the optimal potential energy function, and show that the potential obtained by our method is more likely to produce successful predictions than the true potential.      

Recognition of synthetic deoxy and deoxyfluoro analogs of the acceptor alpha-L-Fuc p-(1-->2)-beta-D-Gal p-OR by the blood-group A and B gene-specified glycosyltransferases

The disaccharide alpha-L-Fuc p-(1-->2)-beta-D-Gal p-O-(CH2)7CH3 (6), is an acceptor for both glycosyltransferases responsible for the biosynthesis of the A and B blood-group antigens. These enzymes transfer GalNAc and Gal, respectively, with an alpha-linkage to OH-3 of the Gal residue in 6. All six possible deoxy and deoxyfluoro analogs of 6, with modifications on the target Gal residue, were chemically synthesized and kinetically evaluated as both substrates and inhibitors for the A and B glycosyltransferases. Both enzymes will tolerate replacement of the hydroxyl groups at the 3 and 6 positions of the Gal residue. Substitution of OH-4 of the Gal residue, however, abolishes recognition by these glycosyltransferases. The 6-deoxy and 6-fluoro compounds are substrates for both enzymes while the 3-deoxy and 3-fluoro compounds are competitive inhibitors, with Ki values in the range 14-110 microM. Kinetic constants have been determined for the 6-deoxy and 6-fluoro derivatives.     

Childhood acute lymphocytic leukemia with a preleukemic phase: report of an associated translocation and review of the literature

A fourteen month old boy presented with hepatosplenomegaly and pancytopenia. An extensive evaluation, including bone marrow aspiration and biopsies of both liver and lymph nodes, revealed a polyclonal B cell proliferation consistent with a reactive process, with no evidence of leukemia. After receiving transfusions of red cells and platelets, his blood counts recovered. Five weeks later, he returned with an elevated white blood count and bone marrow findings diagnostic of acute lymphocytic leukemia. The leukemic blasts contained a novel chromosomal translocation, t(5;14) (q34;q12). We describe the clinical, immunophenotypic and cytogenetic features of this case, review the literature of acute lymphocytic leukemia associated with a preleukemic phase, and discuss the relationship of this clinical entity to the 5q-abnormality associated with myelodysplasia.     

Effect of chromium picolinate on growth and serum and carcass traits of growing-finishing pigs

Three experiments were conducted to evaluate chromium picolinate (CrPic) in growing-finishing pigs. Treatments were replicated four times within each experiment with three pigs per replicate in Exp. 1 and four pigs per replicate in Exp. 2 and 3. Average initial weights were 37.8, 30.5, and 22.4 kg in Exp. 1, 2, and 3, respectively. In Exp. 1, the basal corn-soybean meal diet (B, 120% NRC Lys) was supplemented with 0, 25, 50, 100, or 200 ppb of Cr from CrPic. Daily gain was increased (Cr cubic, P < .02) and serum cholesterol decreased (Cr cubic, P < .08) by addition of CrPic. In Exp. 2, the basal diet was supplemented with 0, 100, 200, 400, or 800 ppb of Cr from CrPic. Daily gain and ADFI were decreased (Cr linear, P < .05) by CrPic. Serum cholesterol also was decreased (Cr quadratic, P < .05) by CrPic. Longissimus muscle area (LMA) and percentage of muscling (MUS) were increased (Cr quadratic, P < .01) and 10th rib fat (TRF) was decreased (Cr quadratic, P < .01) by CrPic. In Exp. 3, pigs were allotted to the following treatments: 1) B, 2) B + 1,467 ppb of picolinate (Pic), 3) B + 200 ppb of Cr from CrCl3.6H2O, 4) B + 1,467 ppb of Pic + 200 ppb of Cr from CrCl3.6H2O, 5) B + 100 ppb of Cr from CrPic, or 6) B + 200 ppb of Cr from CrPic. Longissimus muscle area and MUS were increased (P < .01) and TRF decreased (P < .01) in pigs fed CrPic but not in pigs fed CrCl3.6H2O and(or) Pic.(ABSTRACT TRUNCATED AT 250 WORDS)     

Structure and plasticity of newly formed adult synapses: a morphometric study in the rat hippocampus

Increasing evidence suggests that synaptic structure represents a plastic feature of the neuron, although the plastic nature of newly formed and existing adult synapses has not yet been fully characterized. Following ipsilateral entorhinal cortical lesions, the rat dentate gyrus offers an excellent model for studying synaptogenesis and plasticity in the adult central nervous system. Unilateral entorhinal lesions were performed in young adult male rats. Synaptic counts and structural features were quantified at 3, 6, 10, 15, and 30 days post-lesion. The lesions resulted in an 88% synaptic loss in the denervated dentate middle molecular layer, which was followed by a period of rapid synaptogenesis. Synaptic element size decreased during the period of maximal synaptogenesis, which was associated with a peak in the presence of non-vesicular and perforated synapses. Following this period, synapses showed a gradual increase in the size of their pre- and postsynaptic elements. These data support the suggestion that newly formed adult synapses have smaller synaptic components than existing adult synapses (resembling synapses seen during development), and increase in size over time with usage. The results are discussed in terms of synaptic structural development and plasticity in the adult central nervous system.     

Parent training for attention-deficit hyperactivity disorder: its impact on parent functioning

This study examined changes in parent functioning resulting from parental participation in a behavioral parent training (PT) program specifically designed for school-aged children with attention-deficit hyperactivity disorder (ADHD). Relative to wait list controls, subjects who completed the nine-session PT program showed significant posttreatment gains in both child and parent functioning, which were maintained 2 months after treatment. In particular, there were PT-induced reductions in parenting stress and increases in parenting self-esteem, which accompanied parent-reported improvements in the overall severity of their child's ADHD symptoms. In addition to their statistical importance, these findings are discussed in terms of their clinical significance, utilizing methods developed by Jacobson and Truax (1991).     

Magnetic resonance imaging of the musculoskeletal system. Part 9. Primary Tumors

Magnetic resonance imaging, because of its exquisite soft tissue contrast, has dramatically improved the ability to preoperatively stage primary osseous and soft tissue neoplasms. This technique also has allowed the monitoring of the effects of chemotherapy and the screening for recurrence of neoplasms. The role of magnetic resonance imaging in the preoperative evaluation of the patient with a suspected primary osseous or soft tissue neoplasm is outlined, instances where magnetic resonance imaging potentially may make a specific diagnosis are outlined, the importance of gadolinium enhancement as an adjunct to native magnetic resonance imaging is stressed, and an algorithm for followup of patients after chemotherapy or definitive surgical treatment is presented. In all cases, the magnetic resonance images should be correlated with the plain film, which is still an important aspect of the diagnosis of osseous lesions.     

High-strength, ultra-thin and fiber-reinforced pHEMA artificial skin

Membranes of pHEMA-based composites were manufactured by adding various kinds of weaved and knitted fabrics and fibers into a deionized water solution of HEMA monomer, EGDMA cross-linker and BIE initiator, and followed by polymerization under ultraviolet radiation. By varying the amount of initial water addition (IWA), the dimensional change of pHEMA matrix from the newly fabricated state to the eventually swollen state could be adjusted to reduce the swellability mismatch with the fabrics and the possibility of the swollen membranes becoming folded and curled was avoided. Mechanical properties of the fiber-reinforced pHEMA composites, including yielding strength, maximum strength, Young's modulus and elongation at break, are improved evidently depending on the mechanical characteristics of additives applied. The involvement of fabrics and fibers in the soft pHEMA matrix also provides an alternative of making the ultra-thin membranes to overcome the problem of easily being torn during handling. In addition, some of these membranes also exhibit an improvement in water transmission rate.     

Propagating structure of Alzheimer's beta-amyloid(10-35) is parallel beta-sheet with residues in exact register

The pathognomonic plaques of Alzheimer's disease are composed primarily of the 39- to 43-aa beta-amyloid (Abeta) peptide. Crosslinking of Abeta peptides by tissue transglutaminase (tTg) indicates that Gln15 of one peptide is proximate to Lys16 of another in aggregated Abeta. Here we report how the fibril structure is resolved by mapping interstrand distances in this core region of the Abeta peptide chain with solid-state NMR. Isotopic substitution provides the source points for measuring distances in aggregated Abeta. Peptides containing a single carbonyl 13C label at Gln15, Lys16, Leu17, or Val18 were synthesized and evaluated by NMR dipolar recoupling methods for the measurement of interpeptide distances to a resolution of 0.2 A. Analysis of these data establish that this central core of Abeta consists of a parallel beta-sheet structure in which identical residues on adjacent chains are aligned directly, i. e., in register. Our data, in conjunction with existing structural data, establish that the Abeta fibril is a hydrogen-bonded, parallel beta-sheet defining the long axis of the Abeta fibril propagation.     

Parathyroid hormone-related protein expression in vascular smooth muscle of spontaneously hypertensive rats: evidence for lack of response to angiotensin II

OBJECTIVE: We studied the expression of parathyroid hormone (PTH)-related protein in vascular smooth muscle cells of spontaneously hypertensive rats (SHR) using Wistar-Kyoto (WKY) and Sprague-Dawley rats as normotensive controls. METHODS: Aortae from 4- and 18-week-old SHR versus age-matched WKY and Sprague-Dawley rats were excised to obtain total RNA or smooth muscle cells. The cells were subcultured in Dulbecco's Modified Eagle's Medium containing 10% fetal calf serum, then serum-deprived for 72 h and stimulated with 0.1 micromol/I angiotensin II. PTH-related protein, c-myc and angiotensin II type qa receptor (AT1aR) messenger (m)RNA levels were measured by Northern blot, using total RNA extracted by phenol/chloroform. The effects of PTH-related protein(1-34)NH2 intravenous injections on arterial blood pressure and the heart rate were studied in anesthetized SHR and WKY rats. RESULTS: The Northern blots showed a significantly higher abundance of PTH-related protein mRNA in aortae of SHR versus WKY rats in the prehypertensive state but no significant difference in adult animals. In cultured aortic smooth muscle cells, angiotensin II induced a four- to sixfold increase in PTH-related protein mRNA levels in smooth muscle cells from normotensive animals, but failed to elicit a significant response in smooth muscle cells derived from SHR in either the prehypertensive or the hypertensive state. This lack of response to angiotensin II in SHR smooth muscle cells was not due to decreased expression or responsiveness of the AT1aR, since SHR smooth muscle cells had more AT1aR mRNA than Sprague-Dawley smooth muscle cells, and angiotensin II-induced activation of c-myc was faster and greater in smooth muscle cells derived from 4- or 18-week-old SHR than in Sprague-Dawley smooth muscle cells. In contrast, PTH-related protein(1-34)NH2 induced a long-lasting dose-dependent hypotensive and tachycardic response in both SHR and WKY rats, indicating that SHR retained responsiveness to the vasodilator. CONCLUSIONS: PTH-related protein gene expression in response to angiotensin II is impaired in SHR arteries. A deficiency in this potent local vasodilator may contribute to the development and/or maintenance of arterial hypertension in this model.