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The synthesis of β-hydroxy-γ-amino acids via SmI2-mediated Reformatsky reactions of α-chloroacetyloxazolidinones with aminoaldehydes is reported. Diastereoselective coupling is demonstrated to depend on the absolute configuration of the Evans chiral auxiliary employed in the reaction, allowing erythro or threo products to be obtained selectively. The potential utility of the methodology is exemplified by the facile synthesis of biologically relevant N-Boc-isostatine (2b) and N-Boc-dolaisoleucine (3c). [ABSTRACT FROM AUTHOR]

The article presents information on a research which examines the effectiveness of isothiazolidinone heterocycles as inhibitors of the Yersinia pestis protein tyrosine phosphate. Also included are the materials and methods used in the research as well as a discussion on the results of the study.

Public school districts in the Mississippi (MS) Delta are under severe pressure to make rapid and adaptable changes in response to the federal legislation No Child Left Behind Act of 2001 and the MS Plan for Student Achievement: Assessment, Accreditation, and Accountability. These reform Acts require higher student performance standards and new assessment systems based on high stakes testing programs. Examined in this study are the kinds of classroom assessment techniques currently (2007-2008) used in teaching mathematics and reading in grades three through five in five school districts in the Mississippi Delta. A survey questionnaire instrument was developed to collect data from teachers. The MS Delta public school districts have high poverty rates, overwhelmingly majority-black student bodies and a very high drop out rate (U.S. Census Bureau, 2000). The statistical data analysis was executed using the Statistical Package for the Social Sciences (SPSS). Open-ended questions were scanned to find common themes, placed into categories and coded accordingly. Descriptive statistics were used to address the research questions. Although teachers used a variety of assessment techniques, portfolios, student made questions, and computer-assisted testing were seldom used. Most teachers perceived that the items on their classroom test aligned in content with items found on the Mississippi Curriculum Test. [ABSTRACT FROM AUTHOR]

Newborns represent the pediatric population most at risk for influenza-related morbidity and mortality, especially premature newborns and those with chronic disease. Compounding this problem is the fact that influenza immunizations are ineffective until 6 months of age. This article describes a successful program that follows the "cocoon" theory of immunization. Free influenza vaccines were given in the nursery to all family members, caregivers, and others living in the homes of discharged infants. Planning and implementation steps are described, along with lessons learned during implementation. The response to the program exceeded expectations, with 185 contacts immunized. Future plans include the expansion of the current program to include the H1N1 influenza vaccine and the Tdap vaccine. The described vaccination effort encourages and substantiates the benefits of cocoon immunization in other nurseries across the nation. [ABSTRACT FROM AUTHOR]

Polo-like kinase-1 (Plk1) has a pivotal role in cell proliferation and is considered a potential target for anticancer therapy. The noncatalytic polo-box domain (PBD) of Plk1 forms a phosphoepitope binding module for protein-protein interaction. Here, we report the identification of minimal phosphopeptides that specifically interact with the PBD of human PLK1, but not those of the closely related PLK2 and PLK3. Comparative binding studies and analyses of crystal structures of the PLK1 PBD in complex with the minimal phosphopeptides revealed that the C-terminal SpT dipeptide functions as a high-affinity anchor, whereas the N-terminal residues are crucial for providing specificity and affinity to the interaction. Inhibition of the PLK1 PBD by phosphothreonine mimetic peptides was sufficient to induce mitotic arrest and apoptotic cell death. The mode of interaction between the minimal peptide and PBD may provide a template for designing therapeutic agents that target PLK1. [ABSTRACT FROM AUTHOR]

Objective:This study concerns the question of whether obese subjects in a community sample experience depression in a different way from the nonobese, especially whether they overeat to the point of gaining weight during periods of depression.Design:A representative sample of adults was interviewed regarding depression and obesity.Subjects:The sample consisted of 1396 subjects whose interviews were studied regarding relationships between obesity and depression and among whom 114 had experienced a major depressive episode at some point in their lives and provided information about the symptoms experienced during the worst or only episode of major depression.Measurements:The Diagnostic Interview Schedule (DIS) was used to identify major depressive episodes. Information was also derived from the section on Depression and Anxiety (DPAX) of the Stirling Study Schedule. Obesity was calculated as a body mass index >30. Logistic regressions were employed to assess relationships, controlling for age and gender, by means of odds ratios and 95% confidence intervals.Results:In the sample as a whole, obesity was not related to depression although it was associated with the symptom of hopelessness. Among those who had ever experienced a major depressive episode, obese persons were 5 times more likely than the nonobese to overeat leading to weight gain during a period of depression (P<0.002). These obese subjects, compared to the nonobese, also experienced longer episodes of depression, a larger number of episodes, and were more preoccupied with death during such episodes.Conclusions:Depression among obese subjects in a community sample tends to be more severe than among the nonobese. Gaining weight while depressed is an important marker of that severity. Further research is needed to understand and possibly prevent the associations, sequences and outcomes among depression, obesity, weight gain and other adversities.International Journal of Obesity (2009) 33, 335–341; doi:10.1038/ijo.2008.273; published online 13 January 2009 [ABSTRACT FROM AUTHOR]

Integrase strand transfer inhibitors (INSTIs) are a class of antiretroviral compounds that prevent the insertion of a DNA copy of the viral genome into the host genome by targeting the viral enzyme integrase (IN). Dolutegravir (DTG) is a leading INSTI that is given, usually in combination with nucleoside reverse transcriptase inhibitors (NRTIs), to treat HIV-1 infections. The emergence of resistance to DTG and other leading INSTIs is rare. However, there are recent reports suggesting that drug resistance mutations can occur at positions outside the integrase gene either in the HIV-1 polypurine tract (PPT) or in the envelope gene (env). Here, we used single round infectivity assays to measure the antiviral potencies of several FDA-approved INSTIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs) against a panel of HIV-1 PPT mutants. We also tested several of our promising INSTIs and NNRTIs in these assays. No measurable loss in potency was observed for either INSTIs or NNRTIs against the HIV-1 PPT mutants. This suggests that HIV-1 PPT mutants are not able, by themselves, to confer resistance to INSTIs or NNRTIs. [ABSTRACT FROM AUTHOR]

When organizing new health care interventions among a rural population, a careful planning process respecting community-specific considerations should be used. The project objective centered on the successful implementation of a school-based telehealth clinic serving a rural, health-disparate population. Using an American Academy of Pediatrics Community Access to Child Health planning grant, a needs assessment of the Delta community was conducted. In synthesizing the results of this planning project, consensually addressed issues led to establishing a pilot schoolbased telehealth clinic within the rural county schools. Seven essential steps emerged as a set of guidelines that entities might consider in introducing a telemedicine school-based service in a rural community. The steps included assessing local and regional needs, securing community support and establishing goals, evaluating resources, configuring logistics, training staff, informing parents, and launching the clinic. Proper planning is crucial to the establishment of a rural school-based telehealth clinic. [ABSTRACT FROM AUTHOR]

Selenocysteine is cotranslationally inserted into proteins by recoding the stop codon UGA from termination to selenocysteine insertion. The nucleophilic selenol group of selenocysteine endows this rare amino acid with unique chemical reactivity that allows regio-specific covalent conjugation in the presence of the other natural amino acids. Using a mammalian expression system, we generated an lgG1-derived Fc fragment with a C-terminal selenocysteine in yields comparable to conventional monoclonal antibodies and conjugated it to an electrophilic derivative of a peptidomimetic that binds with high affinity and specificity to integrin α4β1. Through this conjugation, both the biological and chemical components are endowed with pharmacological advantages. We demonstrate that whereas the Fc protein increases the circulatory half-life from minutes to days and mediates transcytosis through binding to the neonatal Fc receptor, the peptidomimetic introduces cross-species binding to cell surface integrin α4β1 and blocks its interaction with vascular cell adhesion molecule-1. Compared with conventional monoclonal antibodies, our technology benefits economically from combining a generic biological component with a variable chemical component. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The purpose of this study was to determine if high-velocity, low-amplitude spinal manipulation (SM) altered the effects of corticospinal excitability on motoneuron activity innervating the paraspinal muscles. In a previous study using transcranial magnetic stimulation (TMS), augmentation of motor-evoked potentials (MEPs) from the gastrocnemius muscle after lumbar SM was reported. To date, there is no known report of the effect of SM on paraspinal muscle excitability. METHODS: The experimental design was a prospective physiologic evaluation of the effects of SM on corticospinal excitability in asymptomatic subjects. The TMS-induced MEPs were recorded from relaxed lumbar erector spinae muscles of 72 asymptomatic subjects. The MEP amplitudes were evaluated pre-SM and post-SM or conditions involving prethrust positioning and joint loading or control. RESULTS: There was a transient increase in MEP amplitudes from the paraspinal muscles as a consequence of lumbar SM (F([6,414]) = 8.49; P < .05) without concomitant changes after prethrust positioning and joint loading or in control subjects (P > .05). These data findings were substantiated by a significant condition x time interaction term (F([12,414]) = 2.28; P < .05). CONCLUSIONS: These data suggest that there is a postsynaptic facilitation of alpha motoneurons and/or corticomotoneurons innervating paraspinal muscles as a consequence of SM. It appears that SM may offer unique sensory input to the excitability of the motor system as compared to prethrust positioning and joint loading and control conditions. [ABSTRACT FROM AUTHOR]

The article discusses the twelve commonly held beliefs relating to breast milk, breastfeeding, pacifier use, emesis, umbilical cord care, and jaundice. Breastmilk is described as the ideal source of nutrition and almost a complete and perfect source of nutrition. It is recommended by the U.S. American Academy of Pediatrics (AAP) that all breast-fed newborns should receive 200 IU/day of vitamin D until they are getting at least 500 ml/day of vitamin-D formula of milk to prevent vitamin D deficiency and subsequent rickets. On the other hand, formula supplements are considered not reasonable or necessary as routine practice.

Birt-Hogg-Dubé syndrome, a hamartoma disorder characterized by benign tumors of the hair follicle, lung cysts, and renal neoplasia, is caused by germ-line mutations in the BHD(FLCN) gene, which encodes a tumor-suppressor protein, folliculin (FLCN), with unknown function. The tumor-suppressor proteins encoded by genes responsible for several other hamartoma syndromes, LKB1, TSC1/2, and PTEN, have been shown to be involved in the mammalian target of rapamycin (mTOR) signaling pathway. Here, we report the identification of the FLCN-interacting protein, FNIP1, and demonstrate its interaction with 5′ AMP-activated protein kinase (AMPK), a key molecule for energy sensing that negatively regulates mTOR activity. FNIP1 was phosphorylated by AMPK, and its phosphorylation was reduced by AMPK inhibitors, which resulted in reduced FNIP1 expression. AMPK inhibitors also reduced FLCN phosphorylation. Moreover, FLCN phosphorylation was diminished by rapamycin and amino acid starvation and facilitated by FNIP1 overexpression, suggesting that FLCN may be regulated by mTOR and AMPK signaling. Our data suggest that FLCN, mutated in Birt-Hogg-Dubé syndrome, and its interacting partner FNIP1 may be involved in energy and/or nutrient sensing through the AMPK and mTOR signaling pathways. [ABSTRACT FROM AUTHOR]

Herein, we report the identification of a unique HIV-1 integrase (IN) inhibitor-binding site using photoaffinity labeling and mass spectrometric analysis. We chemically incorporated a photo-activatable benzophenone moiety into a series of coumarin-containing IN inhibitors. A representative of this series was covalently photo-crosslinked with the IN core domain and subjected to HPLC purification. Fractions were subsequently analyzed by using MALDI-MS and electrospray ionization (ESI)-MS to identify photo-crosslinked products. In this fashion, a single binding site for an inhibitor located within the tryptic peptide 128AACWWAGIK136 was identified. Site-directed mutagenesis followed by in vitro inhibition assays resulted in the identification of two specific amino acid residues, C130 and W132, in which substitutions resulted in a marked resistance to the IN inhibitors. Docking studies suggested a specific disruption in functional oligomeric IN complex formation. The combined approach of photo-affinity labeling/MS analysis with site-directed mutagenesis/molecular modeling is a powerful approach for elucidating inhibitor-binding sites of proteins at the atomic level. This approach is especially important for the study of proteins that are not amenable to traditional x-ray crystallography and NMR techniques. This type of structural information can help illuminate processes of inhibitor resistance and thereby facilitate the design of more potent second-generation inhibitors. [ABSTRACT FROM AUTHOR]

The key DNA cutting and joining steps of retroviral DNA integration are carried out by the viral integrase protein. Structures of the individual domains of integrase have been determined, but their organization in the active complex with viral DNA is unknown. We show that HIV-1 integrase forms stable synaptic complexes in which a tetramer of integrase is stably associated with a pair of viral DNA ends. The viral DNA is processed within these complexes, which go on to capture the target DNA and integrate the viral DNA ends. The joining of the two viral DNA ends to target DNA occurs sequentially, with a stable intermediate complex in which only one DNA end is joined. The integration product also remains stably associated with integrase and likely requires disassembly before completion of the integration process by cellular enzymes. The results define the series of stable nucleoprotein complexes that mediate retroviral DNA integration. [ABSTRACT FROM AUTHOR]

Argonne National Laboratory (Argonne) developed the transportation system capability (TRANSCAP) model to simulate the deployment of forces from Army bases, in collaboration with and under the sponsorship of the Military Transportation Management Command Transportation Engineering Agency (MTMCTEA). TRANSCAP''s design separates its pre- and post-processing modules (developed in Java) from its simulation module (developed in MODSIM III®). This paper describes TRANSCAP''s modelling approach, emphasizing Argonne''s highly detailed, object-oriented, multilanguage software design principles. Fundamental to these design principles is TRANSCAP''s implementation of an improved method for standardizing the transmission of simulated data to output analysis tools and the implementation of three Army deployment/redeployment community standards, all of which are in the final phases of community acceptance. The first is the extensive hierarchy and object representation for transport simulations (EXHORT), which is a reusable, object-oriented deployment simulation source code framework of classes. The second and third are algorithms for rail deployment operations at a military base. [Copyright &y& Elsevier]

Comments on a study published in 'Pediatrics' about the penicillin treatment of group A streptococcal pharyngitis. Endpoint selected in the outcome of the study; Purpose of penicillin in the treatment of streptococcal pharyngitis; Variables association with penicillin treatment failure.

Examines the effect of HIV integrase inhibitors on the RAG 1/2 recombinase. Mechanism of RAG 1/2; Test on DNA cleavage and disintegration activities of RAG 1/2; Similarities between RAG 1/2 and integrase.

Investigates the effect of anti-transforming growth factor-β antibodies in cyclosporine-induced renal dysfunction in rat models. Measurement of creatinine clearance; Assessment of tubulointerstitial damage and arteriolar hyalinosis; Prevention of reduction in creatinine clearance.

Reports an application of a Heck reaction for the preparation of novel phosphotyrosyl residue (pTyr) mimetics. Alpha-azido-based pTyr mimetic; Member of a growing family of alpha-azido acids; Unique azido variant of the pTyr mimetic phosphonomethyl phenylalanine.

Examines the small molecule interactions with protein-tyrosine phosphatase PTP1B and their use in inhibitor design. Indications that the introduction of a hydroxyl could enhance binding interactions; Determination of the X-ray structure of the PTP1B complex; Revelation of the extensive hydrophobic interactions with the naphthalene system.

Describes the development of Src homology 2 (SH2) inhibitory peptides containing phosphatase-resistant phosphotyrosyl (pTyr) surrogates. SH2 domain inhibitor design; Phosphonopeptide binding; Sensitivity to phosphatases.

Discusses the issue of law enforcement officers' practice of deception in order to achieve a speedy and expedient resolution to crisis hostage negotiations. Evolution of police hostage negotiations; Moral reasoning and police practice; Negotiations as a morally superior police response; Ethical systems; Individual or officially sanctioned deception; Negative consequences of lying during crises.

This paper reports on an examination and comparison of the bridge-design advice given in the 1991 book Bridge Aesthetics Around the World by 24 of the world's best-known and respected authorities on bridge-design aesthetics. Although these authorities use various terminologies, comparisons, analogies, and illustrations to discuss the subject of bridge design, it has been found that a majority of them emphasize and discuss only a limited number of primary bridge-design concepts. Chief among these is the concept of bridge/place integration and the use of a contextual-design approach to help achieve such integration. For large and unique structures, they emphasize the importance of a structurally expressive form and simultaneity in design to achieve such a form. With a number of reservations and warnings, a bare majority of these authorities recommend the use of bridge aesthetic guidelines as a means of achieving bridge designs that will be visually suitable for their settings. Finally, the paper identifies and synthesizes the major abstractions appearing in this collection of outstanding papers into an abstraction hierarchy. Consequently, the paper provides a comprehensive glimpse of the present world view of bridge-design aesthetics. [ABSTRACT FROM AUTHOR]

Presents the text of the panel discussion presented by members of the American Bar Association Section of Antitrust Law dealing on the antitrust enforcement in the U.S.

Provides information on a study of the first structure of an inhibitor, Y-3, complexed to the catalytic core of avian sarcoma virus integrase (ASV IN). Methodology and materials used to conduct the study; Results of the study.

A role for histamine in the pathogenesis of uremic pruritus was investigated in maintenance hemodialysis patients. Venous plasma histamine levels, as determined by radioenzymatic assay, were significantly higher (p < 0.05) in hemodialysis patients with pruritus (368 ± 103 pg/ml [mean ± SEM], n = 6) than in those without pruritus (146 ± 22 pg/ml, n = 5) and in normal controls (142 ± 16, n = 5). Arteriovenous fistula histamine levels (202 ± 52 pg/ml, n = 6) were significantly lower (p < 0.05) than simultaneously drawn venous samples. Markedly elevated histamine-degrading enzyme (histaminase) activities were found in both hemodialysis patients with (2.95 ± 0.18 pg histamine degraded/minute) and without (2.44 ± 0.28) pruritus, but was undetectable in normal controls. Histaminase activities did not significantly differ in simultaneously drawn venous and fistula samples. With hemodialysis, Histaminase activities fell significantly (p < 0.01), whereas plasma histamine did not change. We further examined the effects of ketotifen, a putative mast cell stabilizer, on severe uremic pruritus. Five of five patients had significant (p < 0.01) reductions in pruritus, as judged on a six-point pruritus index, after 8 weeks of drug (x = 2.3), as compared to conventional therapy (x = 5.9). Despite these improvements, no significant differences were noted in pre- versus post-drug plasma histamine levels, histaminase activities, or the histamine content per gram of skin biopsy specimen. These data support prior hypotheses that mast cell activation contributes to the pruritus of uremia. [ABSTRACT FROM AUTHOR]

The article focuses on reviewing major objectives and study design of the Field Trials of the 1987 draft on Mental Behavioural and Developmental Disorders of Chapter V. Assessment of the feasibility, suitability and reliability of the new classification are the three over-riding objectives for the Field Trials. Stages in the Field Trials Design include translation, familiarisation, preparation of case summaries, joint assessment of patients, assessment of case summaries and further comments and suggestions.

Comments on an article by Bell et al., which raises issues concerning the taxation of lost future earnings. Consumption opportunities of lump-sum award to a decedent's family; Application of an iteration model for calculating present value under a progressive tax system; Problem posed by interparty transfers.