Present tributes to achievements past

AbstractPerspectives in Structural Biology: a volume in honour of GN Ramachandran (Editors M Vijayan, N Yathindra & AS Kolaskar), University Press (India), Hyderabad & Indian Academy of Sciences, Bangalore, 1999. $20.95 (paperback) ISBN 81 7371 254 9

Halogen Bonds Form the Basis for Selective P-TEFb Inhibition by DRB

SummaryCdk9, the kinase of the positive transcription elongation factor b, is required for processive transcription elongation by RNA polymerase II. Cdk9 inhibition contributes to the anticancer activity of many Cdk inhibitors under clinical investigation and hence there is interest in selective Cdk9 inhibitors. DRB (5,6-dichlorobenzimidazone-1-β-D-ribofuranoside) is a commonly used reagent for Cdk9 inhibition in cell biology studies. The crystal structures of Cdk9 and Cdk2 in complex with DRB reported here describe the molecular basis for the DRB selectivity toward Cdk9. The DRB chlorine atoms form halogen bonds that are specific for the Cdk9 kinase hinge region. Kinetic and thermodynamic experiments validate the structural findings and implicate the C-terminal residues of Cdk9 in contributing to the affinity for DRB. These results open the possibility to exploit halogen atoms in inhibitor design to specifically target Cdk9

Simulation of Diffusion Time of Small Molecules in Protein Crystals

SummaryA simple model for evaluation of diffusion times of small molecule into protein crystals has been developed, which takes into account the physical and chemical properties both of protein crystal and the diffusing molecules. The model also includes consideration of binding and the binding affinity of a ligand to the protein. The model has been validated by simulation of experimental set-ups of several examples found in the literature. These experiments cover a wide range of situations: from small to relatively large diffusing molecules, crystals having low, medium, or high protein density, and different size. The reproduced experiments include ligand exchange in protein crystals by soaking techniques. Despite the simplifying assumptions of the model, theoretical and experimental data are in agreement with available data, with experimental diffusion times ranging from a few seconds to several hours. The method has been used successfully for planning intermediate cryotrapping experiments in maltodextrin phosphorylase crystals

Towards a new model of attentional biases in the development, maintenance, and management of pain

Individuals with chronic pain demonstrate attentional biases towards pain-related stimuli. However, the clinical importance of these biases is yet to be determined and a sound theoretical model for explaining the role of attentional biases in the development and maintenance of pain is lacking. Within this article, we (1) systematically review prospective and experimental research exploring attentional biases and pain outcomes in light of current theoretical models and (2) propose a theoretical framework for understanding attention bias in pain. Across prospective research, an attentional pattern of vigilance-avoidance was observed. Interventions targeting attentional biases were less consistent; however, there were promising findings amongst studies that found attentional training effects, particularly for laboratory research. The proposed Threat Interpretation Model suggests a relationship between threat, interpretation and stimuli in determining attentional processes, which whilst tentative generates important testable predictions regarding the role of attention in pain, and builds upon previous theoretical and empirical work in this area

Understanding the Effect of Information Presentation Order and Orientation on Information Search and Treatment Evaluation

Background. Past research finds that treatment evaluations are more negative when risks are presented after benefits. This study investigates this order effect: manipulating tabular orientation and order of risk–benefit information, and examining information search order and gaze duration via eye-tracking. Design. 108 (Study 1) and 44 (Study 2) participants viewed information about treatment risks and benefits, in either a horizontal (left-right) or vertical (above-below) orientation, with the benefits or risks presented first (left side or at top). For 4 scenarios, participants answered 6 treatment evaluation questions (1–7 scales) that were combined into overall evaluation scores. In addition, Study 2 collected eye-tracking data during the benefit–risk presentation. Results. Participants tended to read one set of information (i.e., all risks or all benefits) before transitioning to the other. Analysis of order of fixations showed this tendency was stronger in the vertical (standardized mean rank difference further from 0, M = ±.88) than horizontal orientation (M = ± 0.71). Approximately 50% of the time was spent reading benefits when benefits were shown first, but this was reduced to ~40% when risks were presented first (regression coefficient: B = −4.52, p <.001). Eye-tracking measures did not strongly predict treatment evaluations, although time percentage reading benefits positively predicted evaluation when holding other variables constant (B = 0.02, p =.023). Conclusion. These results highlight the impact of seemingly arbitrary design choices on inspection order. For instance, presenting risks where they will be seen first leads to relatively less time spent considering treatment benefits. Other research suggests these changes to inspection order can influence multi-option and multi-attribute choices, and represent an area for future research

Assessment of the Sensitizing Potential of Processed Peanut Proteins in Brown Norway Rats: Roasting Does Not Enhance Allergenicity

Background: IgE-binding of process-modified foods or proteins is the most common method for examination of how food processing affects allergenicity of food allergens. How processing affects sensitization capacity is generally studied by administration of purified food proteins or food extracts and not allergens present in their natural food matrix. [br/] Objectives: The aim was to investigate if thermal processing increases sensitization potential of whole peanuts via the oral route. In parallel, the effect of heating on sensitization potential of the major peanut allergen Ara h 1 was assessed via the intraperitoneal route. Methods: Sensitization potential of processed peanut products and Ara h 1 was examined in Brown Norway (BN) rats by oral administration of blanched or oil-roasted peanuts or peanut butter or by intraperitoneal immunization of purified native (N-), heated (H-) or heat glycated (G-) Ara h 1. Levels of specific IgG and IgE were determined by ELISA and IgE functionality was examined by rat basophilic leukemia (RBL) cell assay. [br/] Results: In rats dosed orally, roasted peanuts induced significant higher levels of specific IgE to NAra h 1 and 2 than blanched peanuts or peanut butter but with the lowest level of RBL degranulation. However, extract from roasted peanuts was found to be a superior elicitor of RBL degranulation. Process-modified Ara h 1 had similar sensitizing capacity as NAra h 1 but specific IgE reacted more readily with process-modified Ara h 1 than with native. [br/] Conclusions: Peanut products induce functional specific IgE when dosed orally to BN rats. Roasted peanuts do not have a higher sensitizing capacity than blanched peanuts. In spite of this, extract from roasted peanuts is a superior elicitor of RBL cell degranulation irrespectively of the peanut product used for sensitization. The results also suggest that new epitopes are formed or disclosed by heating Ara h 1 without glucose

Degenerative encephalopathy in Nova Scotia Duck Tolling Retrievers presenting with a rapid eye movement sleep behavior disorder

BACKGROUND: Neurodegenerative diseases are a heterogeneous group of disorders characterized by loss of neurons and are commonly associated with a genetic mutation. HYPOTHESIS/OBJECTIVES: To characterize the clinical and histopathological features of a novel degenerative neurological disease affecting the brain of young adult Nova Scotia Duck Tolling Retrievers (NSDTRs). ANIMALS: Nine, young adult, related NSDTRs were evaluated for neurological dysfunction and rapid eye movement sleep behavior disorder. METHODS: Case series review. RESULTS: Clinical signs of neurological dysfunction began between 2 months and 5 years of age and were progressive in nature. They were characterized by episodes of marked movements during sleep, increased anxiety, noise phobia, and gait abnormalities. Magnetic resonance imaging documented symmetrical, progressively increasing, T2‐weighted image intensity, predominantly within the caudate nuclei, consistent with necrosis secondary to gray matter degeneration. Abnormalities were not detected on clinicopathological analysis of blood and cerebrospinal fluid, infectious disease screening or urine metabolite screening in most cases. Postmortem examination of brain tissue identified symmetrical malacia of the caudate nuclei and axonal dystrophy within the brainstem and spinal cord. Genealogical analysis supports an autosomal recessive mode of inheritance. CONCLUSIONS AND CLINICAL IMPORTANCE: A degenerative encephalopathy was identified in young adult NSDTRs consistent with a hereditary disease. The prognosis is guarded due to the progressive nature of the disease, which is minimally responsive to empirical treatment

Prigodom 60-godišnjice zadružne mlekarne u Škofjoj Loki

Background The Parent Report of Children's Abilities–Revised (PARCA-R) can be used to identify preterm born children at risk for developmental delay at age 24 months. However, standardised scores for assessing all children in the general population and quantifying development relative to the norm are unavailable, thus limiting the use of the questionnaire. We aimed to develop scores that are standardised by age and sex for the PARCA-R to assess children's cognitive and language development at age 24–27 months. Methods Anonymised data from PARCA-R questionnaires that were completed by parents of 2-year-old children in three previous studies were obtained to form a standardisation sample that was representative of the UK general population. Anonymised data were obtained from three further studies to assess the external validity and clinical validity of the standardised scores. We used the lambda-mu-sigma (lambda for skewness, mu for median, sigma for the coefficient of variation) method to develop scores that are standardised by age and sex for three scales (non-verbal cognitive development, language development, and total parent report composite [PRC]) for children in four 1-month age bands, spanning age 23·5–27·5 months. Findings We included 6402 children (mean age 25 months and 1 day [range 23 months and 16 days to 27 months and 15 days]) in the standardisation sample and 709 (mean age 24 months and 19 days [23 months and 16 days to 27 months and 15 days]) to test the external validity and 1456 (mean age 24 months and 8·5 days [23 months and 16 days to 27 months and 15 days]) to test the clinical validity of the standardised scores. For all PARCA-R scales, mean standardised scores approximated 100 (SD 15) in both sexes and all age groups. These scores were independent of socioeconomic status. Standardised scores were close to 100 (15) in the external validation sample, showing the validity of the scores. Standardised scores for the total PRC scale for children born very preterm (<32 weeks' gestation) were 0·47 SD lower on average than the normative mean, and for children with neonatal sepsis were 0·73 SD lower on average than the normative mean. These scores were equivalent to a standardised score of 93 (95% CI 91–94) for children born very preterm and 89 (88–91) for children with neonatal sepsis, thus showing clinical validity. Interpretation The PARCA-R provides a norm-referenced, standardised assessment of cognitive and language development at 24–27 months of age. The questionnaire is available non-commercially in English with translations available in 14 other languages, thus providing clinicians and researchers with a cost-effective tool for assessing development and identifying children with delay

Clinical relevance of biomarkers of oxidative stress

SIGNIFICANCE Oxidative stress is considered to be an important component of various diseases. A vast number of methods have been developed and used in virtually all diseases to measure the extent and nature of oxidative stress, ranging from oxidation of DNA to proteins, lipids, and free amino acids. Recent Advances: An increased understanding of the biology behind diseases and redox biology has led to more specific and sensitive tools to measure oxidative stress markers, which are very diverse and sometimes very low in abundance. CRITICAL ISSUES The literature is very heterogeneous. It is often difficult to draw general conclusions on the significance of oxidative stress biomarkers, as only in a limited proportion of diseases have a range of different biomarkers been used, and different biomarkers have been used to study different diseases. In addition, biomarkers are often measured using nonspecific methods, while specific methodologies are often too sophisticated or laborious for routine clinical use. FUTURE DIRECTIONS Several markers of oxidative stress still represent a viable biomarker opportunity for clinical use. However, positive findings with currently used biomarkers still need to be validated in larger sample sizes and compared with current clinical standards to establish them as clinical diagnostics. It is important to realize that oxidative stress is a nuanced phenomenon that is difficult to characterize, and one biomarker is not necessarily better than others. The vast diversity in oxidative stress between diseases and conditions has to be taken into account when selecting the most appropriate biomarker. Antioxid. Redox Signal. 00, 000-000