Orientation-dependent backbone-only residue pair scoring functions for fixed backbone protein design

<p>Abstract</p> <p>Background</p> <p>Empirical scoring functions have proven useful in protein structure modeling. Most such scoring functions depend on protein side chain conformations. However, backbone-only scoring functions do not require computationally intensive structure optimization and so are well suited to protein design, which requires fast score evaluation. Furthermore, scoring functions that account for the distinctive relative position and orientation preferences of residue pairs are expected to be more accurate than those that depend only on the separation distance.</p> <p>Results</p> <p>Residue pair scoring functions for fixed backbone protein design were derived using only backbone geometry. Unlike previous studies that used spherical harmonics to fit 2D angular distributions, Gaussian Mixture Models were used to fit the full 3D (position only) and 6D (position and orientation) distributions of residue pairs. The performance of the 1D (residue separation only), 3D, and 6D scoring functions were compared by their ability to identify correct threading solutions for a non-redundant benchmark set of protein backbone structures. The threading accuracy was found to steadily increase with increasing dimension, with the 6D scoring function achieving the highest accuracy. Furthermore, the 3D and 6D scoring functions were shown to outperform side chain-dependent empirical potentials from three other studies. Next, two computational methods that take advantage of the speed and pairwise form of these new backbone-only scoring functions were investigated. The first is a procedure that exploits available sequence data by averaging scores over threading solutions for homologs. This was evaluated by applying it to the challenging problem of identifying interacting transmembrane alpha-helices and found to further improve prediction accuracy. The second is a protein design method for determining the optimal sequence for a backbone structure by applying Belief Propagation optimization using the 6D scoring functions. The sensitivity of this method to backbone structure perturbations was compared with that of fixed-backbone all-atom modeling by determining the similarities between optimal sequences for two different backbone structures within the same protein family. The results showed that the design method using 6D scoring functions was more robust to small variations in backbone structure than the all-atom design method.</p> <p>Conclusions</p> <p>Backbone-only residue pair scoring functions that account for all six relative degrees of freedom are the most accurate and including the scores of homologs further improves the accuracy in threading applications. The 6D scoring function outperformed several side chain-dependent potentials while avoiding time-consuming and error prone side chain structure prediction. These scoring functions are particularly useful as an initial filter in protein design problems before applying all-atom modeling.</p

Clonal selection in the human Vδ1 T cell repertoire indicates γδ TCR-dependent adaptive immune surveillance

γδ T cells are considered to be innate-like lymphocytes that respond rapidly to stress without clonal selection and differentiation. Here we use next-generation sequencing to probe how this paradigm relates to human Vδ2neg T cells, implicated in responses to viral infection and cancer. The prevalent Vδ1 T cell receptor (TCR) repertoire is private and initially unfocused in cord blood, typically becoming strongly focused on a few high-frequency clonotypes by adulthood. Clonal expansions have differentiated from a naive to effector phenotype associated with CD27 downregulation, retaining proliferative capacity and TCR sensitivity, displaying increased cytotoxic markers and altered homing capabilities, and remaining relatively stable over time. Contrastingly, Vδ2+ T cells express semi-invariant TCRs, which are present at birth and shared between individuals. Human Vδ1+ T cells have therefore evolved a distinct biology from the Vδ2+ subset, involving a central, personalized role for the γδ TCR in directing a highly adaptive yet unconventional form of immune surveillance

What Do We Know About Neuropsychological Aspects Of Schizophrenia?

Application of a neuropsychological perspective to the study of schizophrenia has established a number of important facts about this disorder. Some of the key findings from the existing literature are that, while neurocognitive impairment is present in most, if not all, persons with schizophrenia, there is both substantial interpatient heterogeneity and remarkable within-patient stability of cognitive function over the long-term course of the illness. Such findings have contributed to the firm establishment of neurobiologic models of schizophrenia, and thereby help to reduce the social stigma that was sometimes associated with purely psychogenic models popular during parts of the 20th century. Neuropsychological studies in recent decades have established the primacy of cognitive functions over psychopathologic symptoms as determinants of functional capacity and independence in everyday functioning. Although the cognitive benefits of both conventional and even second generation antipsychotic medications appear marginal at best, recognition of the primacy of cognitive deficits as determinants of functional disability in schizophrenia has catalyzed recent efforts to develop targeted treatments for the cognitive deficits of this disorder. Despite these accomplishments, however, some issues remain to be resolved. Efforts to firmly establish the specific neurocognitive/neuropathologic systems responsible for schizophrenia remain elusive, as do efforts to definitively demonstrate the specific cognitive deficits underlying specific forms of functional impairment. Further progress may be fostered by recent initiatives to integrate neuropsychological studies with experimental neuroscience, perhaps leading to measures of deficits in cognitive processes more clearly associated with specific, identifiable brain systems

Determination of sub-nanomolar levels of iron in seawater using flow injection with chemiluminescence detection

The development of a highly sensitive system for the shipboard determination of dissolved iron at the sub-nM level is presented. The technique is based on a flow injection method coupled with luminol chemiluminescence detection. Dissolved Fe(II+lII) levels are determined after Fe(III) reduction using sulphite and in-line matrix elimination/preconcentration on an 8-hydroxyquinoline (8-quinolinol) chelating resin column. The detection limit (3s) is 40 pM when 1.5 ml of sample is loaded onto the column, and the relative standard deviation is 3.2 (n=5) for a 1.0 nM Fe sample. One analytical cycle can be completed in 3 min. The automated method proved reliable when employed on-board the RRS James Clark Ross during Autumn 1996, mapping dissolvable Fe(II+III) levels along the Atlantic Meridional Transect from 50°N to 50°S. Data from vertical profiles through the upper water column are presented

Biogeochemistry of Fe and other trace elements (Al Co Ni) in the upper Atlantic Ocean

Iron and other trace metals (Al, Co, Ni) were measured through the upper water column during two north–south transects of the Atlantic Ocean (approximately 50°N–50°S), from the United Kingdom (UK) to the Falkland Islands (September/October 1996) and from South Africa to the UK (May/June 1998). Total dissolvable iron (TD-Fe) concentrations in the surface layers (&lt;200 m) of the open Atlantic Ocean averaged 0.95±0.67 nM (n=142) during the 1996 cruise and 1.08±0.59 nM (n=160) during the 1998 cruise, with increased values in shelf waters at both extremes of the transects. Iron enrichments, fingerprinted via correlation with other trace metals, macronutrients and hydrography, correlated well with dry aerosol deposition off the west African continent and wet deposition in the Inter-Tropical Convergence Zone (ITCZ), with levels &gt;2.2 nM observed in surface waters in these regions. Benthic fluxes provided a significant amount of Fe (2–38 nM) to the base of the water column in coastal zones. In addition, samples collected from one Atlantic Meridional Transect (AMT) expedition were re-analysed after a 16 month acidification period and showed significant increases over shipboard analyses (average values increasing to 2.26±1.50 nM), indicating the extended release of Fe from leachable particulate material in the stored samples. Detailed profiling through the euphotic zone revealed TD-Fe distributions that exhibited strong relationships with biological uptake, regeneration and water column hydrography. In equatorial and tropical North Atlantic waters, trace elemental distributions showed evidence of recent atmospheric deposition through a history of stratified mixed layers

Robert Biket, Il Corno Magico

Edizione critica del 'lai' (racconto breve) del 'Corno magico', opera dell'anglo-normanno Robert Biket (1170c.