2,189 research outputs found
Engineering tyrosine-based electron flow pathways in proteins: The case of aplysia myoglobin
Tyrosine residues can act as redox cofactors that provide an electron transfer ("hole-hopping") route that enhances the rate of ferryl heme iron reduction by externally added reductants, for example, ascorbate. Aplysia fasciata myoglobin, having no naturally occurring tyrosines but 15 phenylalanines that can be selectively mutated to tyrosine residues, provides an ideal protein with which to study such through-protein electron transfer pathways and ways to manipulate them. Two surface exposed phenylalanines that are close to the heme have been mutated to tyrosines (F42Y, F98Y). In both of these, the rate of ferryl heme reduction increased by up to 3 orders of magnitude. This result cannot be explained in terms of distance or redox potential change between donor and acceptor but indicates that tyrosines, by virtue of their ability to form radicals, act as redox cofactors in a new pathway. The mechanism is discussed in terms of the Marcus theory and the specific protonation/deprotonation states of the oxoferryl iron and tyrosine. Tyrosine radicals have been observed and quantified by EPR spectroscopy in both mutants, consistent with the proposed mechanism. The location of each radical is unambiguous and allows us to validate theoretical methods that assign radical location on the basis of EPR hyperfine structure. Mutation to tyrosine decreases the lipid peroxidase activity of this myoglobin in the presence of low concentrations of reductant, and the possibility of decreasing the intrinsic toxicity of hemoglobin by introduction of these pathways is discussed. © 2012 American Chemical Society
A new generation computerised metacognitive cognitive remediation programme for schizophrenia (CIRCuiTS): a randomised controlled trial
Background: Cognitive remediation (CR) is a psychological therapy which improves cognitive and social functioning in people with schizophrenia. It is now being implemented within routine clinical services and mechanisms of change are being explored. We designed a new generation computerised CR programme, CIRCuiTS, to enhance strategic and metacognitive processing, with an integrated focus on the transfer of cognitive skills to daily living. This large trial tested its feasibility to be delivered in therapist-led and independent sessions, and its efficacy for improved cognitive and social functioning.
Methods: A two arm single blind randomised superiority trial comparing CIRCuiTS plus treatment-as-usual (TAU) with TAU alone in 93 people with a diagnosis of schizophrenia. Cognitive, social functioning and symptom outcomes were assessed at pre- and post-therapy and three months later.
Results: 85% adhered to CIRCuiTS, completing a median of 28 sessions. There were significant improvements in visual memory at post-treatment (p=0.009) and follow-up (p=0.001), and a trend for improvements in executive function at post-treatment (p=0.056) in favour of the CIRCuiTS group. Community function was also differentially and significantly improved in the CIRCuiTS group at post-treatment (p=0.003) but not follow-up, and was specifically predicted by improved executive functions.
Conclusions: CIRCuiTS was beneficial for improving memory and social functioning. Improved executive functioning emerges as a consistent predictor of functional gains and should be considered an important CR target to achieve functional change. A larger-scale effectiveness trial of CIRCuiTS is now indicated
Alternatively spliced variants of the cell adhesion molecule CD44 and tumour progression in colorectal cancer.
Increased expression of alternatively spliced variants of the CD44 family of cell adhesion molecules has been associated with tumour metastasis. In the present study, expression of alternatively spliced variants of CD44 and their cellular distribution have been investigated in human colonic tumours and in the corresponding normal mucosa, in addition to benign adenomatous polyps. The expression of CD44 alternatively spliced variants has been correlated with tumour progression according to Dukes' histological stage. CD44 variant expression was determined by immunohistochemisty using monoclonal antibodies directed against specific CD44 variant domains together with RT-PCR analysis of CD44 variant mRNA expression in the same tissue specimens. We demonstrate that as well as being expressed in colonic tumour cells, the full range of CD44 variants, CD44v2-v10, are widely expressed in normal colonic crypt epithelium, predominantly in the crypt base. CD44v6, the epitope which is most commonly associated with tumour progression and metastasis, was not only expressed by many benign colonic tumours, but was expressed as frequently in normal basal crypt epithelium as in malignant colonic tumour cells, and surprisingly, was even absent from some metastatic colorectal tumours. Expression of none of the CD44 variant epitopes was found to be positively correlated with tumour progression or with colorectal tumour metastasis to the liver, results which are inconsistent with a role for CD44 variants as indicators of colonic cancer progression
Monopolar and dipolar relaxation in spin ice HoTiO
When degenerate states are separated by large energy barriers, the approach
to thermal equilibrium can be slow enough that physical properties are defined
by the thermalization process rather than the equilibrium. The exploration of
thermalization pushes experimental boundaries and provides refreshing insights
into atomic scale correlations and processes that impact steady state dynamics
and prospects for realizing solid state quantum entanglement. We present a
comprehensive study of magnetic relaxation in HoTiO based on
frequency-dependent susceptibility measurements and neutron diffraction studies
of the real-time atomic-scale response to field quenches. Covering nearly ten
decades in time scales, these experiments uncover two distinct relaxation
processes that dominate in different temperature regimes. At low temperatures
(0.6K<T<1K) magnetic relaxation is associated with monopole motion along the
applied field direction through the spin-ice vacuum. The increase of the
relaxation time upon cooling indicates reduced monopole conductivity driven by
decreasing monopole concentration and mobility as in a semiconductor. At higher
temperatures (1K<T<2K) magnetic relaxation is associated with the reorientation
of monopolar bound states as the system approaches the single-spin tunneling
regime. Spin fractionalization is thus directly exposed in the relaxation
dynamics
Large-scale inference of liver fat with neural networks on UK Biobank body MRI
The UK Biobank Imaging Study has acquired medical scans of more than 40,000
volunteer participants. The resulting wealth of anatomical information has been
made available for research, together with extensive metadata including
measurements of liver fat. These values play an important role in metabolic
disease, but are only available for a minority of imaged subjects as their
collection requires the careful work of image analysts on dedicated liver MRI.
Another UK Biobank protocol is neck-to-knee body MRI for analysis of body
composition. The resulting volumes can also quantify fat fractions, even though
they were reconstructed with a two- instead of a three-point Dixon technique.
In this work, a novel framework for automated inference of liver fat from UK
Biobank neck-to-knee body MRI is proposed. A ResNet50 was trained for
regression on two-dimensional slices from these scans and the reference values
as target, without any need for ground truth segmentations. Once trained, it
performs fast, objective, and fully automated predictions that require no
manual intervention. On the given data, it closely emulates the reference
method, reaching a level of agreement comparable to different gold standard
techniques. The network learned to rectify non-linearities in the fat fraction
values and identified several outliers in the reference. It outperformed a
multi-atlas segmentation baseline and inferred new estimates for all imaged
subjects lacking reference values, expanding the total number of liver fat
measurements by factor six
Effect of the distal histidine on the peroxidatic activity of monomeric cytoglobin
The reaction of hydrogen peroxide with ferric human cytoglobin and a number of distal histidine variants were studied. The peroxidase activity of the monomeric wildtype protein with an internal disulfide bond, likely to be the form of the protein in vivo, exhibits a high peroxidase-like activity above that of other globins such as myoglobin. Furthermore, the peroxidatic activity of wildtype cytoglobin shows increased resistance to radical-based degradation compared to myoglobin. The ferryl form of wildtype cytoglobin is unstable, but is able to readily oxidize substrates such as guaiacol. In contrast distal histidine mutants of cytoglobin (H81Y and H81V) show very low peroxidase activity but enhanced radical-induced degradation. Therefore, the weakly bound distal histidine appears to modulate ferryl stability and limit haem degradation. These data are consistent with a role of a peroxidase activity of cytoglobin in cell stress response mechanisms.</ns4:p
Measurements of Charged Current Reactions of on
Charged Current reactions of on have been studied using a
decay-at-rest beam at the Los Alamos Neutron Science Center.
The cross section for the exclusive reaction
was measured to be cm. The observed
energy dependence of the cross section and angular distribution of the outgoing
electron agree well with theoretical expectations. Measurements are also
presented for inclusive transitions to excited states,
and compared with theoretical expectations. The
measured cross section, cm, is somewhat
lower than previous measurements and than a continuum random phase
approximation calculation. It is in better agreement with a recent shell model
calculation.Comment: 34 pages, 18 figures, accepted to PRC, replaced with the accepted on
Indigenous oyster fisheries persisted for millennia and should inform future management
Historical ecology has revolutionized our understanding of fisheries and cultural landscapes, demonstrating the value of historical data for evaluating the past, present, and future of Earth’s ecosystems. Despite several important studies, Indigenous fisheries generally receive less attention from scholars and managers than the 17th–20th century capitalist commercial fisheries that decimated many keystone species, including oysters. We investigate Indigenous oyster harvest through time in North America and Australia, placing these data in the context of sea level histories and historical catch records. Indigenous oyster fisheries were pervasive across space and through time, persisting for 5000–10,000 years or more. Oysters were likely managed and sometimes “farmed,” and are woven into broader cultural, ritual, and social traditions. Effective stewardship of oyster reefs and other marine fisheries around the world must center Indigenous histories and include Indigenous community members to co-develop more inclusive, just, and successful strategies for restoration, harvest, and management.Results - Indigenous fisheries of abundance. - Oysters in monuments and ritual landscapes. - Not all forgotten: Indigenous use of oysters. Indigenous - Capitalist commercial fisheries and ecological collapse. Discussion Method
Half Life of the Doubly-magic r-Process Nucleus 78Ni
Nuclei with magic numbers serve as important benchmarks in nuclear theory. In
addition, neutron-rich nuclei play an important role in the astrophysical rapid
neutron-capture process (r-process). 78Ni is the only doubly-magic nucleus that
is also an important waiting point in the r-process, and serves as a major
bottleneck in the synthesis of heavier elements. The half-life of 78Ni has been
experimentally deduced for the first time at the Coupled Cyclotron Facility of
the National Superconducting Cyclotron Laboratory at Michigan State University,
and was found to be 110 (+100 -60) ms. In the same experiment, a first
half-life was deduced for 77Ni of 128 (+27 -33) ms, and more precise half-lives
were deduced for 75Ni and 76Ni of 344 (+20 -24) ms and 238 (+15 -18) ms
respectively.Comment: 4 pages, 3 figure
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