734 research outputs found
The Bell Laboratories (13)CO Survey: Longitude-Velocity Maps
A survey is presented of the Galactic plane in the J=1-0 transition of
(13)CO. About 73,000 spectra were obtained with the 7 m telescope at Bell
Laboratories over a ten-year period. The coverage of survey is (l, b) = (-5 to
117, -1 to +1), or 244 square degrees, with a grid spacing of 3' for |b| < 0.5,
and a grid spacing of 6' for |b| > 0.5. The data presented here have been
resampled onto a 3' grid. For 0.68 km/s channels, the rms noise level of the
survey is 0.1 K on the scale. The raw data have been transformed into
FITS format, and all the reduction processes, such as correcting for emission
in the reference positions, baseline removal and interpolation were conducted
within IRAF using the FCRAO task package and additional programs. The reduced
data are presented here in the form of longitude-velocity color maps at each
latitude. These data allow identification and classification of molecular
clouds with masses in excess of ~ 1,000 solar masses throughout the first
quadrant of the Galaxy. Spiral structure is manifested by the locations of the
largest and brightest molecular clouds.Comment: 23 pages, 7 figures, ApJS submitted (out of 41 frames of Figure4,
only one is included becaue of size limit
De novo protein design:How do we expand into the universe of possible protein structures?
Protein scientists are paving the way to a new phase in protein design and engineering. Approaches and methods are being developed that could allow the design of proteins beyond the confines of natural protein structures. This possibility of designing entirely new proteins opens new questions: What do we build? How do we build into protein-structure space where there are few, if any, natural structures to guide us? To what uses can the resulting proteins be put? And, what, if anything, does this pursuit tell us about how natural proteins fold, function and evolve? We describe the origins of this emerging area of fully de novo protein design, how it could be developed, where it might lead, and what challenges lie ahead
Computational design of water-soluble α-helical barrels
The design of protein sequences that fold into prescribed de novo structures is challenging. General solutions to this problem require geometric descriptions of protein folds and methods to fit sequences to these. The α-helical coiled coils present a promising class of protein for this and offer considerable scope for exploring hitherto unseen structures. For α-helical barrels, which have more than four helices and accessible central channels, many of the possible structures remain unobserved. Here, we combine geometrical considerations, knowledge-based scoring, and atomistic modeling to facilitate the design of new channel-containing α-helical barrels. X-ray crystal structures of the resulting designs match predicted in silico models. Furthermore, the observed channels are chemically defined and have diameters related to oligomer state, which present routes to design protein function
Managing diabetes in people with dementia: protocol for a realist review
Background
Worldwide, the prevalences of diabetes and dementia are both increasing, particularly in older people. Rates of diabetes in people with dementia are between 13 and 20 %. Diabetes management and diabetic self-care may be adversely affected by the presence of dementia. There is a need to know what interventions work best in the management of diabetes in people living with dementia (PLWD) in different settings and at different stages of the dementia trajectory. The overall aim is to develop an explanatory account or programme theory about âwhat worksâ in the management of diabetes in people in what context and to identify promising interventions that merit further evaluation.
Methods/design
This study uses a realist approach including studies on the management of diabetes in older people, medication management, diabetes-related self-care, workforce issues and assessment and treatment. We will use an iterative, stakeholder driven, four-stage approach. Phase 1: development of initial programme theory/ies through a first scoping of the literature and consultation with key stakeholder groups (user/patient representatives, dementia-care providers, clinicians, diabetes and dementia researchers and diabetes specialists). Phase 2: systematic searches of the evidence to test and develop the theories identified in phase 1. Phase 3: validation of programme theory/ies with a purposive sample of participants from phase 1. Phase 4: actionable recommendations for the management of diabetes in PLWD.
Discussion
A realist synthesis of the evidence will provide a theoretical framework (i.e. an explanation of how interventions work, for whom, in what context and why) for practice and future research work that articulates the barriers and facilitators to effective management of diabetes in people with dementia. By providing possible explanations for the way in which interventions are thought to work and how change is achieved, it will demonstrate how to tailor an intervention to the setting and patient group. The propositions arising from the review will also inform the design of future intervention studies.
Systematic review registration
PROSPERO registration number CRD42015020625
Navigating the structural landscape of de Novo α-helical bundles
The
association of amphipathic α helices in water leads to
α-helical-bundle protein structures. However, the driving force
for thisîžthe hydrophobic effectîžis not specific and
does not define the number or the orientation of helices in the associated
state. Rather, this is achieved through deeper sequence-to-structure
relationships, which are increasingly being discerned. For example,
for one structurally extreme but nevertheless ubiquitous class of
bundleîžthe α-helical coiled coilsîžrelationships
have been established that discriminate between all-parallel dimers,
trimers, and tetramers. Association states above this are known, as
are antiparallel and mixed arrangements of the helices. However, these
alternative states are less well understood. Here, we describe a synthetic-peptide
system that switches between parallel hexamers and various upâdownâupâdown
tetramers in response to single-amino-acid changes and solution conditions.
The main accessible states of each peptide variant are characterized
fully in solution and, in most cases, to high resolution with X-ray
crystal structures. Analysis and inspection of these structures helps
rationalize the different states formed. This navigation of the structural
landscape of α-helical coiled coils above the dimers and trimers
that dominate in nature has allowed us to design rationally a well-defined
and hyperstable antiparallel coiled-coil tetramer (apCC-Tet). This
robust de novo protein provides another scaffold for further structural
and functional designs in protein engineering and synthetic biology
Chronic myocardial infarction promotes atrial action potential alternans, afterdepolarisations and fibrillation
Aims: Atrial fibrillation (AF) is increased in patients with heart failure resulting from myocardial infarction (MI). We aimed to determine the effects of chronic ventricular MI in rabbits on the susceptibility to AF, and underlying atrial electrophysiological and Ca2+-handling mechanisms. Methods and results: In Langendorff-perfused rabbit hearts, under beta-adrenergic-stimulation with isoproterenol (1 ”M; ISO), 8 weeks MI decreased AF threshold, indicating increased AF-susceptibility. This was associated with increased atrial action potential duration-alternans at 90% repolarisation, by 147%, and no significant change in mean APD or atrial global conduction velocity (n=6-13 non-MI hearts, 5-12 MI). In atrial isolated myocytes, also under beta-stimulation, L-type Ca2+ current (ICaL) density and intracellular Ca2+-transient amplitude were decreased by MI, by 35% and 41%, respectively, and the frequency of spontaneous depolarisations (SDs) was substantially increased. MI increased atrial myocyte size and capacity, and markedly decreased transverse-tubule density. In non-MI hearts perfused with ISO, the ICaL-blocker nifedipine, at a concentration (0.02 ”M) causing an equivalent ICaL-reduction (35%) to that from the MI, did not affect AF-susceptibility, and decreased APD. Conclusion: chronic MI in rabbits remodels atrial structure, electrophysiology and intracellular Ca2+-handling. Increased susceptibility to AF by MI, under beta-adrenergic-stimulation, may result from associated production of atrial APD-alternans and SDs, since steady-state APD and global conduction velocity were unchanged under these conditions, and may be unrelated to the associated reduction in whole-cell ICaL. Future studies may clarify potential contributions of local conduction changes, and cellular and sub-cellular mechanisms of alternans, to the increased AF-susceptibility
Probing ISM Structure in Trumpler 14 & Carina I Using The Stratospheric Terahertz Observatory 2
We present observations of the Trumpler 14/Carina I region carried out using
the Stratospheric Terahertz Observatory 2 (STO2). The Trumpler 14/Carina I
region is in the west part of the Carina Nebula Complex, which is one of the
most extreme star-forming regions in the Milky Way. We observed Trumpler
14/Carina I in the 158 m transition of [C\,{\sc ii}] with a spatial
resolution of 48 and a velocity resolution of 0.17 km s. The
observations cover a 0.25 by 0.28 area with central position
{\it l} = 297.34, {\it b} = -0.60. The kinematics show that
bright [C\,{\sc ii}] structures are spatially and spectrally correlated with
the surfaces of CO clouds, tracing the photodissociation region and ionization
front of each molecular cloud. Along 7 lines of sight that traverse Tr 14 into
the dark ridge to the southwest, we find that the [C\,{\sc ii}] luminosity from
the HII region is 3.7 times that from the PDR. In same los we find in the PDRs
an average ratio of 1:4.1:5.6 for the mass in atomic gas:dark-CO gas: molecular
gas traced by CO. Comparing multiple gas tracers including HI 21cm, [C\,{\sc
ii}], CO, and radio recombination lines, we find that the HII regions of the
Carina Nebula Complex are well-described as HII regions with one-side freely
expanding towards us, consistent with the champagne model of ionized gas
evolution. The dispersal of the GMC in this region is dominated by EUV
photoevaporation; the dispersal timescale is 20-30 Myr.Comment: ApJ accepte
Differential sensing with arrays of de novo designed peptide assemblies
Differential sensing attempts to mimic the mammalian senses of smell and taste to identify analytes and complex mixtures. In place of hundreds of complex, membrane-bound G-protein coupled receptors, differential sensors employ arrays of small molecules. Here we show that arrays of computationally designed de novo peptides provide alternative synthetic receptors for differential sensing. We use self-assembling α-helical barrels (αHBs) with central channels that can be altered predictably to vary their sizes, shapes and chemistries. The channels accommodate environment-sensitive dyes that fluoresce upon binding. Challenging arrays of dye-loaded barrels with analytes causes differential fluorophore displacement. The resulting fluorimetric fingerprints are used to train machine-learning models that relate the patterns to the analytes. We show that this system discriminates between a range of biomolecules, drink, and diagnostically relevant biological samples. As αHBs are robust and chemically diverse, the system has potential to sense many analytes in various settings
Installing hydrolytic activity into a completely <i>de novo </i>protein framework
The design of enzyme-like catalysts tests our understanding of sequence-to-structure/function relationships in proteins. Here we install hydrolytic activity predictably into a completely de novo and thermostable α-helical barrel, which comprises seven helices arranged around an accessible channel. We show that the lumen of the barrel accepts 21 mutations to functional polar residues. The resulting variant, which has cysteineâhistidineâglutamic acid triads on each helix, hydrolyses p-nitrophenyl acetate with catalytic efficiencies that match the most-efficient redesigned hydrolases based on natural protein scaffolds. This is the first report of a functional catalytic triad engineered into a de novo protein framework. The flexibility of our system also allows the facile incorporation of unnatural side chains to improve activity and probe the catalytic mechanism. Such a predictable and robust construction of truly de novo biocatalysts holds promise for applications in chemical and biochemical synthesis
The Back 2 Activity Trial: education and advice versus education and advice plus a structured walking programme for chronic low back pain
<p>Abstract</p> <p>Background</p> <p>Current evidence supports the use of exercise-based treatment for chronic low back pain that encourages the patient to assume an active role in their recovery. Walking has been shown it to be an acceptable type of exercise with a low risk of injury. However, it is not known whether structured physical activity programmes are any more effective than giving advice to remain active.</p> <p>Methods/Design</p> <p>The proposed study will test the feasibility of using a pedometer-driven walking programme, as an adjunct to a standard education and advice session in participants with chronic low back pain. Fifty adult participants will be recruited via a number of different sources. Baseline outcome measures including self reported function; objective physical activity levels; fear-avoidance beliefs and health-related quality of life will be recorded. Eligible participants will be randomly allocated under strict, double blind conditions to one of two treatments groups. Participants in group A will receive a single education and advice session with a physiotherapist based on the content of the 'Back Book'. Participants in group B will receive the same education and advice session. In addition, they will also receive a graded pedometer-driven walking programme prescribed by the physiotherapist. Follow up outcomes will be recorded by the same researcher, who will remain blinded to group allocation, at eight weeks and six months post randomisation. A qualitative exploration of participants' perception of walking will also be examined by use of focus groups at the end of the intervention. As a feasibility study, treatment effects will be represented by point estimates and confidence intervals. The assessment of participant satisfaction will be tabulated, as will adherence levels and any recorded difficulties or adverse events experienced by the participants or therapists. This information will be used to modify the planned interventions to be used in a larger randomised controlled trial.</p> <p>Discussion</p> <p>This paper describes the rationale and design of a study which will test the feasibility of using a structured, pedometer-driven walking programme in participants with chronic low back pain.</p> <p>Trial Registration</p> <p>[ISRCTN67030896]</p
- âŠ