802 research outputs found
Muscle recruitment patterns during the prone leg extension
BACKGROUND: The prone leg extension (PLE) is a clinical test used to evaluate the function of the lumbopelvis. It has been theorized that a normal and consistent pattern of muscle activation exists. Previous research has found two contradictory patterns of muscle activation during PLE in normal individuals. One study shows an almost simultaneous activation of the lower erector spinae and hamstring muscle group with a delayed activation of the gluteus maximus, while the second describes the order of activation being ipsilateral erector spinae (to the leg being extended), hamstrings, contralateral erector spinae and gluteus maximus. Due to the different conclusions from these two studies and the lack of quantified muscle onset times, expressed in absolute time this study attempted to quantify the muscle onset times (in milliseconds) during the prone leg extension, while noting if a consistent order of activation exists and whether a timing relationship also exists between the gluteus maximus and contralateral latissimus dorsi. METHODS: 10 asymptomatic males (Average height: 175.2 cm (SD 6.5), Average Weight 75.9 kg (SD 6.5), Average Age: 27.1(SD 1.28)) and 4 asymptomatic females (Average height 164.5 (SD 2.9), weight: 56.2 (SD 8.9), Average Age: 25 (SD 1)) performed the prone leg extension task while the myoelectric signal was recorded from the bilateral lower erector spinae, gluteus maximus and hamstring muscle groups. Activation onsets were determined from the rectified EMG signal relative to the onset of the hamstrings muscle group. RESULTS: No consistent recruitment patterns were detected for prone leg extension among the hamstring muscle group and the erector spinae. However, a consistent delay in the Gluteus Maximus firing of approximately 370 ms after the first muscle activated was found. Five out of 14 asymptomatic subjects showed a delay in gluteus maximus firing exceeding the average delay found in previous research of subjects considered to have a dysfunctional firing pattern. CONCLUSION: A consistent pattern of activation was not found. Variability was seen across subjects. These findings suggest the PLE is not sufficient for a diagnostic test due to the notable physiological variation. An overlap between normal and potentially abnormal activation patterns may exist
Two Stellar Components in the Halo of the Milky Way
The halo of the Milky Way provides unique elemental abundance and kinematic
information on the first objects to form in the Universe, which can be used to
tightly constrain models of galaxy formation and evolution. Although the halo
was once considered a single component, evidence for its dichotomy has slowly
emerged in recent years from inspection of small samples of halo objects. Here
we show that the halo is indeed clearly divisible into two broadly overlapping
structural components -- an inner and an outer halo -- that exhibit different
spatial density profiles, stellar orbits and stellar metallicities (abundances
of elements heavier than helium). The inner halo has a modest net prograde
rotation, whereas the outer halo exhibits a net retrograde rotation and a peak
metallicity one-third that of the inner halo. These properties indicate that
the individual halo components probably formed in fundamentally different ways,
through successive dissipational (inner) and dissipationless (outer) mergers
and tidal disruption of proto-Galactic clumps.Comment: Two stand-alone files in manuscript, concatenated together. The first
is for the main paper, the second for supplementary information. The version
is consistent with the version published in Natur
Crystal Structure of the PIM2 Kinase in Complex with an Organoruthenium Inhibitor
BACKGROUND: The serine/threonine kinase PIM2 is highly expressed in human leukemia and lymphomas and has been shown to positively regulate survival and proliferation of tumor cells. Its diverse ATP site makes PIM2 a promising target for the development of anticancer agents. To date our knowledge of catalytic domain structures of the PIM kinase family is limited to PIM1 which has been extensively studied and which shares about 50% sequence identity with PIM2. PRINCIPAL FINDINGS: Here we determined the crystal structure of PIM2 in complex with an organoruthenium complex (inhibition in sub-nanomolar level). Due to its extraordinary shape complementarity this stable organometallic compound is a highly potent inhibitor of PIM kinases. SIGNIFICANCE: The structure of PIM2 revealed several differences to PIM1 which may be explored further to generate isoform selective inhibitors. It has also demonstrated how an organometallic inhibitor can be adapted to the binding site of protein kinases to generate highly potent inhibitors. ENHANCED VERSION: This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1
Improving uptake of Fracture Prevention drug treatments: a protocol for Development of a consultation intervention (iFraP-D).
Funder: Wellcome TrustINTRODUCTION: Prevention of fragility fractures, a source of significant economic and personal burden, is hindered by poor uptake of fracture prevention medicines. Enhancing communication of scientific evidence and elicitation of patient medication-related beliefs has the potential to increase patient commitment to treatment. The Improving uptake of Fracture Prevention drug treatments (iFraP) programme aims to develop and evaluate a theoretically informed, complex intervention consisting of a computerised web-based decision support tool, training package and information resources, to facilitate informed decision-making about fracture prevention treatment, with a long-term aim of improving informed treatment adherence. This protocol focuses on the iFraP Development (iFraP-D) work. METHODS AND ANALYSIS: The approach to iFraP-D is informed by the Medical Research Council complex intervention development and evaluation framework and the three-step implementation of change model. The context for the study is UK fracture liaison services (FLS), which enact secondary fracture prevention. An evidence synthesis of clinical guidelines and Delphi exercise will be conducted to identify content for the intervention. Focus groups with patients, FLS clinicians and general practitioners and a usual care survey will facilitate understanding of current practice, and investigate barriers and facilitators to change. Design of the iFraP intervention will be informed by decision aid development standards and theories of implementation, behaviour change, acceptability and medicines adherence. The principles of co-design will underpin all elements of the study through a dedicated iFraP community of practice including key stakeholders and patient advisory groups. In-practice testing of the prototype intervention will inform revisions ready for further testing in a subsequent pilot and feasibility randomised trial. ETHICS AND DISSEMINATION: Ethical approval was obtained from North West-Greater Manchester West Research Ethics Committee (19/NW/0559). Dissemination and knowledge mobilisation will be facilitated through national bodies and networks, publications and presentations. TRIAL REGISTRATION NUMBER: researchregistry5041
Regulation of mammary gland branching morphogenesis by the extracellular matrix and its remodeling enzymes.
A considerable body of research indicates that mammary gland branching morphogenesis is dependent, in part, on the extracellular matrix (ECM), ECM-receptors, such as integrins and other ECM receptors, and ECM-degrading enzymes, including matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs). There is some evidence that these ECM cues affect one or more of the following processes: cell survival, polarity, proliferation, differentiation, adhesion, and migration. Both three-dimensional culture models and genetic manipulations of the mouse mammary gland have been used to study the signaling pathways that affect these processes. However, the precise mechanisms of ECM-directed mammary morphogenesis are not well understood. Mammary morphogenesis involves epithelial 'invasion' of adipose tissue, a process akin to invasion by breast cancer cells, although the former is a highly regulated developmental process. How these morphogenic pathways are integrated in the normal gland and how they become dysregulated and subverted in the progression of breast cancer also remain largely unanswered questions
The Course of Habituation of the Proboscis Extension Reflex Can Be Predicted by Sucrose Responsiveness in Drosophila
The proboscis extension reflex (PER) is triggered when insects’ gustatory receptors contact appetitive stimuli, so it provides a behavioral readout for perceptual encoding of tastants. Research on the experience dependent modulation of PER in Drosophila has been hindered by the difficulty of obtaining reliable measures of memory-driven change in PER probability in the background of larger changes induced by physiological state. In this study, we showed that the course of PER habituation can be predicted by the degree of sucrose responsiveness in Drosophila. We assessed early response parameters, including the number of proboscis extensions and labellar movements in the first five trials, the trial to start responding, and the trial to make the first stop to quantify responsiveness, which predicted the upcoming pattern of both the short-term and 1 hour memory of PER habituation for individual flies. The cAMP signaling pathway mutant rutabaga displayed deficits in attunement of perceptual salience of sucrose to physiological demands and stimulus-driven sensitization
Two chemically similar stellar overdensities on opposite sides of the plane of the Galaxy
Our Galaxy is thought to have undergone an active evolutionary history
dominated by star formation, the accretion of cold gas, and, in particular,
mergers up to 10 gigayear ago. The stellar halo reveals rich fossil evidence of
these interactions in the form of stellar streams, substructures, and
chemically distinct stellar components. The impact of dwarf galaxy mergers on
the content and morphology of the Galactic disk is still being explored. Recent
studies have identified kinematically distinct stellar substructures and moving
groups, which may have extragalactic origin. However, there is mounting
evidence that stellar overdensities at the outer disk/halo interface could have
been caused by the interaction of a dwarf galaxy with the disk. Here we report
detailed spectroscopic analysis of 14 stars drawn from two stellar
overdensities, each lying about 5 kiloparsecs above and below the Galactic
plane - locations suggestive of association with the stellar halo. However, we
find that the chemical compositions of these stars are almost identical, both
within and between these groups, and closely match the abundance patterns of
the Milky Way disk stars. This study hence provides compelling evidence that
these stars originate from the disk and the overdensities they are part of were
created by tidal interactions of the disk with passing or merging dwarf
galaxies.Comment: accepted for publication in Natur
p53 Interacts with RNA Polymerase II through Its Core Domain and Impairs Pol II Processivity In Vivo
The tumor suppressor p53 principally functions as a gene-specific transcription factor. p53 triggers a variety of anti-proliferative programs by activating or repressing the transcription of effector genes in response to genotoxic stress. To date, much effort has been placed on understanding p53's ability to affect transcription in the context of its DNA-binding activity. How p53 regulates transcriptional output independent of DNA binding is less well understood. Here we provide evidence that human p53 can physically interact with the large subunit of RNA polymerase II (Pol II) both in in vitro interaction assays and in whole cell extracts, and that this interaction is mediated (at least in part) through p53's core DNA-binding domain and the Ser5-phosphorylated CTD of Pol II. Ectopic expression of p53, combined with mutations in transcription elongation factors or exposure to drugs that inhibit Pol II elongation, elicit sickness or lethality in yeast cells. These phenotypes are suppressed by oncogenic point mutations within p53's core domain. The growth phenotypes raise the possibility that p53 impairs Pol II elongation. Consistent with this, a p53-dependent increase in Pol II density is seen at constitutively expressed genes without a concomitant increase in transcript accumulation. Additionally, p53-expressing yeast strains exhibit reduced transcriptional processivity at an episomal reporter gene; this inhibitory activity is abolished by a core domain point mutation. Our results suggest a novel mechanism by which p53 can regulate gene transcription, and a new biological function for its core domain that is susceptible to inactivation by oncogenic point mutations
Expression of Distal-less, dachshund, and optomotor blind in Neanthes arenaceodentata (Annelida, Nereididae) does not support homology of appendage-forming mechanisms across the Bilateria
The similarity in the genetic regulation of
arthropod and vertebrate appendage formation has been
interpreted as the product of a plesiomorphic gene
network that was primitively involved in bilaterian
appendage development and co-opted to build appendages
(in modern phyla) that are not historically related
as structures. Data from lophotrochozoans are needed to
clarify the pervasiveness of plesiomorphic appendage forming
mechanisms. We assayed the expression of three
arthropod and vertebrate limb gene orthologs, Distal-less
(Dll), dachshund (dac), and optomotor blind (omb), in
direct-developing juveniles of the polychaete Neanthes
arenaceodentata. Parapodial Dll expression marks premorphogenetic
notopodia and neuropodia, becoming restricted
to the bases of notopodial cirri and to ventral
portions of neuropodia. In outgrowing cephalic appendages,
Dll activity is primarily restricted to proximal
domains. Dll expression is also prominent in the brain. dac
expression occurs in the brain, nerve cord ganglia, a pair
of pharyngeal ganglia, presumed interneurons linking a
pair of segmental nerves, and in newly differentiating
mesoderm. Domains of omb expression include the brain,
nerve cord ganglia, one pair of anterior cirri, presumed
precursors of dorsal musculature, and the same pharyngeal
ganglia and presumed interneurons that express dac.
Contrary to their roles in outgrowing arthropod and
vertebrate appendages, Dll, dac, and omb lack comparable
expression in Neanthes appendages, implying independent
evolution of annelid appendage development. We infer
that parapodia and arthropodia are not structurally or
mechanistically homologous (but their primordia might
be), that Dll’s ancestral bilaterian function was in sensory
and central nervous system differentiation, and that
locomotory appendages possibly evolved from sensory
outgrowths
Formation of Supermassive Black Holes
Evidence shows that massive black holes reside in most local galaxies.
Studies have also established a number of relations between the MBH mass and
properties of the host galaxy such as bulge mass and velocity dispersion. These
results suggest that central MBHs, while much less massive than the host (~
0.1%), are linked to the evolution of galactic structure. In hierarchical
cosmologies, a single big galaxy today can be traced back to the stage when it
was split up in hundreds of smaller components. Did MBH seeds form with the
same efficiency in small proto-galaxies, or did their formation had to await
the buildup of substantial galaxies with deeper potential wells? I briefly
review here some of the physical processes that are conducive to the evolution
of the massive black hole population. I will discuss black hole formation
processes for `seed' black holes that are likely to place at early cosmic
epochs, and possible observational tests of these scenarios.Comment: To appear in The Astronomy and Astrophysics Review. The final
publication is available at http://www.springerlink.co
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