Biomedical subjects

Lone Hansen

Publications and source records attributed to Lone Hansen.

8 recordsLinked to original sources

PubMed2006

A generic detailed rigid-body lumbar spine model.

The objective of this work is to present a musculo-skeletal model of the lumbar spine, which can be shared and lends itself to investigation in many locations by different researchers. This has the potential for greater reproducibility and subsequent improvement of its quality from the combined effort of different research groups. The model is defined in a text-based, declarative, object-oriented language in the AnyBody Modelling System software. Text-based models will facilitate sharing of the models between different research groups. The necessary data for the model has been taken from the literature. The work resulted in a detailed lumbar spine model with seven rigid segments with 18 degrees-of-freedom and 154 muscles. The model is able to produce a maximum extension moment of 238 Nm around L5/S1. Moreover, a comparison was made with in vivo intradiscal pressure measurements of the L4-5 disc available from the literature. The model is based on inverse dynamics, where the redundancy problem is solved using optimization in order to compute the individual muscle forces and joint reactions. With the presented model it is possible to investigate a range of research questions, because the model is relatively easy to share and modify due to the use of a well-defined and self-contained scripting language. Validation is though still necessary for specific cases.

Compressive Strength↗

PubMed2006

Anatomy and biomechanics of the back muscles in the lumbar spine with reference to biomechanical modeling.

STUDY DESIGN: This article describes the development of a musculoskeletal model of the human lumbar spine with focus on back muscles. It includes data from literature in a structured form. OBJECTIVE: To review the anatomy and biomechanics of the back muscles related to the lumbar spine with relevance for biomechanical modeling. SUMMARY OF BACKGROUND DATA: To reduce complexity, muscle units have been incorporated in an abridged manner, reducing their actions more or less to a single force equivalent. In early models of the lumbar spine, this may have been a necessary step to reduce complexity and, thereby, calculation time. The muscles of the spine are well described in the literature, but mainly qualitatively. Most of the literature provides a description of the structures without precise data of fiber length, muscle length, cross-sectional areas, moment arms, forces, etc. The predicted output of musculoskeletal models is very much dependent on the input parameters. The information needed to improve models consists of better approximations of the attachments to the vertebrae, and more precise data. METHOD: Review of literature. RESULTS: The predicted output of musculoskeletal models is very much dependent on the input parameters. Moderate changes in the assumed muscle line-of-action (i.e., moment arm) could substantially alter the magnitudes of predicted muscle and spinal forces, while the choice of optimization formulation is less sensitive. CONCLUSIONS: Input parameters, moment arms, as well as physiologic cross-sectional areas have a profound effect on the predicted muscle forces. Therefore, it is important to choose the values for moment arm and physiologic cross-sectional area carefully because they are essential input parameters to biomechanical models.

Back↗

PubMed2005

Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB.

We show that NF-kappaB and transcriptional targets are activated in liver by obesity and high-fat diet (HFD). We have matched this state of chronic, subacute 'inflammation' by low-level activation of NF-kappaB in the liver of transgenic mice, designated LIKK, by selectively expressing constitutively active IKK-b in hepatocytes. These mice exhibit a type 2 diabetes phenotype, characterized by hyperglycemia, profound hepatic insulin resistance, and moderate systemic insulin resistance, including effects in muscle. The hepatic production of proinflammatory cytokines, including IL-6, IL-1beta and TNF-alpha, was increased in LIKK mice to a similar extent as induced by HFD in in wild-type mice. Parallel increases were observed in cytokine signaling in liver and mucscle of LIKK mice. Insulin resistance was improved by systemic neutralization of IL-6 or salicylate inhibition of IKK-beta. Hepatic expression of the IkappaBalpha superrepressor (LISR) reversed the phenotype of both LIKK mice and wild-type mice fed an HFD. These findings indicate that lipid accumulation in the liver leads to subacute hepatic 'inflammation' through NF-kappaB activation and downstream cytokine production. This causes insulin resistance both locally in liver and systemically.

Animals↗

PubMed2005

Kinase activation through dimerization by human SH2-B.

The isoforms of SH2-B, APS, and Lnk form a family of signaling proteins that have been described as activators, mediators, or inhibitors of cytokine and growth factor signaling. We now show that the three alternatively spliced isoforms of human SH2-B readily homodimerize in yeast two-hybrid and cellular transfections assays, and this is mediated specifically by a unique domain in its amino terminus. Consistent with previous reports, we further show that the SH2 domains of SH2-B and APS bind JAK2 at Tyr813. These findings suggested a model in which two molecules of SH2-B or APS homodimerize with their SH2 domains bound to two JAK2 molecules, creating heterotetrameric JAK2-(SH2-B)2-JAK2 or JAK2-(APS)2-JAK2 complexes. We further show that APS and SH2-B isoforms heterodimerize. At lower levels of SH2-B or APS expression, dimerization approximates two JAK2 molecules to induce transactivation. At higher relative concentrations of SH2-B or APS, kinase activation is blocked. SH2-B or APS homodimerization and SH2-B/APS heterodimerization thus provide direct mechanisms for activating and inhibiting JAK2 and other kinases from the inside of the cell and for potentiating or attenuating cytokine and growth factor receptor signaling when ligands are present.

Adaptor Proteins, Signal Transducing↗

PubMed2004

A phenylalanine zipper mediates APS dimerization.

The APS, SH2-B and LNK proteins are adapters that activate and modulate receptor tyrosine kinase and JAK/STAT signaling. We now show that a conserved N-terminal domain mediates APS homodimerization. We determined the crystal structure of the dimerization domain at a resolution of 1.7 A using bromide ion MAD phasing. Each molecule contributes two helices to a compact four-helix bundle having a bisecting-U topology. Its most conspicuous feature is a stack of interdigitated phenylalanine side chains at the domain core. These residues create a new motif we refer to as a 'phenylalanine zipper,' which is critical to dimerization. A newly developed bridging yeast tri-hybrid assay showed that APS dimerizes JAK2, insulin receptor and IGF1 receptor kinases using its SH2 and dimerization domains. Dimerization via the phenylalanine zipper domain provides a mechanism for activating and modulating tyrosine kinase activity even in the absence of extracellular ligands.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Insulin resistance due to phosphorylation of insulin receptor substrate-1 at serine 302.

Inhibitory serine phosphorylation is a potential molecular mechanism for insulin resistance. We have developed a new variant of the yeast two-hybrid method, referred to as disruptive yeast tri-hybrid (Y3H), to identify inhibitory kinases and sites of phosphorylation in insulin receptors (IR) and IR substrates, IRS-1. Using IR and IRS-1 as bait and prey, respectively, and c-Jun NH(2)-terminal kinase (JNK1) as the disruptor, we now show that phosphorylation of IRS-1 Ser-307, a previously identified site, is necessary but not sufficient for JNK1-mediated disruption of IR/IRS-1 binding. We further identify a new phosphorylation site, Ser-302, and show that this too is necessary for JNK1-mediated disruption. Seven additional kinases potentially linked to insulin resistance similarly block IR/IRS-1 binding in the disruptive Y3H, but through distinct Ser-302- and Ser-307-independent mechanisms. Phosphospecific antibodies that recognize sequences surrounding Ser(P)-302 or Ser(P)-307 were used to determine whether the sites were phosphorylated under relevant conditions. Phosphorylation was promoted at both sites in Fao hepatoma cells by reagents known to promote Ser/Thr phosphorylation, including the phorbol ester phorbol 12-myristate 13-acetate, anisomycin, calyculin A, and insulin. The antibodies further showed that Ser(P)-302 and Ser(P)-307 are increased in animal models of obesity and insulin resistance, including genetically obese ob/ob mice, diet-induced obesity, and upon induction of hyperinsulinemia. These findings demonstrate that phosphorylation at both Ser-302 and Ser-307 is necessary for JNK1-mediated inhibition of the IR/IRS-1 interaction and that Ser-302 and Ser-307 are phosphorylated in parallel in cultured cells and in vivo under conditions that lead to insulin resistance.

Animals↗

PubMed2004

Physiological profile and activity pattern of young soccer players during match play.

PURPOSE: The purpose of this study was to examine aerobic demands and activity patterns during match play in young soccer players with respect to competition level, age, and biological maturity. METHODS: Ten nonelite players (NbP) and nine elite players (EbP) in their early puberty (12 yr), and seven elite players (EeP) in their late puberty (14 yr) were studied. Heart rate (HR) and activity pattern were recorded during match play, whereas corresponding .VO(2) and HR values were obtained during submaximal and maximal treadmill tests in the laboratory. The maturity status was assessed from testicular volume. RESULTS: No difference in .VO(2max) was observed between the nonelite and the elite players in the beginning of puberty (58.7 +/- 5.3 vs 58.6 +/- 5.0 mL O(2).min-1.kg(-1)), whereas the elite players in the end of puberty were significantly more fit (63.7 +/- 8.5 mL O(2).min(-1).kg(-1)). During match play, a higher HR was recorded in the elite players in the beginning of puberty than their nonelite counterparts, whereas the two elite groups showed the same HR responses (HR 1st half/2nd half-NbP: 162/157; EbP: 177/174; EeP: 178/173). The elite players in the end of puberty thus performed a higher absolute and relative .VO(2) (.VO(2).min(-1) and mL O(2).min(-1).kg(-1)) compared with the nonelite players during both halves, corresponding to more time spent in standing/walking in the nonelite group. The elite players in the end of puberty showed higher absolute .V(O2) values during match play than the young elite players but identical relative aerobic loads. It seems that the midfield/attack group had the highest absolute .VO(2max) and was performing at the highest HR during the matches. CONCLUSION: The present study shows that young soccer players are highly specialized both according to playing level and position on the field.

Adolescent↗

PubMed2002

Diabetes mutations delineate an atypical POU domain in HNF-1alpha.

Mutations in Hnf-1alpha are the most common Mendelian cause of diabetes mellitus. To elucidate the molecular function of a mutational hotspot, we cocrystallized human HNF-1alpha 83-279 with a high-affinity promoter and solved the structure of the complex. Two identical protein molecules are bound to the promoter. Each contains a homeodomain and a second domain structurally similar to POU-specific domains that was not predicted on the basis of amino acid sequence. Atypical elements in both domains create a stable interface that further distinguishes HNF-1alpha from other flexible POU-homeodomain proteins. The numerous diabetes-causing mutations in HNF-1alpha thus identified a previously unrecognized POU domain which was used as a search model to identify additional POU domain proteins in sequence databases.

Amino Acid Sequence↗