Biomedical subjects

R Starr

Publications and source records attributed to R Starr.

At least 19 recordsLinked to original sources

PubMed2006

SOCS1: a potent and multifaceted regulator of cytokines and cell-mediated inflammation.

Suppressor of cytokine signalling-1 (SOCS1), as the name implies, is a protein that functions as a negative regulator of cytokine signalling. Initially characterized for its ability to inhibit JAK phosphorylation and function, SOCS1 also targets proteins for degradation by the proteosome machinery. The expression of SOCS1 can be regulated at the transcription, translation and protein level. Despite the broad spectrum of cytokines that can induce SOCS1 expression and/or be inhibited by SOCS1 in vitro, the use of genetically modified mice has revealed a more specific role for SOCS1 in vivo including a critical role in the regulation of IFNgamma signalling. In addition, SOCS1 has a complex role in T cell activation, and studies have revealed significant roles for SOCS1 in the regulation of IL-4, IL-12 and IL-15 in vivo. Interestingly, SOCS1 action is not limited to the regulation of the classical JAK/STAT-signalling pathway, because SOCS1 also inhibits cytokines like insulin and toll-like receptor signal transduction, neither of which activates the JAK/STAT pathway. Evidence is emerging for a role for aberrant SOCS1 expression in human disease, particularly in a number of malignancies.

Animals↗

PubMed2003

Functional expression cloning reveals proapoptotic role for protein phosphatase 4.

Functional expression cloning strategies are highly suitable for the analysis of the molecular control of apoptosis. This approach has two critical advantages. Firstly, it eliminates prior assumptions about the properties of the proteins involved, and, secondly, it selectively targets proteins that are causally involved in apoptosis control and which affect the crucial cellular decision between survival and death. The application of this strategy to the isolation of cDNAs conferring resistance to dexamethasone and gamma-irradiation resulted in the isolation of a partial cDNA for the catalytic subunit of protein phosphatase 4 (PP4). Cells transfected with this partial cDNA in an expression vector downregulated PP4 and were resistant to both dexamethasone and UV radiation, as demonstrated by both membrane integrity and colony-forming assays. These observations suggest that PP4 plays an important proapoptotic role in T lymphocytes.

Animals↗

PubMed2002

Distribution of hydrogen in the near surface of Mars: evidence for subsurface ice deposits.

Using the Gamma-Ray Spectrometer on the Mars Odyssey, we have identified two regions near the poles that are enriched in hydrogen. The data indicate the presence of a subsurface layer enriched in hydrogen overlain by a hydrogen-poor layer. The thickness of the upper layer decreases with decreasing distance to the pole, ranging from a column density of about 150 grams per square centimeter at -42 degrees latitude to about 40 grams per square centimeter at -77 degrees. The hydrogen-rich regions correlate with regions of predicted ice stability. We suggest that the host of the hydrogen in the subsurface layer is ice, which constitutes 35 +/- 15% of the layer by weight.

Atmosphere↗

PubMed2001

SOCS1 regulates interferon-gamma mediated sensory neuron survival.

Differentiation and survival of sensory neurons is regulated by factors such as NGF and LIF. Regulation of signal transduction pathways downstream of such factor signalling by suppressor of cytokine signalling (SOCS) proteins, which negatively regulate the JAK/STAT pathway, may modulate biological outcome. In this study, SOCS1 regulation of growth factor mediated sensory neuron survival was examined. SOCS1 expression by sensory neurons was up-regulated by IFNgamma. Survival of sensory neurons from SOCS1 null mice in NGF or LIF was similar to wildtype mice. IFNgamma partially supported survival of wildtype neurons but supported survival of SOCS1 null neurons as effectively as NGF or LIF. Thus it appears that SOCS1 is a major regulator of sensory neuron responses to the inflammatory cytokine, IFNgamma.

Animals↗

PubMed2001

The SOCS box of suppressor of cytokine signaling-1 is important for inhibition of cytokine action in vivo.

Suppressor of Cytokine Signaling-1 (SOCS-1) is an essential physiological inhibitor of IFN-gamma signaling. Mice lacking this gene die in the early postnatal period from a disease characterized by hyperresponsiveness to endogenous IFN-gamma. The SOCS box is a C-terminal domain shared with over 30 other proteins that links SOCS proteins to an E3 ubiquitin ligase activity and the proteasome, but whether it contributes to inhibition of cytokine signaling is currently disputed. We have deleted only the SOCS box of the SOCS-1 gene in mice and show that such mice have an increased responsiveness to IFN-gamma and slowly develop a fatal inflammatory disease. These results demonstrate that deletion of the SOCS box leads to a partial loss of function of SOCS-1.

Animals↗

PubMed2001

SOCS1 deficiency results in accelerated mammary gland development and rescues lactation in prolactin receptor-deficient mice.

Prolactin is essential for proliferation and differentiation of the developing mammary gland. We have explored a role for Suppressor of Cytokine Signaling 1 (SOCS1) as a modulator of the prolactin response using mice deficient in SOCS1, which were rescued from neonatal death by deletion of the Interferon gamma (IFN gamma) gene. SOCS1(-/-)/IFN gamma(-/-) mice exhibited accelerated lobuloalveolar development in the mammary gland during late pregnancy and precocious lactation. Significantly, the lactogenic defect in prolactin receptor heterozygous females could be rescued by deletion of a single SOCS1 allele. These findings establish a role for SOCS1 as a negative regulator of prolactin signaling and suggest that SOCS1 is required for the prevention of lactation prior to parturition.

Alleles↗

PubMed2001

Suppressor of cytokine signaling-1 attenuates the duration of interferon gamma signal transduction in vitro and in vivo.

Suppressor of cytokine signaling-1 (SOCS-1) is a cytokine-inducible intracellular protein that functions to negatively regulate cytokine signal transduction pathways. Studies in vitro have shown that constitutive overexpression of SOCS-1 inhibits signaling in response to a range of cytokines, including interferons (IFN). Mice lacking SOCS-1 die from a complex disease characterized by liver degeneration and massive inflammation. Whereas there is clear evidence of increased IFNgamma signaling in SOCS-1(-/-) mice, it is unclear to what extent this is due to increased IFNgamma levels or to increased IFNgamma sensitivity. Here we have used SOCS-1(-/-) IFNgamma(-/-) mice, which remain healthy and produce no endogenous IFNgamma, to demonstrate that in vitro and in vivo hepatocytes lacking SOCS-1 exhibit a prolonged response to IFNgamma and that this correlates with a dramatically increased sensitivity to the toxic effects of IFNgamma in vivo. Thus, SOCS-1 is required for the timely attenuation of IFNgamma signaling in vivo.

Animals↗

PubMed2001

A comparison of overground and treadmill running for measuring the three-dimensional kinematics of the lumbo-pelvic-hip complex.

OBJECTIVE: To compare overground and treadmill running for differences in the three-dimensional angular kinematics of the lumbo-pelvic-hip complex. DESIGN: A within-subject repeated measures design. BACKGROUND: The treadmill is an attractive research instrument as speed and slope are easily controlled and the required calibration volume is reduced. However, the degree to which treadmill running simulates overground running has not been resolved in the literature to date. METHODS: 10 able-bodied subjects ran overground and on a treadmill at a self-selected speed. The treadmill speed was matched to each subjects respective average overground speed. The time-distance and the three-dimensional angular kinematic data were captured using a passive marker based motion analysis system. A set of angular and temporal kinematic parameters were extracted from the data and subjected to statistical analyses. RESULTS: Significant differences were found between overground and treadmill running for all the time-distance parameters. Despite this, the kinematics of the lumbar spine and pelvis were similar between the two running conditions, with only three parameters being significantly different. These were lumbar extension at initial contact, anterior pelvic tilt at initial contact and the first maximum anterior pelvic tilt. Hip flexion-extension parameters were also only found to display subtle differences. Of the 17 hip parameters analysed, only hip flexion at initial contact, maximum hip flexion at loading response, hip extension at toe off, maximum hip extension and hip flexion-extension range of motion were found to be significantly different. CONCLUSION: A high powered treadmill with a minimal belt speed fluctuation is capable of being used to obtain a representation of the typical three-dimensional kinematic pattern of the lumbo-pelvic-hip complex during running. RELEVANCE: In order for the treadmill to be accepted as a useful research and/or clinical assessment instrument, it must be demonstrated that it does not significantly alter the performance of the evaluated activity. In this respect, a treadmill with minimal intra-stride belt speed variability and similar surface stiffness to the relevant overground condition is likely to be capable of being used to obtain a representation of the typical human running action for well accommodated subjects.

Adult↗

PubMed2001

The effect of differing Cardan angle sequences on three dimensional lumbo-pelvic angular kinematics during running.

The variability in the three dimensional (3D) lumbo-pelvic angular kinematic patterns during running when using differing Cardan angle sequences was quantified. Data for four able-bodied subjects running on a treadmill at 4.0 m/s were captured using a motion analysis system with six cameras operating at 200 Hz. The adjusted coefficient of multiple correlation was used to compare graphical waveforms whilst the maximum root mean square of the differences was used to express the magnitude of any discrepancy in absolute units. Minimal qualitative differences were found between the various sequences. Quantitative differences between each of the Cardan angle sequences were not found to exceed 7.0 degrees and 2.8 degrees for the lumbar spine and pelvic rotations respectively. It was concluded that different Cardan angle sequences were not found to substantially affect typical 3D lumbo-pelvic angular kinematic patterns during running.

Adult↗

PubMed2000

Gigantism in mice lacking suppressor of cytokine signalling-2.

Suppressor of cytokine signalling-2 (SOCS-2) is a member of the suppressor of cytokine signalling family, a group of related proteins implicated in the negative regulation of cytokine action through inhibition of the Janus kinase (JAK) signal transducers and activators of transcription (STAT) signal-transduction pathway. Here we use mice unable to express SOCS-2 to examine its function in vivo. SOCS-2(-/-) mice grew significantly larger than their wild-type littermates. Increased body weight became evident after weaning and was associated with significantly increased long bone lengths and the proportionate enlargement of most organs. Characteristics of deregulated growth hormone and insulin-like growth factor-I (IGF-I) signalling, including decreased production of major urinary protein, increased local IGF-I production, and collagen accumulation in the dermis, were observed in SOCS-2-deficient mice, indicating that SOCS-2 may have an essential negative regulatory role in the growth hormone/IGF-I pathway.

Animals↗

PubMed2000

Interplanetary Network Localization of GRB 991208 and the Discovery of its Afterglow.

The extremely energetic ( approximately 10-4 ergs cm-2) gamma-ray burst (GRB) of 1999 December 8 was triangulated to an approximately 14 arcmin2 error box approximately 1.8 days after its arrival at Earth with the third interplanetary network (IPN), which consists of the Ulysses, Near-Earth Asteroid Rendezvous, and Wind spacecraft. Radio observations with the Very Large Array approximately 2.7 days after the burst revealed a bright fading counterpart whose position is consistent with that of an optical transient source with a redshift of 0.707. We present the time history, peak flux, fluence, and refined 1.3 arcmin2 error box of this event and discuss its energetics. This is the first time that a counterpart has been found for a GRB localized only by the IPN.

Journal Article↗

PubMed2000

Biomechanical transformation of the gastroc-soleus muscle with botulinum toxin A in children with cerebral palsy.

Objective measures (kinematics and kinetics) were used to study prospectively the effects of botulinum toxin A (BTX/A) on the gastro-soleus muscle in ambulant children with cerebral palsy. In this prospective before and after trial, 15 children with diplegia and 10 children with hemiplegia were studied (mean age 5 years 7 months, range 4 years to 9 years). A range of standardized clinical measures was undertaken but the emphasis for this report is on the three-dimensional gait analysis (3DGA) results. All children showed improvements in sagittal ankle kinematics, as has been previously reported. Two new measures of ankle kinetics were devised: ankle moment quotient (AMQ), and ankle power quotient (APQ). Before intervention, ankle moments were characterized by a 'double bump' ankle moment. A typical abnormal baseline ankle-power curve was triphasic with an initial trough of absorption followed by abnormal mid-stance power generation, instead of the usual A1 pattern, and reduced terminal stance power generation (A2). Three weeks after treatment with BTX/A alone there was a statistically significant improvement of AMQ and APQ; some patients required potentiation of BTX/A with a short period of serial casts. Both groups (BTX/A alone and BTX/A plus casting) continued to show improvement in ankle kinetics from baseline after 12 and 24 weeks. This is the first study to demonstrate improvements in the typical abnormal ankle kinetics which we believe provides evidence of the 'biomechanical transformation of muscle'.

Ankle Joint↗

PubMed1999

Different protein turnover of interleukin-6-type cytokine signalling components.

Interleukin (IL)-6 and IL-6-type cytokines signal through the gp130/Jak/STAT signal transduction pathway. The key components involved are the signal transducing receptor subunit gp130, the Janus kinases Jak1, Jak2 and Tyk2, STAT1 and STAT3 of the family of signal transducers and activators of transcription, the protein tyrosine phosphatase SHP2 and the suppressors of cytokine signalling SOCS1, SOCS2 and SOCS3. Whereas considerable information has been accumulated concerning the time-course of activation for the individual signalling molecules, data on the availability of the proteins involved in IL-6-type cytokine signal transduction are scarce. Nevertheless, availability of these molecules, determined by the balance of protein synthesis and degradation, also influences IL-6-type cytokine signal transduction. Here, we present a comprehensive set of data on the half-lives of the key molecules involved in the IL-6 signal transduction pathway. The turnover rates for the various proteins differ substantially. Three groups of signalling proteins can be discriminated: whereas the feedback inhibitors SOCS1, SOCS2 and SOCS3 are very short-lived, STAT1, STAT3 and SHP2 have an extremely slow turnover rate. Interestingly, the half-life of STAT3beta, a splice variant of STAT3alpha, is reduced to almost 50% of the half-life of STAT3alpha. The Janus kinases Jak1, Jak2, Tyk2 and gp130 show intermediate half-lives. Our data imply that signalling components activated by post-translational modifications are long-lived whereas the activity of very short-lived proteins is regulated mainly at the transcriptional level.

Antigens, CD↗

PubMed1999

SOCS1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal actions of this cytokine.

Mice lacking suppressor of cytokine signaling-1 (SOCS1) develop a complex fatal neonatal disease. In this study, SOCS1-/- mice were shown to exhibit excessive responses typical of those induced by interferon gamma (IFNgamma), were hyperresponsive to viral infection, and yielded macrophages with an enhanced IFNgamma-dependent capacity to kill L. major parasites. The complex disease in SOCS1-/- mice was prevented by administration of anti-IFNgamma antibodies and did not occur in SOCS1-/- mice also lacking the IFNgamma gene. Although IFNgamma is essential for resistance to a variety of infections, the potential toxic action of IFNgamma, particularly in neonatal mice, appears to require regulation. Our data indicate that SOCS1 is a key modulator of IFNgamma action, allowing the protective effects of this cytokine to occur without the risk of associated pathological responses.

Alphavirus Infections↗

PubMed1999

Mutational analyses of the SOCS proteins suggest a dual domain requirement but distinct mechanisms for inhibition of LIF and IL-6 signal transduction.

SOCS-1 (suppressor of cytokine signaling-1) is a representative of a family of negative regulators of cytokine signaling (SOCS-1 to SOCS-7 and CIS) characterized by a highly conserved C-terminal SOCS box preceded by an SH2 domain. This study comprehensively examined the ability of several SOCS family members to negatively regulate the gp130 signaling pathway. SOCS-1 and SOCS-3 inhibited both interleukin-6 (IL-6)- and leukemia inhibitory factor (LIF)-induced macrophage differentiation of murine monocytic leukemic M1 cells and LIF induction of a Stat3-responsive reporter construct in 293T fibroblasts. Deletion of amino acids 51-78 in the N-terminal region of SOCS-1 prevented inhibition of LIF signaling. The SOCS-1 and SOCS-3 N-terminal regions were functionally interchangeable, but this did not extend to other SOCS family members. Mutation of SH2 domains abrogated the ability of both SOCS-1 and SOCS-3 to inhibit LIF signal transduction. Unlike SOCS-1, SOCS-3 was unable to inhibit JAK kinase activity in vitro, suggesting that SOCS-1 and SOCS-3 act on the JAK-STAT pathway in different ways. Thus, although inhibition of signaling by SOCS-1 and SOCS-3 requires both the SH2 and N-terminal domains, their mechanisms of action appear to be biochemically different.

Animals↗

PubMed1999

Negative regulation of the JAK/STAT pathway.

Cytokines induce a variety of biological responses by binding to specific cell surface receptors and activating cytoplasmic signal transduction pathways, such as the JAK/STAT pathway. Although these responses are generally transient, few molecules have been characterised that switch the signal off. Several different steps of the signal transduction pathway appear to be targeted by negative regulators, including the receptor/ligand complex, JAK kinases, and STAT transcription factors. Negative regulation is achieved by dephosphorylation of signalling intermediates by protein tyrosine phosphatases such as SHP-1, and by proteolytic degradation. Recent studies have identified two new families of negative regulatory molecules, SOCS and PIAS, which function in novel ways to suppress signal transduction pathways. The duration and intensity of a cell's response to cytokine therefore appear to be determined by the net effect of several regulatory mechanisms.

Animals↗

PubMed1999

Suppressors of cytokine signaling (SOCS): negative regulators of signal transduction.

SOCS-1 was originally identified as an inhibitor of interleukin-6 signal transduction and is a member of a family of proteins (SOCS-1 to SOCS-7 and CIS) that contain an SH2 domain and a conserved carboxyl-terminal SOCS box motif. Mutation studies have established that critical contributions from both the amino-terminal and SH2 domains are essential for SOCS-1 and SOCS-3 to inhibit cytokine signaling. Inhibition of cytokine-dependent activation of STAT3 occurred in cells expressing either SOCS-1 or SOCS-3, but unlike SOCS-1, SOCS-3 did not directly interact with or inhibit the activity of JAK kinases. Although the conserved SOCS box motif appeared to be dispensable for SOCS-1 and SOCS-3 action when overexpressed, this domain interacts with elongin proteins and may be important in regulating protein turnover. In gene knockout studies, SOCS-1(-/-) mice were born but failed to thrive and died within 3 weeks of age with fatty degeneration of the liver and hemopoietic infiltration of several organs. The thymus in SOCS-1(-/-) mice was small, the animals were lymphopenic, and deficiencies in B lymphocytes were evident within hemopoietic organs. We propose that the absence of SOCS-1 in these mice prevents lymphocytes and liver cells from appropriately controlling signals from cytokines with cytotoxic side effects.

Animals↗

PubMed1999

High- or low- technology measurements of energy expenditure in clinical gait analysis?

The repeatability of energy-expenditure measurements were studied in five children and four adults without disabilities using the Cosmed K4 (high technology). The ability to detect change in measurements was compared between this instrument and the Physiological Cost Index (PCI; low technology). The results of repeatability (95% range) for oxygen cost were 13.1% in children and 13% in adults. In contrast, the SD of PCI was 6 to 72% of the mean in adults and wider in children (91%; 95% range). The validity of PCI as an outcome measure was questioned. In addition, 177 children with motor disability were prospectively studied using the Cosmed K4. Previous experience with the Cosmed K2 (intermediate technology) helped to develop a practical and repeatable protocol for testing children with disability using the Cosmed K4. The protocol commenced with 5 minutes of rest to achieve baseline values of heart rate and oxygen consumption, followed by 10 minutes of continuous walking at a self-selected speed on a 10-metre level oval walking track. The test concluded with 5 minutes of rest to monitor the return to baseline values. Ninety-one percent of the children with disability quickly reached a steady-state of oxygen consumption and carbon-dioxide production. The carbon-dioxide sensor in the Cosmed K4 has enabled a new group of severely involved children with cerebral palsy (9%) to be defined. These children have been termed 'physiologically marginal ambulators'.

Adult↗