UBE2QL1 is Disrupted by a Constitutional Translocation Associated with Renal Tumor Predisposition and is a Novel Candidate Renal Tumor Suppressor Gene

Investigation of rare familial forms of renal cell carcinoma (RCC) has led to the identification of genes such as VHL and MET that are also implicated in the pathogenesis of sporadic RCC. In order to identify a novel candidate renal tumor suppressor gene, we characterized the breakpoints of a constitutional balanced translocation, t(5;19)(p15.3;q12), associated with familial RCC and found that a previously uncharacterized gene UBE2QL1 was disrupted by the chromosome 5 breakpoint. UBE2QL1 mRNA expression was downregulated in 78.6% of sporadic RCC and, although no intragenic mutations were detected, gene deletions and promoter region hypermethylation were detected in 17.3% and 20.3%, respectively, of sporadic RCC. Reexpression of UBE2QL1 in a deficient RCC cell line suppressed anchorage-independent growth. UBE2QL1 shows homology to the E2 class of ubiquitin conjugating enzymes and we found that (1) UBE2QL1 possesses an active-site cysteine (C88) that is monoubiquitinated in vivo, and (2) UBE2QL1 interacts with FBXW7 (an F box protein providing substrate recognition to the SCF E3 ubiquitin ligase) and facilitates the degradation of the known FBXW7 targets, CCNE1 and mTOR. These findings suggest UBE2QL1 as a novel candidate renal tumor suppressor gen

Reliability of knee joint position sense measurement: a comparison between goniometry and image capture methods

Aims: Evaluate the intra-rater and inter-rater reliability of hand-held goniometry compared to image capture (IMC) in the assessment of joint position sense (JPS) in healthy participants. Methodology: Repeated-measures observational study design was undertaken with 36 asymptomatic university students of both genders aged between 18 to 45 years. JPS in the knee was assessed by two assessors over two sessions (one-week interval) using hand-held goniometry and IMC methods. Joint position sense was assessed at four target knee flexion angles. Intra- and inter-rater reliability was assessed with absolute error (AE), relative error (RE) and intra-class correlation coefficient. Findings: Inter-rater reliability for goniometry was poor to substantial (ICC: 0.00 to 0.64) and was poor to moderate (ICC: 0.00 to 0.47) for IMC. Intra-rater reliability for goniometry was poor to moderate (ICC: 0.00 to 0.42) and poor to moderate for IMC (ICC: 0.00 to 0.41). AE for goniometry ranged from 3.2° to 8.6°, with RE from 0.1°-8.3°. For IMC, AE for goniometry was 5.3° to 12.5°, with RE ranging from 0.1° to 11.1°. Principal Conclusions: Neither goniometry nor IMC appeared superior to the other in JPS assessment. Caution should be made when considering the reliability for goniometry and IMC before clinical assessment is made

Massively Parallel Sequencing Reveals the Complex Structure of an Irradiated Human Chromosome on a Mouse Background in the Tc1 Model of Down Syndrome

Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and presents a complex phenotype that arises from abnormal dosage of genes on this chromosome. However, the individual dosage-sensitive genes underlying each phenotype remain largely unknown. To help dissect genotype – phenotype correlations in this complex syndrome, the first fully transchromosomic mouse model, the Tc1 mouse, which carries a copy of human chromosome 21 was produced in 2005. The Tc1 strain is trisomic for the majority of genes that cause phenotypes associated with DS, and this freely available mouse strain has become used widely to study DS, the effects of gene dosage abnormalities, and the effect on the basic biology of cells when a mouse carries a freely segregating human chromosome. Tc1 mice were created by a process that included irradiation microcell-mediated chromosome transfer of Hsa21 into recipient mouse embryonic stem cells. Here, the combination of next generation sequencing, array-CGH and fluorescence in situ hybridization technologies has enabled us to identify unsuspected rearrangements of Hsa21 in this mouse model; revealing one deletion, six duplications and more than 25 de novo structural rearrangements. Our study is not only essential for informing functional studies of the Tc1 mouse but also (1) presents for the first time a detailed sequence analysis of the effects of gamma radiation on an entire human chromosome, which gives some mechanistic insight into the effects of radiation damage on DNA, and (2) overcomes specific technical difficulties of assaying a human chromosome on a mouse background where highly conserved sequences may confound the analysis. Sequence data generated in this study is deposited in the ENA database, Study Accession number: ERP000439

Do we use a priori knowledge of gravity when making elbow rotations?

In this study, we aim to investigate whether motor commands, emanating from movement planning, are customized to movement orientation relative to gravity from the first trial on. Participants made fast point-to-point elbow flexions and extensions in the transverse plane. We compared movements that had been practiced in reclined orientation either against or with gravity with the same movement relative to the body axis made in the upright orientation (neutral compared to gravity). For each movement type, five rotations from reclined to upright orientation were made. For each rotation, we analyzed the first trial in upright orientation and the directly preceding trial in reclined orientation. Additionally, we analyzed the last five trials of a 30-trial block in upright position and compared these trials with the first trials in upright orientation. Although participants moved fast, gravitational torques were substantial. The change in body orientation affected movement planning: we found a decrease in peak angular velocity and a decrease in amplitude for the first trials made in the upright orientation, regardless of whether the previous movements in reclined orientation were made against or with gravity. We found that these decreases disappeared after participants familiarized themselves with moving in upright position in a 30-trial block. These results indicate that participants used a general strategy, corresponding to the strategy observed in situations with unreliable or limited information on external conditions. From this, we conclude that during movement planning, a priori knowledge of gravity was not used to specifically customize motor commands for the neutral gravity condition

The cross on rings performed by an Olympic champion

The cross is a key skill in Male Artistic Gymnastics rings routines. However, few researches were found about this skill. There is knowledge about the forces needed to perform the cross, or about muscles activation, separately. The aim of this paper was to accomplish a comprehensive research about the biomechanics of cross on rings, in order to obtain a descriptive model about this skill. Therefore, the currently Olympic champion on rings event volunteered in this research. He performed three crosses with the usual apparatus in his training gym. The measurement methods were combined: One digital video camera, one strain gauge in each cable and surface electromyography of nine right shoulder muscles were used. Statistical analyses were performed by parametric and non parametric tests and descriptive statistics. Symmetry values were calculated for shoulder angles and cables of right and left side. Coefficient of variation of muscle activation and co contraction were verified. Within gymnast variability was calculated using biological coefficient of variation (BCV), discretely for kinematic measures. Low variability values of shoulder angles and cable forces were verified and low values of asymmetry as well. Muscle activation varied according to muscle function, while co-contraction values were different among trials. These results pointed out the characteristics of the cross performed by an elite gymnast. Knowledge about the characteristics of cross can inform coaches, practitioners and clinicians how a successful skill should be presented

Tradeoff between Stability and Maneuverability during Whole-Body Movements

Understanding how stability and/or maneuverability affects motor control strategies can provide insight on moving about safely in an unpredictable world. Stability in human movement has been well-studied while maneuverability has not. Further, a tradeoff between stability and maneuverability during movement seems apparent, yet has not been quantified. We proposed that greater maneuverability, the ability to rapidly and purposefully change movement direction and speed, is beneficial in uncertain environments. We also hypothesized that gaining maneuverability comes at the expense of stability and perhaps also corresponds with decreased muscle coactivation.We used a goal-directed forward lean movement task that integrated both stability and maneuverability. Subjects (n = 11) used their center of pressure to control a cursor on a computer monitor to reach a target. We added task uncertainty by shifting the target anterior-posterior position mid-movement. We used a balance board with a narrow beam that reduced the base of support in the medio-lateral direction and defined stability as the probability that subjects could keep the balance board level during the task.During the uncertainty condition, subjects were able to change direction of their anterior-posterior center of pressure more rapidly, indicating that subjects were more maneuverable. Furthermore, medio-lateral center of pressure excursions also approached the edges of the beam and reduced stability margins, implying that subjects were less stable (i.e. less able to keep the board level). On the narrow beam board, subjects increased muscle coactivation of lateral muscle pairs and had greater muscle activity in the left leg. However, there were no statistically significant differences in muscle activity amplitudes or coactivation with uncertainty.These results demonstrate that there is a tradeoff between stability and maneuverability during a goal-directed whole-body movement. Tasks with added uncertainty could help individuals learn to be more maneuverable yet sufficiently stable

Characterising chromosome rearrangements: recent technical advances in molecular cytogenetics

Genomic rearrangements can result in losses, amplifications, translocations and inversions of DNA fragments thereby modifying genome architecture, and potentially having clinical consequences. Many genomic disorders caused by structural variation have initially been uncovered by early cytogenetic methods. The last decade has seen significant progression in molecular cytogenetic techniques, allowing rapid and precise detection of structural rearrangements on a whole-genome scale. The high resolution attainable with these recently developed techniques has also uncovered the role of structural variants in normal genetic variation alongside single-nucleotide polymorphisms (SNPs). We describe how array-based comparative genomic hybridisation, SNP arrays, array painting and next-generation sequencing analytical methods (read depth, read pair and split read) allow the extensive characterisation of chromosome rearrangements in human genomes

In Vivo Dynamics of the Musculoskeletal System Cannot Be Adequately Described Using a Stiffness-Damping-Inertia Model

Background: Visco-elastic properties of the (neuro-)musculoskeletal system play a fundamental role in the control of posture and movement. Often, these properties are described and identified using stiffness-damping-inertia (KBI) models. In such an approach, perturbations are applied to the (neuro-)musculoskeletal system and subsequently KBI-model parameters are optimized to obtain a best fit between simulated and experimentally observed responses. Problems with this approach may arise because a KBI-model neglects critical aspects of the real musculoskeletal system. Methodology/Principal Findings: The purpose of this study was to analyze the relation between the musculoskeletal properties and the stiffness and damping estimated using a KBI-model, to analyze how this relation is affected by the nature of the perturbation and to assess the sensitivity of the estimated stiffness and damping to measurement errors. Our analyses show that the estimated stiffness and damping using KBI-models do not resemble any of the dynamical parameters of the underlying system, not even when the responses are very accurately fitted by the KBI-model. Furthermore, the stiffness and damping depend non-linearly on all the dynamical parameters of the underlying system, influenced by the nature of the perturbation and the time interval over which the KBI-model is optimized. Moreover, our analyses predict a very high sensitivity of estimated parameters to measurement errors. Conclusions/Significance: The results of this study suggest that the usage of stiffness-damping-inertia models t

Influence of non-nucleoside reverse transcriptase inhibitors (efavirenz and nevirapine) on the pharmacodynamic activity of gliclazide in animal models

<p>Abstract</p> <p>Background</p> <p>Type 2 diabetes may occur as a result of HIV infection and/or its treatment. Gliclazide is a widely used drug for the treatment of type 2 diabetes. Efavirenz and nevirapine are widely used non-nucleoside reverse transcriptase inhibitors for the treatment of HIV infection. The role of Efavirenz and nevirapine on the pharmacodynamic activity of gliclazide is not currently known. The objective of this study was to examine the effect of oral administration of efavirenz and nevirapine on blood glucose and investigate their effect on the activity of gliclazide in rats (normal and diabetic) and rabbits to evaluate the safety and effectiveness of the combination.</p> <p>Methods</p> <p>Studies in normal and alloxan induced diabetic rats were conducted with oral doses of 2 mg/kg bd. wt. of gliclazide, 54 mg/kg bd. wt. of efavirenz or 18 mg/kg bd. wt. of nevirapine and their combination with adequate washout periods in between treatments. Studies in normal rabbits were conducted with 5.6 mg/1.5 kg bd. wt. of gliclazide, 42 mg/1.5 kg bd. wt. of efavirenz or 14 mg/1.5 kg bd. wt. of nevirapine and their combination given orally. Blood samples were collected at regular time intervals in rats from retro orbital puncture and by marginal ear vein puncture in rabbits. All the blood samples were analysed for blood glucose by GOD/POD method.</p> <p>Results</p> <p>Efavirenz and nevirapine alone have no significant effect on the blood glucose level in rats and rabbits. Gliclazide produced hypoglycaemic/antidiabetic activity in normal and diabetic rats with peak activity at 2 h and 8 h and hypoglycaemic activity in normal rabbits at 3 h. In combination, efavirenz reduced the effect of gliclazide in rats and rabbits, and the reduction was more significant with the single dose administration of efavirenz than multiple dose administration. In combination, nevirapine has no effect on the activity of gliclazide in rats and rabbits.</p> <p>Conclusion</p> <p>Thus, it can be concluded that the combination of efavirenz and gliclazide may need dose adjustment and care should be taken when the combination is prescribed for their clinical benefit in diabetic patients. The combination of nevirapine and gliclazide was safe. However, further studies are warranted.</p