1,118 research outputs found

    Tuberin haploinsufficiency is associated with the loss of OGG1 in rat kidney tumors

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    <p>Abstract</p> <p>Background</p> <p>Tuberous sclerosis complex (TSC) is caused by defects in one of two tumor suppressor genes, <it>TSC-1 </it>or <it>TSC-2</it>. <it>TSC-2 </it>gene encodes tuberin, a protein involved in the pathogenesis of kidney tumors. Loss of heterozygosity (LOH) at the <it>TSC2 </it>locus has been detected in <it>TSC</it>-associated renal cell carcinoma (RCC) and in RCC in the Eker rat. Tuberin downregulates the DNA repair enzyme 8-oxoguanine DNA-glycosylase (OGG1) with important functional consequences, compromising the ability of cells to repair damaged DNA resulting in the accumulation of the mutagenic oxidized DNA, 8-oxo-dG. Loss of function mutations of OGG1 also occurs in human kidney clear cell carcinoma and may contribute to tumorgenesis. We investigated the distribution of protein expression and the activity of OGG1 and 8-oxo-dG and correlated it with the expression of tuberin in kidneys of wild type and Eker rats and tumor from Eker rat.</p> <p>Results</p> <p>Tuberin expression, OGG1 protein expression and activity were higher in kidney cortex than in medulla or papilla in both wild type and Eker rats. On the other hand, 8-oxo-dG levels were highest in the medulla, which expressed the lowest levels of OGG1. The basal levels of 8-oxo-dG were also higher in both cortex and medulla of Eker rats compared to wild type rats.</p> <p>In kidney tumors from Eker rats, the loss of the second <it>TSC2 </it>allele is associated with loss of OGG1 expression. Immunostaining of kidney tissue shows localization of tuberin and OGG1 mainly in the cortex.</p> <p>Conclusion</p> <p>These results demonstrate that OGG1 localizes with tuberin preferentially in kidney cortex. Loss of tuberin is accompanied by the loss of OGG1 contributing to tumorgenesis. In addition, the predominant expression of OGG1 in the cortex and its decreased expression and activity in the Eker rat may account for the predominant cortical localization of renal cell carcinoma.</p

    Distributed Edge Connectivity in Sublinear Time

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    We present the first sublinear-time algorithm for a distributed message-passing network sto compute its edge connectivity λ\lambda exactly in the CONGEST model, as long as there are no parallel edges. Our algorithm takes O~(n11/353D1/353+n11/706)\tilde O(n^{1-1/353}D^{1/353}+n^{1-1/706}) time to compute λ\lambda and a cut of cardinality λ\lambda with high probability, where nn and DD are the number of nodes and the diameter of the network, respectively, and O~\tilde O hides polylogarithmic factors. This running time is sublinear in nn (i.e. O~(n1ϵ)\tilde O(n^{1-\epsilon})) whenever DD is. Previous sublinear-time distributed algorithms can solve this problem either (i) exactly only when λ=O(n1/8ϵ)\lambda=O(n^{1/8-\epsilon}) [Thurimella PODC'95; Pritchard, Thurimella, ACM Trans. Algorithms'11; Nanongkai, Su, DISC'14] or (ii) approximately [Ghaffari, Kuhn, DISC'13; Nanongkai, Su, DISC'14]. To achieve this we develop and combine several new techniques. First, we design the first distributed algorithm that can compute a kk-edge connectivity certificate for any k=O(n1ϵ)k=O(n^{1-\epsilon}) in time O~(nk+D)\tilde O(\sqrt{nk}+D). Second, we show that by combining the recent distributed expander decomposition technique of [Chang, Pettie, Zhang, SODA'19] with techniques from the sequential deterministic edge connectivity algorithm of [Kawarabayashi, Thorup, STOC'15], we can decompose the network into a sublinear number of clusters with small average diameter and without any mincut separating a cluster (except the `trivial' ones). Finally, by extending the tree packing technique from [Karger STOC'96], we can find the minimum cut in time proportional to the number of components. As a byproduct of this technique, we obtain an O~(n)\tilde O(n)-time algorithm for computing exact minimum cut for weighted graphs.Comment: Accepted at 51st ACM Symposium on Theory of Computing (STOC 2019

    Concomitant rotator cuff repair and instability surgery provide good patient-reported functional outcomes in patients aged 40 years or older with shoulder dislocation

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    Background: Recurrent anterior shoulder dislocation in patients aged \u3e /= 40 years is not as rare as once thought. The mechanism of instability in this patient population is different-more likely to be attributed to rotator cuff pathology-compared with that in younger individuals. With an increasingly aging active population, surgical management has a rising role in preventing morbidity associated with recurrent instability. Our purpose was to evaluate outcomes of anterior shoulder instability repair (ie, Bankart or bony Bankart repair) with and without rotator cuff repair (RCR) in patients aged \u3e /= 40 years. Methods: We conducted a retrospective chart review of all patients aged \u3e /= 40 years who underwent surgical repair for anterior shoulder instability from 2008-2016. Patients were categorized into 4 cohorts: Bankart repair only, bony Bankart repair only, Bankart repair with concomitant RCR, and bony Bankart repair with concomitant RCR. Demographic and history-of-instability data were collected. Clinical and functional outcomes assessed included the Single Assessment Numeric Evaluation score, American Shoulder and Elbow Surgeons score, Penn Shoulder Score, visual analog scale score for pain, Western Ontario Shoulder Instability Index score, and patient satisfaction score. Results: A total of 146 patients were included in this study, with 103 patients (71%) having \u3e /=2-year outcome scores. Outcome scores were not significantly different among groups. For patients who underwent Bankart repair only, bony Bankart repair only, Bankart repair with RCR, and bony Bankart repair with RCR, the Single Assessment Numeric Evaluation scores were 80.8 +/- 19.7, 90.0 +/- 10.7, 79.3 +/- 29.4, and 87.2 +/- 10.6, respectively (P = .284); American Shoulder and Elbow Surgeons scores, 83.8 +/- 19.7, 92.4 +/- 17.4, 82.5 +/- 25.6, and 85.6 +/- 12.7, respectively (P = .114); Penn Shoulder Scores for function, 84.5 +/- 17.9, 90.9 +/- 15.3, 83.6 +/- 25.1, and 95.7 +/- 13.0, respectively (P = .286); and Western Ontario Shoulder Instability Index scores, 481.0 +/- 519.5, 292.1 +/- 414.3, 548.9 +/- 690.5, and 320.6 +/- 258.7, respectively (P = .713). Age at the time of surgery significantly differed between cohorts (P \u3c .001). No patients had recurrence of instability during the study period. Conclusion: Similar functional outcomes can be achieved in the surgical management of anterior instability in patients aged \u3e /= 40 years. Rotator cuff tears should be suspected and repaired in patients with anterior instability, especially those aged \u3e /= 50 years

    Variation of corticospinal excitability during kinesthetic illusion induced by musculotendinous vibration

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    Abtract Despite being studied for more than 50 years, the neurophysiological mechanisms underlying vibration (VIB)-induced kinesthetic illusions are still unclear. The aim of this study was to investigate how corticospinal excitability tested by transcranial magnetic stimulation (TMS) is modulated during VIB-induced illusions. Twenty healthy adults received vibration over wrist flexor muscles (80 Hz, 1 mm, 10 s). TMS was applied over the primary motor cortex representation of wrist extensors at 120% of resting motor threshold in four random conditions (10 trials/condition): baseline (without VIB), 1 s, 5 s, and 10 s after VIB onset. Means of motor-evoked potential (MEP) amplitudes and latencies were calculated. Statistical analysis found a significant effect of conditions (stimulation timings) on MEP amplitudes (P = 0.035). Paired-comparisons demonstrated lower corticospinal excitability during VIB at 1 s compared with 5 s (P = 0.025) and 10 s (P = 0.003), although none of them differed from baseline values. Results suggest a time-specific modulation of corticospinal excitability in muscles antagonistic to those vibrated, i.e., muscles involved in the perceived movement. An early decrease of excitability was observed at 1 s followed by a stabilization of values near baseline at subsequent time points. At 1 s, the illusion is not yet perceived or not strong enough to upregulate corticospinal networks coherent with the proprioceptive input. Spinal mechanisms, such as reciprocal inhibition, could also contribute to lower the corticospinal drive of nonvibrated muscles in short period before the illusion emerges. Our results suggest that neuromodulatory effects of VIB are likely time-dependent, and that future work is needed to further investigate underlying mechanisms. NEW & NOTEWORTHY The modulation of corticospinal excitability when perceiving a vibration (VIB)-induced kinesthetic illusion evolves dynamically over time. This modulation might be linked to the delayed occurrence and progressive increase in strength of the illusory perception in the first seconds after VIB start. Different spinal/cortical mechanisms could be at play during VIB, depending on the tested muscle, presence/absence of an illusion, and the specific timing at which corticospinal drive is tested pre/post VIB

    Suicide inhibition of alpha-oxamine synthases:structures of the covalent adducts of 8-amino-7-oxononanoate synthase with trifluoroalanine

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    The suicide inhibition of the α-oxamine synthases by the substrate analog, L-trifluoroalanine was investigated. The inhibition resulted in the formation of a complex with loss of all three fluorine atoms. Decarboxylation and loss of fluoride occurred immediately after aldimine formation. The inherent flexibility could allow the difluorinated intermediate complex to adopt a suitable conformation. Decarboxylation in the normal mechanism occurs after formation of the ketoacid intermediate.link_to_subscribed_fulltex

    The effect of parathyroid hormone on the uptake and retention of 25-hydroxyvitamin D in skeletal muscle cells

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    © 2017 Elsevier Ltd Data from our studies, and those of others, support the proposal that there is a role for skeletal muscle in the maintenance of vitamin D status. We demonstrated that skeletal muscle is able to internalise extracellular vitamin D binding protein, which then binds to actin in the cytoplasm, to provide high affinity binding sites which accumulate 25-hydroxyvitamin D3 (25(OH)D3) [1]. This study investigated the concentration- and time-dependent effects of parathyroid hormone (PTH) on the capacity of muscle cells to take up and release 3H-25(OH)D3. Uptake and retention studies for 3H-25(OH)D3 were carried out with C2C12 cells differentiated into myotubes and with primary mouse muscle fibers as described [1]. The presence of PTH receptors on mouse muscle fibers was demonstrated by immunohistochemistry and PTH receptors were detected in differentiated myotubes, but not myoblasts, and on muscle fibers by Western blot. Addition of low concentrations of vitamin D binding protein to the incubation media did not alter uptake of 25(OH)D3. Pre-incubation of C2 myotubes or primary mouse muscle fibers with PTH (0.1 to 100 pM) for 3 h resulted in a concentration-dependent decrease in 25(OH)D3 uptake after 4 or 16 h. These effects were significant at 0.1 or 1 pM PTH (p \u3c 0.001) and plateaued at 10 pM, with 25(OH)D3 uptake reduced by over 60% (p \u3c 0.001) in both cell types. In C2 myotubes, retention of 25(OH)D3 was decreased after addition of PTH (0.1 to 100 pM) in a concentration-dependent manner by up to 80% (p \u3c 0.001) compared to non-PTH treated-C2 myotubes. These data show that muscle uptake and retention of 25(OH)D3 are modulated by PTH, a physiological regulator of mineral homeostasis, but the cell culture model may not be a comprehensive reflection of vitamin D homeostatic mechanisms in whole animals

    Comparison of Asymmetric Reaming versus a Posteriorly Augmented Component for Posterior Glenoid Wear and Retroversion: A Radiographic Study.

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    Background: Managing posterior glenoid wear and retroversion remains a challenge in shoulder arthroplasty. Correcting glenoid version through asymmetric reaming (AR) with placement of a standard glenoid component and the use of posteriorly augmented glenoid (PAG) components are two methods used to address this problem. Our objective is to report the radiographic outcomes of patients with posterior glenoid wear and/or retroversion treated with either approach. Methods: Patients with posterior glenoid wear and a minimum of 15 degrees of retroversion, treated with AR and standard glenoid component or with a PAG component (3 mm, 5 mm, or 7 mm posterior augmentation), were consecutively identified through retrospective chart review. Pre-operative axillary views were evaluated for version, humeral head subluxation in relation to scapular axis and to mid-glenoid face. Post-operative axillary views were reviewed to measure corrected inversion and humeral head subluxation. Results: There were 48 patients in the AR group and 49 patients in the PAG group. Version improved 6.8 degrees in the AR group. In the PAG group, version improved 8.8 degrees with 3 mm augment, 13.4 degrees with 5 mm augment, and 12.8 with 7 mm augments. There were significantly more central peg perforations in the 5 mm PAG group compared to other groups. The humeral head was re-centered within 6.1% of normal in all groups except 7 mm augments. Conclusion: This study demonstrates that AR and PAGs have the ability to re-center the humeral head when utilized in patients with retroversion and posterior wear. Use of a PAG component may allow for greater correction of glenoid retroversion, however, there is an increased risk for central peg perforation with the specific implant utilized in this study. Long-term follow-up is ongoing and needed to understand the clinical implications of these findings
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