The relationship between mirror movements and corticospinal tract connectivity in children with unilateral spastic cerebral palsy

Unilateral Spastic Cerebral Palsy (USCP) is caused by an early brain lesion in which the Corticospinal Tract (CST), the primary pathway controlling upper extremity (UE) movements, is affected. The CST connectivity after early brain injury (i.e., an ipsilateral, contralateral, or bilateral connectivity) may influence treatment outcomes. Transcranial magnetic stimulation (TMS) is a common method to probe CST connectivity. However, TMS is limited to children without seizures. Mirror movements (MM), an involuntary imitation of movements by one limb during the contralateral limb voluntary movements, are common in USCP. MM may result when both UEs are controlled by the contralesional motor cortex. Here we investigated the relationship between MM and CST connectivity in children with USCP. We hypothesized that stronger MM were associated with an ipsilateral connectivity. Our secondary aim was to investigate whether the amount of MM was reduced after intensive therapy. Thirty-three children with USCP (mean age=9yrs 6mos; MACS: I-III) participated and were randomized to receive 90hrs of unimanual (n=16) or bimanual (n=17) intensive training. Assessments were measured at baseline and immediately after training. We used TMS and diffusion tensor imaging (DTI) to determine the CST connectivity. We used three approaches to quantify MM: 1) behavioral MM assessment during contralateral movements, including hand opening/closing, finger opposition, finger individuation, and finger walking, 2) involuntary grip force oscillations recorded by force transducer (FT) when the contralateral hand performed repetitive pinching, and 3) involuntary muscle contractions measured by electromyography (EMG) when the contralateral hand performed pinching. Results showed that strong MM (scores ≥3) in the more-affected hand while hand opening/closing were associated with an ipsilateral pathway (Fisher's exact test, p= 0.02). This association was not found in the remaining tasks (Fisher’s exact test, opposition, p≥ 0.99; individuation, p≥ 0.99; finger walking, p≥ 0.99). Involuntary GF oscillations were measured in a subset of 16 children. Presence of FT-measured MM in the less-affected hand (> 0.3N) was not associated with TMS-probed connectivity (Fisher’s exact test, p= 0.59). Nevertheless, presence of FT-measured MM was associated with DTI-assessed connectivity (Fisher’s exact test, p= 0.0498). Similarly, presence of EMG-measured MM in the more-affected hand was not associated with TMS-probed connectivity (Fisher’s exact test, p= 0.59). Nevertheless, presence of EMG-measured MM was associated with DTI-assessed connectivity (Fisher’s exact test, p= 0.03). The amount of MM did not change after training (p> 0.06 among all measures). In conclusion, strong MM in the more-affected hand while hand opening/closing may be indicative of an ipsilateral connectivity identified by TMS. Presence of MM measured by FT may be a predictor of DTI-assessed CST pattern. Findings of this study may help researchers and clinicians understand the relationship between the CST connectivity and its behavioral manifestation in children with USCP. Such relationship may further guide therapeutic strategies in a wider range of children with USCP

A 7R Spatial Linkage for Ankle Rehabilitation with an Arbitrary Ankle Rotation Axis

In this paper, a 7R spatial linkage for ankle rehabilitation was proposed. Thanks to its kinematic geometry, the output joint, which is accommodated by the patient\u27s ankle, of the linkage can possess an arbitrary joint axis at any configuration. This advantage allows the patient achieving a flexible ankle motion in 3-D space while performing the rehabilitation exercise. The design concept of the 7R linkage is explained, and the displacement and force relationships between the input and output joints (i.e., the motor and patient\u27s ankle) are analyzed through an equivalent RSSR linkage. A prototype is built to validate the proposed design concept

Down-regulation of Survivin enhances sensitivity to BPR0L075 in human cancer cells via caspase-independent mechanisms

Background: BPR0L075 [6-methoxy-3-(3',4',5'-trimethoxy-benzoyl)-1H-indole] is a novel anti-cancer compound. It inhibits tubulin polymerization and induces mitochondrial-dependent apoptosis in various human cancer cells with different multi-drug resistance (MDR) status. Over-expression of an anti-apoptotic molecule, survivin, causes drug-resistance in various cancers. Survivin inhibits apoptosis by interfering caspase-3 and promotes cell growth by stabilizing microtubule networks. Here, we determined the effects of down-regulation of survivin in BPR0L075 (L075) treatment. Methods: Western blot analysis was used to determine the expression level of survivin in L075-untreated/-treated human oral carcinoma KB and nasopharyngeal carcinoma HONE-1 cancer cells. siRNA was used to down-regulate endogenous survivin. MTT cell viability assay, real-time caspase-3 activity assay and immuno-fluorescence microscopy were used to analyze downstream effects. Results: Survivin expression was up-regulated in both KB and HONE-1 cells in response to L075 treatment. Down-regulation of survivin induced hyper-sensitivity to L075 in KB and re-stored sensitivity to L075 in KB-derived L075-resistant KB-L30 cancer cells. At the molecular level, down-regulation of survivin induced changes in microtubule dynamics in both KB and KB-L30 cells. Surprisingly, down-regulation of survivin did not enhance the activity of caspase-3 in L075 therapy. Instead, down-regulation of survivin induced translocation of the apoptosis-inducing factor (AIF) from cytoplasm to nucleus. Conclusion: Down-regulation of survivin improved drug sensitivity to L075 in both KB and L075-resistant KB-L30 cancer cells, possibly through a tubulin-dependent and caspase-independent mechanism. We suggest that combining BPR0L075 and survivin inhibitor may give better clinical outcome than the use of BPR0L075 monotherapy in future clinical trials

Metabolic Stress-Induced Phosphorylation of KAP1 Ser473 Blocks Mitochondrial Fusion in Breast Cancer Cells

Mitochondrial dynamics during nutrient starvation of cancer cells likely exert profound effects on their capability for metastatic progression. Here, we report that KAP1 (TRIM28), a transcriptional coadaptor protein implicated in metastatic progression in breast cancer, is a pivotal regulator of mitochondrial fusion in glucose-starved cancer cells. Diverse metabolic stresses induced Ser473 phosphorylation of KAP1 (pS473-KAP1) in a ROS- and p38-dependent manner. Results from live-cell imaging and molecular studies revealed that during the first 6 to 8 hours of glucose starvation, mitochondria initially underwent extensive fusion, but then subsequently fragmented in a pS473-KAP1-dependent manner. Mechanistic investigations using phosphorylation-defective mutants revealed that KAP1 Ser473 phosphorylation limited mitochondrial hyperfusion in glucose-starved breast cancer cells, as driven by downregulation of the mitofusin protein MFN2, leading to reduced oxidative phosphorylation and ROS production. In clinical specimens of breast cancer, reduced expression of MFN2 corresponded to poor prognosis in patients. In a mouse xenograft model of human breast cancer, there was an association in the core region of tumors between MFN2 downregulation and the presence of highly fragmented mitochondria. Collectively, our results suggest that KAP1 Ser473 phosphorylation acts through MFN2 reduction to restrict mitochondrial hyperfusion, thereby contributing to cancer cell survival under conditions of sustained metabolic stress

Using diffusion tensor imaging to identify corticospinal tract projection patterns in children with unilateral spastic cerebral palsy.

AIM: To determine whether diffusion tensor imaging (DTI) can be an independent assessment for identifying the corticospinal tract (CST) projecting from the more-affected motor cortex in children with unilateral spastic cerebral palsy (CP). METHOD: Twenty children with unilateral spastic CP participated in this study (16 males, four females; mean age 9y 2mo [standard deviation (SD) 3y 2mo], Manual Ability Classification System [MACS] level I-III). We used DTI tractography to reconstruct the CST projecting from the more-affected motor cortex. We mapped the motor representation of the more-affected hand by stimulating the more- and the less-affected motor cortex measured with single-pulse transcranial magnetic stimulation (TMS). We then verified the presence or absence of the contralateral CST by comparing the TMS map and DTI tractography. Fisher's exact test was used to determine the association between findings of TMS and DTI. RESULTS: DTI tractography successfully identified the CST controlling the more-affected hand (sensitivity=82%, specificity=78%). INTERPRETATION: Contralateral CST projecting from the lesioned motor cortex assessed by DTI is consistent with findings of TMS mapping. Since CST connectivity may be predictive of response to certain upper extremity treatments, DTI-identified CST connectivity may potentially be valuable for determining such connectivity where TMS is unavailable or inadvisable for children with seizures.K08 NS073796 - NINDS NIH HHS; TL1 RR024158 - NCRR NIH HHS; K01 NS062116 - NINDS NIH HHS; UL1 RR024156 - NCRR NIH HHS; KL2 RR024157 - NCRR NIH HHS; R01 HD076436 - NICHD NIH HHSPublished versio

Survivin counteracts the therapeutic effect of microtubule de-stabilizers by stabilizing tubulin polymers

<p>Abstract</p> <p>Background</p> <p>Survivin is a dual function protein. It inhibits the apoptosis of cells by inhibiting caspases, and also promotes cell growth by stabilizing microtubules during mitosis. Over-expression of survivin has been demonstrated to induce drug-resistance to various chemo-therapeutic agents such as cisplatin (DNA damaging agent) and paclitaxel (microtubule stabilizer) in cancers. However, survivin-induced resistance to microtubule de-stabilizers such as <it>Vinca </it>alkaloids and Combretastatin A-4 (CA-4)-related compounds were seldom demonstrated in the past. Furthermore, the question remains as to whether survivin plays a dominant role in processing cytokinesis or inhibiting caspases activity in cells treated with anti-mitotic compounds. The purpose of this study is to evaluate the effect of survivin on the resistance and susceptibility of human cancer cells to microtubule de-stabilizer-induced cell death.</p> <p>Results</p> <p>BPR0L075 is a CA-4 analog that induces microtubule de-polymerization and subsequent caspase-dependent apoptosis. To study the relationship between the expression of survivin and the resistance to microtubule de-stabilizers, a KB-derived BPR0L075-resistant cancer cell line, KB-<it>L30</it>, was generated for this study. Here, we found that survivin was over-expressed in the KB-<it>L30 </it>cells. Down-regulation of survivin by siRNA induced hyper-sensitivity to BPR0L075 in KB cells and partially re-stored sensitivity to BPR0L075 in KB-<it>L30 </it>cells. Western blot analysis revealed that down-regulation of survivin induced microtubule de-stabilization in both KB and KB-<it>L30 </it>cells. However, the same treatment did not enhance the down-stream caspase-3/-7 activities in BPR0L075-treated KB cells. Translocation of a caspase-independent apoptosis-related molecule, apoptosis-inducing factor (AIF), from cytoplasm to the nucleus was observed in survivin-targeted KB cells under BPR0L075 treatment.</p> <p>Conclusion</p> <p>In this study, survivin plays an important role in the stability of microtubules, but not with caspases inhibition. Over-expression of survivin counteracts the therapeutic effect of microtubule de-stabilizer BPR0L075 probably by stabilizing tubulin polymers, instead of the inhibition of caspase activity in cancer cells. Besides microtubule-related caspase-dependent cell death, caspase-independent mitotic cell death could be initiated in survivin/BPR0L075 combination treatments. We suggest that combining microtubule de-stabilizers with a survivin inhibitor may attribute to a better clinical outcome than the use of anti-mitotic monotherapy in clinical situations.</p

Wide Dynamic Range CMOS Potentiostat for Amperometric Chemical Sensor

Presented is a single-ended potentiostat topology with a new interface connection between sensor electrodes and potentiostat circuit to avoid deviation of cell voltage and linearly convert the cell current into voltage signal. Additionally, due to the increased harmonic distortion quantity when detecting low-level sensor current, the performance of potentiostat linearity which causes the detectable current and dynamic range to be limited is relatively decreased. Thus, to alleviate these irregularities, a fully-differential potentiostat is designed with a wide output voltage swing compared to single-ended potentiostat. Two proposed potentiostats were implemented using TSMC 0.18-μm CMOS process for biomedical application. Measurement results show that the fully differential potentiostat performs relatively better in terms of linearity when measuring current from 500 pA to 10 uA. Besides, the dynamic range value can reach a value of 86 dB

Metabolic Stress-Induced Phosphorylation of KAP1 Ser473 Blocks Mitochondrial Fusion in Breast Cancer Cells

Mitochondrial dynamics during nutrient starvation of cancer cells likely exert profound effects on their capability for metastatic progression. Here, we report that KAP1 (TRIM28), a transcriptional coadaptor protein implicated in metastatic progression in breast cancer, is a pivotal regulator of mitochondrial fusion in glucose-starved cancer cells. Diverse metabolic stresses induced Ser473 phosphorylation of KAP1 (pS473-KAP1) in a ROS- and p38-dependent manner. Results from live-cell imaging and molecular studies revealed that during the first 6 to 8 hours of glucose starvation, mitochondria initially underwent extensive fusion, but then subsequently fragmented in a pS473-KAP1-dependent manner. Mechanistic investigations using phosphorylation-defective mutants revealed that KAP1 Ser473 phosphorylation limited mitochondrial hyperfusion in glucose-starved breast cancer cells, as driven by downregulation of the mitofusin protein MFN2, leading to reduced oxidative phosphorylation and ROS production. In clinical specimens of breast cancer, reduced expression of MFN2 corresponded to poor prognosis in patients. In a mouse xenograft model of human breast cancer, there was an association in the core region of tumors between MFN2 downregulation and the presence of highly fragmented mitochondria. Collectively, our results suggest that KAP1 Ser473 phosphorylation acts through MFN2 reduction to restrict mitochondrial hyperfusion, thereby contributing to cancer cell survival under conditions of sustained metabolic stress

Soluble Form of Receptor for Advanced Glycation End Products Is Associated with Obesity and Metabolic Syndrome in Adolescents

The aim of this cross-sectional study was to investigate the relationship between soluble form of receptor for advanced glycation end products (sRAGE), obesity, and metabolic syndrome (MetS) in adolescents. A total of 522 male and 561 female adolescents were enrolled into the final analyses. Anthropometric parameters, blood pressure, blood biochemistry, fasting insulin, and plasma sRAGE levels were measured. In males, sRAGE was significantly and inversely correlated with waist circumference (WC), body mass index (BMI), systolic blood pressure, triglyceride (TG), low density lipoprotein cholesterol (LDL-C), and homeostasis model assessment-insulin resistance (HOMA-IR). Only WC and BMI were significantly and inversely correlated with sRAGE in females. Using linear regression analysis adjusting for age and gender, significant association was found between sRAGE and WC, BMI, TG, LDL-C, and HOMA-IR in adolescents of either gender (P<0.05). This association was abolished when further adjusting BMI. In addition, sRAGE was significantly and inversely correlated with the increasing number of components of MetS in males (P for trend = 0.006) but not in females (P for trend = 0.422). In conclusion, plasma sRAGE is associated with obesity and MetS among adolescents. BMI may be the most important determinant of sRAGE levels in adolescents

Acknowledgements

In this book, an international team of fourteen scholars investigates the Chinese reception of Indian Buddhist ideas, especially in the sixth and seventh centuries. Topics include Buddhist logic and epistemology (pramāṇa, yinming); commentaries on Indian Buddhist texts; Chinese readings of systems as diverse as Madhyamaka, Yogācāra and tathāgatagarbha; the working out of Indian concepts and problematics in new Chinese works; and previously under-studied Chinese evidence for developments in India. The authors aim to consider the ways that these Chinese materials might furnish evidence of broader Buddhist trends, thereby problematizing a prevalent notion of “sinification”, which has led scholars to consider such materials predominantly in terms of trends ostensibly distinctive to China. The volume also tries to go beyond seeing sixth- and seventh-century China primarily as the age of the formation and establishment of the Chinese Buddhist “schools”. The authors attempt to view the ideas under study on their own terms, as valid Buddhist ideas engendered in a rich, “liminal” space of interchange between two large traditions.In this book, an international team of fourteen scholars investigates the Chinese reception of Indian Buddhist ideas, especially in the sixth and seventh centuries. Topics include Buddhist logic and epistemology (pramāṇa, yinming); commentaries on Indian Buddhist texts; Chinese readings of systems as diverse as Madhyamaka, Yogācāra and tathāgatagarbha; the working out of Indian concepts and problematics in new Chinese works; and previously under-studied Chinese evidence for developments in India. The authors aim to consider the ways that these Chinese materials might furnish evidence of broader Buddhist trends, thereby problematizing a prevalent notion of “sinification”, which has led scholars to consider such materials predominantly in terms of trends ostensibly distinctive to China. The volume also tries to go beyond seeing sixth- and seventh-century China primarily as the age of the formation and establishment of the Chinese Buddhist “schools”. The authors attempt to view the ideas under study on their own terms, as valid Buddhist ideas engendered in a rich, “liminal” space of interchange between two large traditions