International Advisory Board: James Archibald (Translation Studies) - Hugo de Burgh (Chinese Media Studies) - Kristen Brustad (Arabic Linguistics) - Daniel Coste (French Language) - Luciano Curreri (Italian Literature) - Claudio Di Meola (German Linguistics) - Donatella Dolcini (Hindi Studies) - Johann Drumbl (German Linguistics) - Denis Ferraris (Italian Literature) - Lawrence Grossberg (Cultural Studies) - Stephen Gundle (Film and Television Studies) - Tsuchiya Junji (Sociology) - John McLeod (Post-colonial Studies) - Estrella Montolío Durán (Spanish Language) - Silvia Morgana (Italian Linguistics) - Samir Marzouki (Translation, Cultural Relations) - Mbare Ngom (Post-Colonial Literatures) - Christiane Nord (Translation Studies) - Roberto Perin (History) - Giovanni Rovere (Italian Linguistics) - Lara Ryazanova-Clarke (Russian Studies) - Shi-Xu (Discourse and Cultural Studies) - Srikant Sarangi (Discourse analysis) - Françoise Sabban, Centre d'études sur la Chine moderne et contemporaine (Chinese Studies) - Itala Vivan (Cultural Studies, Museum Studies)
Wuqiao County (simplified Chinese: 吴桥县; traditional Chinese: 吳橋縣; pinyin: Wúqiáo Xiàn, literally "Wu Bridge") is a county of southeastern Hebei province, China, bordering Shandong province to the southeast. It is the southernmost county-level division of the prefecture-level city of Cangzhou. Wuqiao covers an area of 583 km2 (225 sq mi) with a population of 280,000 and 444 natural villages under its jurisdiction. Over a period of more than 1500 years, Wuqiao is an old county with a vivid and rich history and culture. Wuqiao is situated in the center of the Huabei Plains and has a pleasant climate most of the year round and it is possible to pleasurably visit here at almost any time of the year.[citation needed]
In advanced traditional Chinese kung fu (martial arts), Neijing (Traditional Chinese: 內勁; pinyin: nèijìng) refers to the conscious control of the practitioner's qi, or "life energy", to gain advantages in combat.[1] Nèijìng is developed by using "Neigong" (Traditional Chinese: 內功; pinyin: nèigōng) (內功), or "internal exercises," as opposed to "wàigōng" (外功), "external exercises."
The fabrication of composite cathode with boroxine ring for all-solid-polymer lithium cell was described. Composite polymer electrolyte (CPE) was applied between the lithium metal anode and the composite cathode in a coin-shaped cell in order to prepare the solid-polymer electrolyte cell. The CPE films were cast on a flat polytetrafluoroethylene vessel from an acetonitrile slurry containing BaTiO ... [Show full abstract]Read more
The tomb murals of the Eastern Wei Dynasty (534–550) in the Southern and Northern Dynasties Period (386–581) unearthed from Xiaomachang Village of Wuqiao County in 1958 depict the performances of handstands, plate spinning, deft horsemanship and so on. However, it was after the Yuan Dynasty (1271–1368) that acrobatics of Wuqiao gained much reputation. Before that, acrobatics in Henan Province was much more influential. After the Yuan Dynasty was established, the capital was moved from Kaifeng of Henan to Beijing, and the acrobatics in Wuqiao of Hebei, which neighbors Beijing, began to prosper and was increasingly influential.
To determine if patient iMN degeneration resulted from bona fide ALS disease processes specific for motor neurons, we measured the survival of induced dopaminergic neurons (iDAs) generated by expression of FoxA2, Lmx1a, Brn2, Ascl1, and Myt1l 29. These neurons expressed high levels of tyrosine hydroxylase, indicating they had established a key aspect of the dopamine synthesis pathway and were distinct from iMNs, which do not express this enzyme 24 (Supplementary Fig. 3m, n). Unlike iMN cultures, iDA cultures from C9ORF72 patients (n=2 patients) did not show reduced survival compared to controls (n=2 controls) in either glutamate treatment and neurotrophic factor withdrawal conditions (Fig. 1h and Supplementary Fig. 3o), indicating that the in vitro neurodegenerative phenotype elicited by the C9ORF72 mutation is selective for motor neurons.
Given our observation that iMNs with reduced C9ORF72 levels are hypersensitive to DPR toxicity, we wondered if this might be due to a general disruption of protein turnover by DPRsHowever, PR50-GFP expression did not impair turnover of APP or Tau (Supplementary Fig. 14f, g and Supplementary Fig. 5l). Thus the neurotoxicity caused by DPRs that accumulate rapidly in C9-ALS motor neurons due to reduced C9ORF72 levels is not due to global disruption of protein turnover.
The GGGGCC repeat expansion in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), accounting for about 10% of each disease worldwide 1–4. In the central nervous system (CNS), neurons and microglia express the highest levels of C9ORF72 5, suggesting that C9ORF72 acts in part cell autonomously and effects in neurons are a key source of disease etiology. Studies showing that the repeat expansion generates neurotoxic species including nuclear RNA foci 6–8, RNA/DNA G-quadruplexes 9, and dipeptide repeat proteins (DPRs) 10–12 have oriented the field towards a therapeutic focus on blocking the toxicity of these products 6–8,13,14. However, these strategies have not fully rescued the degeneration of patient-derived neurons 7,13. Moreover, tandem GGGGCC repeats are transcribed from over 80 other genomic locations within human spinal motor neurons (Supplementary Tables 1 and 2), yet genetic studies have not linked repeat expansions in these regions to ALS/FTD. In addition, hexanucleotide repeat-mediated toxicity in mice requires supraphysiological expression levels or a specific genetic background 14–16. These observations suggest that there are additional pathogenic triggers caused by repeat expansion within C9ORF72.
To study the pathogenic mechanism of the C9ORF72 repeat expansion in human motor neurons, we used the forced expression of the transcription factors Ngn2, Isl1, Lhx3, NeuroD1, Brn2, Ascl1, and Myt1l, to convert control and C9ORF72 ALS/FTD patient induced pluripotent stem cells (iPSCs)(for iPSC characterization, see Supplementary Fig. 1 and Supplementary Tables 3, 4) into iMNs (Supplementary Fig. 2a, b) 10,24. Control and patient iMNs labeled with an Hb9::RFP+ lentiviral reporter construct (Supplementary Fig. 2b-d)25 co-expressed spinal motor neuron markers including TUJ1, HB9, and VACHT; were produced at similar rates amongst different iPSC lines; and possessed electrophysiological properties of motor neurons (Supplementary Fig. 2c-i). Depolarizing voltage steps induced currents characteristic of sodium and potassium channels and iMNs fired single or repetitive action potentials (patient - 90%, n=10; control – 100%, n=10)(Supplementary Fig. 2g-i). When co-cultured with primary chick muscle, channel rhodopsin-expressing control and patient iMNs repeatedly induced myotube contraction upon depolarization with green light, indicating they formed neuromuscular junctions and actuated muscle contraction (Supplementary Fig. 2j and Supplementary Videos 1, 2).

Given our observation that iMNs with reduced C9ORF72 levels are hypersensitive to DPR toxicity, we wondered if this might be due to a general disruption of protein turnover by DPRsHowever, PR50-GFP expression did not impair turnover of APP or Tau (Supplementary Fig. 14f, g and Supplementary Fig. 5l). Thus the neurotoxicity caused by DPRs that accumulate rapidly in C9-ALS motor neurons due to reduced C9ORF72 levels is not due to global disruption of protein turnover.

Since glutamate receptor activation and neuronal firing both induce calcium influx, we determined their relative contributions to the increased Gcamp6 activation by. using the ion channel inhibitors TTX and TEA to block neuronal firing. C9ORF72+/− iMNs still displayed more frequent Gcamp6 activation than C9ORF72+/+ iMNs (Supplementary Fig. 13a), indicating that part of the hyperexcitability is due to increased glutamate receptor activation. To determine which receptors were responsible for the increased glutamate response, we tested small molecule agonists of specific glutamate receptor subtypes. Activation of NMDA, AMPA, and kainate receptors was higher in C9ORF72+/− iMNs than controls (Supplementary Fig. 13a).
However, C9orf72-deficient mice do not display overt neurodegenerative phenotypes 14,18,19,22. Moreover, no studies have shown that reduced C9ORF72 activity leads to the degeneration of C9ORF72 ALS patient-derived motor neurons, nor have any provided direct evidence identifying a cellular pathway through which C9ORF72 activity modulates neuronal survival. Additionally, a patient homozygous for the C9ORF72 repeat expansion had clinical and pathological phenotypes that were severe but nonetheless did not fall outside the range of heterozygous patients, leaving it uncertain if reductions in C9ORF72 protein levels directly correlate with disease severity 23. Thus, the role of the C9ORF72 protein in C9ORF72 ALS/FTD disease pathogenesis remains unclear.
The key to unlock and nurture Neijing is said to be the practice of ‘song’ (Traditional Chinese: 鬆 ). The term ‘song’ can function as a verb which means to keep one's mind and body loose resilient and expanding like the consistency of cotton or clouds or relaxed yet concentrated like the sharp alertness of cats immediately before attack.[8] The term can also be used as an adjective which has the same meaning as described above. The greater the extent one can achieve ‘song’ and minimize the use of Li, the greater the release of Neijing force.[9][10]

Our iMN survival results (Fig. 1c-e) suggest that the repeat expansion alters iMN glutamate sensing. In cortical neurons, homeostatic synaptic plasticity is maintained through endocytosis and subsequent lysosomal degradation of glutamate receptors in response to chronic glutamate signaling 45,46. Defects in this process lead to the accumulation of glutamate receptors on the cell surface 45,46.
To provide a quantitative measure of (GGGGCC)n hexanuceotide expansion in C9ORF72, 100 ng of genomic DNA was amplified by touchdown PCR using primers shown in Supplementary Data Table 4, in a 28-µl PCR reaction consisting of 0.2 mM each of 7-deaza-2-deoxyguanine triphosphate (deaza-dGTP) (NEB), dATP, dCTP and dTTP, 7% DMSO, 1X Q-Solution, 1X Taq PCR buffer (Roche), 0.9 mM MgCl2, 0.7 µM reverse primer (four GGGGCC repeats with an anchor tail), 1.4 µM 6FAM-fluorescently labeled forward primer, and 1.4 µM anchor primer corresponding to the anchor tail of reverse primer (Supplementary Data Table 4). During the PCR, the annealing temperature was gradually decreased from 70 ºC and 56 ºC in 2 ºC increments with a 3 min extension time for each cycle. The PCR products were purified using the QiaQuick PCR purification kit (Qiagen) and analyzed using an ABI3730 DNA Analyzer and Peak Scanner™ Software v1.0 (Life Technologies).
Therapeutic strategies in development for C9ORF72 ALS/FTD target gain-of-function mechanisms. These include ASOs 6–8 and small molecules 13 that disrupt RNA foci formation. However, these approaches have not fully rescued neurodegeneration in human patient-derived neurons 6–8,13, indicating that replacing C9ORF72 function or new therapeutic targets may be required.
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