Metabolic and functional characterization of adult skeletal muscle in Down syndrome mouse model (Ts1Cje): insight into the muscle weakness (hypotonia) seen in the human condition.

Persons with Down syndrome (DS) exhibit low muscle strength that significantly impairs their physical functioning. The Ts65Dn mouse model of DS also exhibits muscle weakness in vivo and may be a useful model to examine DS-associated muscle dysfunction. Therefore, the purpose of this experiment was to directly assess skeletal muscle function in the Ts65Dn mouse and to reveal potential mechanisms of DS-associated muscle weakness. Soleus muscles were harvested from anesthetized male Ts65Dn and wild-type (WT) colony controls. In vitro muscle contractile experiments revealed normal force generation of nonfatigued Ts65Dn soleus, but a 12% reduction in force was observed during recovery from fatiguing contractions compared with WT muscle ( P < 0.05). Indicators of oxidative stress and mitochondrial oxidative capacity were assessed to reveal potential mechanisms of DS-associated muscle weakness. Protein expression of copper-zinc superoxide dismutase (SOD1), a triplicated gene in persons with DS and Ts65Dn mice, was increased 25% ( P < 0.05) in Ts65Dn soleus. Nontriplicated antioxidant protein expression was similar between groups. Lipid peroxidation was unaltered in Ts65Dn animals, but protein oxidation was 20% greater compared with controls ( P < 0.05). Cytochrome- c oxidase expression was 22% lower in Ts65Dn muscle ( P < 0.05), while expression of citrate synthase was similar between groups. Microarray analysis revealed alteration of numerous pathways in Ts65Dn muscle, including proteolysis, glucose and fat metabolism, neuromuscular transmission, and ATP biosynthesis. In summary, despite biochemical and gene expression differences in soleus muscle of Ts65Dn animals, the functional properties of skeletal muscle likely contribute a minor part to the in vivo muscle weakness.

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Transcriptomic profiling of skeletal muscle from the Ts1Cje mouse model of Down syndrome suggests dysregulation of trisomic genes associated with neuromuscular junction signaling, oxidative stress and chronic inflammation

Neuroscience Research Notes ◽

10.31117/neuroscirn.v1i1.12 ◽

2018 ◽

Vol 1 (1) ◽

pp. 21-41 ◽

Cited By ~ 1

Author(s):

Melody Pui Yee Leong ◽

Usman Bala ◽

Chai Ling Lim ◽

Rozita Rosli ◽

Pike-See Cheah ◽

...

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Skeletal Muscle ◽

Down Syndrome ◽

Neuromuscular Junction ◽

Mouse Model ◽

Chronic Inflammation ◽

Muscle Weakness ◽

Protein Modification ◽

Chromosome 21

Ts1Cje is a mouse model of Down syndrome (DS) with partial triplication of chromosome 16, which encompasses a high number of human chromosome 21 (HSA21) orthologous genes. The mouse model exhibits muscle weakness resembling hypotonia in DS individuals. The effect of extra gene dosages on muscle weakness or hypotonia in Ts1Cje and DS individuals remains unknown. To identify molecular dysregulation of the skeletal muscle, we compared the transcriptomic signatures of soleus and extensor digitorum longus (EDL) muscles between the adult Ts1Cje and disomic littermates. A total of 166 and 262 differentially expressed protein-coding genes (DEGs) were identified in the soleus and EDL muscles, respectively. The partial trisomy of MMU16 in Ts1Cje mice has a greater effect on gene expression in EDL. Top-down clustering analysis of all DEGs for represented functional ontologies revealed 5 functional clusters in soleus associated with signal transduction, development of reproductive system, nucleic acid biosynthesis, protein modification and metabolism as well as regulation of gene expression. On the other hand, only 3 functional clusters were observed for EDL namely neuron and cell development, protein modification and metabolic processes as well as ion transport. A total of 11 selected DEGs were validated using qPCR (disomic DEGs: Mansc1; trisomic DEGs: Itsn1, Rcan1, Synj1, Donson, Dyrk1a, Ifnar1, Ifnar2, Runx1, Sod1 and Tmem50b). The validated DEGs were implicated in neuromuscular junction signalling (Itsn1, Syn1), oxidative stress (Sod1, Runx1) and chronic inflammation processes (Runx1, Rcan1, Ifnar1, Ifnar2). Other validated DEGs have not been well-documented as involved in the skeletal muscle development or function, thus serve as interesting novel candidates for future investigations. To our knowledge, the study was the first attempt to determine the transcriptomic profiles of both soleus and EDL muscles in Ts1Cje mice. It provides new insights on the possible disrupted molecular pathways associated with hypotonia in DS individuals.

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Identification of Thyroid Hormones and Functional Characterization of Thyroid Hormone Receptor in the Pacific Oyster Crassostrea gigas Provide Insight into Evolution of the Thyroid Hormone System

PLoS ONE ◽

10.1371/journal.pone.0144991 ◽

2015 ◽

Vol 10 (12) ◽

pp. e0144991 ◽

Cited By ~ 22

Author(s):

Wen Huang ◽

Fei Xu ◽

Tao Qu ◽

Rui Zhang ◽

Li Li ◽

...

Keyword(s):

Thyroid Hormone ◽

Thyroid Hormones ◽

Hormone Receptor ◽

Pacific Oyster ◽

Thyroid Hormone Receptor ◽

Functional Characterization ◽

The Pacific ◽

Hormone System ◽

Insight Into

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Functional Characterization of the Oxantel-Sensitive Acetylcholine Receptor from Trichuris muris

Pharmaceuticals ◽

10.3390/ph14070698 ◽

2021 ◽

Vol 14 (7) ◽

pp. 698

Author(s):

Tina V. A. Hansen ◽

Richard K. Grencis ◽

Mohamed Issouf ◽

Cédric Neveu ◽

Claude L. Charvet

Keyword(s):

Single Dose ◽

Mouse Model ◽

Xenopus Laevis ◽

Acetylcholine Receptor ◽

Drug Target ◽

Functional Characterization ◽

Xenopus Laevis Oocytes ◽

Trichuris Muris ◽

Electrode Voltage

The human whipworm, Trichuris trichiura, is estimated to infect 289.6 million people globally. Control of human trichuriasis is a particular challenge, as most anthelmintics have a limited single-dose efficacy, with the striking exception of the narrow-spectrum anthelmintic, oxantel. We recently identified a novel ACR-16-like subunit from the pig whipworm, T. suis which gave rise to a functional acetylcholine receptor (nAChR) preferentially activated by oxantel. However, there is no ion channel described in the mouse model parasite T. muris so far. Here, we have identified the ACR-16-like and ACR-19 subunits from T. muris, and performed the functional characterization of the receptors in Xenopus laevis oocytes using two-electrode voltage-clamp electrophysiology. We found that the ACR-16-like subunit from T. muris formed a homomeric receptor gated by acetylcholine whereas the ACR-19 failed to create a functional channel. The subsequent pharmacological analysis of the Tmu-ACR-16-like receptor revealed that acetylcholine and oxantel were equally potent. The Tmu-ACR-16-like was more responsive to the toxic agonist epibatidine, but insensitive to pyrantel, in contrast to the Tsu-ACR-16-like receptor. These findings confirm that the ACR-16-like nAChR from Trichuris spp. is a preferential drug target for oxantel, and highlights the pharmacological difference between Trichuris species.

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On the Harm of Genocide

Forum Philosophicum ◽

10.35765/forphil.2017.2201.02 ◽

2018 ◽

Vol 22 (1) ◽

pp. 31-49

Author(s):

Paul Kucharski

Keyword(s):

Human Nature ◽

The State ◽

Human Condition ◽

Human Beings ◽

Community Or ◽

The World ◽

Scholarly Discussion ◽

Insight Into ◽

Individual Human ◽

The Human Condition

My aim in this essay is to advance the state of scholarly discussion on the harms of genocide. The most obvious harms inflicted by every genocide are readily evident: the physical harm inflicted upon the victims of genocide and the moral harm that the perpetrators of genocide inflict upon themselves. Instead, I will focus on a kind of harm inflicted upon those who are neither victims nor perpetrators, on those who are outside observers, so to speak. My thesis will be that when a whole community or culture is eliminated, or even deeply wounded, the world loses an avenue for insight into the human condition. My argument is as follows. In order to understand human nature, and that which promotes its flourishing, we must certainly study individual human beings. But since human beings as rational and linguistic animals are in part constituted by the communities in which they live, the study of human nature should also involve the study of communities and cultures—both those that are well ordered and those that are not. No one community or culture has expressed all that can be said about the human way of existing and flourishing. And given that the unity and wholeness of human nature can only be glimpsed in a variety of communities and cultures, then part of the harm of genocide consists in the removal of a valuable avenue for human beings to better understand themselves.

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Functional characterization of a promoter polymorphism that drives ACSL5 gene expression in skeletal muscle and associates with diet‐induced weight loss

The FASEB Journal ◽

10.1096/fj.08-120998 ◽

2009 ◽

Vol 23 (6) ◽

pp. 1705-1709 ◽

Cited By ~ 14

Author(s):

Allen C. T. Teng ◽

Kristi Adamo ◽

Frédérique Tesson ◽

Alexandre F. R. Stewart

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Weight Loss ◽

Functional Characterization ◽

Promoter Polymorphism

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Functional characterization of the enzymes with 2,3-bisphosphoglycerate phosphatase activity from pig skeletal muscle

Comparative Biochemistry and Physiology Part B Comparative Biochemistry ◽

10.1016/0305-0491(86)90191-4 ◽

1986 ◽

Vol 85 (4) ◽

pp. 879-885 ◽

Cited By ~ 3

Author(s):

Gabriel Pons ◽

José Carreras

Keyword(s):

Skeletal Muscle ◽

Phosphatase Activity ◽

Functional Characterization

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Beyond Quietism: Transformative Experience in Pyrrhonism and Wittgenstein

International Journal for the Study of Skepticism ◽

10.1163/22105700-20191344 ◽

2020 ◽

Vol 10 (2) ◽

pp. 105-128 ◽

Cited By ~ 1

Author(s):

Rico Gutschmidt

Keyword(s):

Everyday Life ◽

Human Condition ◽

Transformative Experience ◽

Philosophical Practice ◽

Transformative Experiences ◽

Everyday Lives ◽

Pyrrhonian Skepticism ◽

Philosophical Questions ◽

Insight Into ◽

The Human Condition

Pyrrhonian skepticism is usually understood as a form of quietism, since it is supposed to bring us back to where we were in our everyday lives before we got disturbed by philosophical questions. Similarly, the ‘therapeutic’ and ‘resolute’ readings of Wittgenstein claim that Wittgenstein’s ‘philosophical practice’ results in the dissolution of the corresponding philosophical problems and brings us back to our everyday life. Accordingly, Wittgenstein is often linked to Pyrrhonism and classified as a quietist. Against this reading, I will employ Laurie Paul’s notion of epistemically transformative experience and argue that Pyrrhonian skepticism and Wittgenstein’s philosophy can be interpreted as a philosophical practice that changes our self-understanding in significant ways. I will argue that this practice can evoke transformative experiences and is thereby able to yield a non-propositional insight into the finitude of the human condition. This shows that Pyrrhonian skepticism and Wittgenstein’s philosophy go beyond quietism.

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