Role of Insulin-Like Growth Factor Receptor 2 across Muscle Homeostasis: Implications for Treating Muscular Dystrophy

The insulin-like growth factor 2 receptor (IGF2R) plays a major role in binding and regulating the circulating and tissue levels of the mitogenic peptide insulin-like growth factor 2 (IGF2). IGF2/IGF2R interaction influences cell growth, survival, and migration in normal tissue development, and the deregulation of IGF2R expression has been associated with growth-related disease and cancer. IGF2R overexpression has been implicated in heart and muscle disease progression. Recent research findings suggest novel approaches to target IGF2R action. This review highlights recent advances in the understanding of the IGF2R structure and pathways related to muscle homeostasis

Severe Respiratory and Skeletal Muscles Involvement in a Carrier of Dysferlinopathy With Chronic Obstructive Pulmonary Disease

The natural course of progressive neuromuscular diseases can be complicated by respiratory muscle involvement. In muscular dystrophies such as Duchenne muscular dystrophy and myotonic dystrophy, respiratory muscle involvement is common. In others such as Becker, limb-girdle, and facioscapulo-humeral dystrophies, respiratory muscle involvement is infrequent and generally occurs in the more severe cases. Recently, it was reported that a mutation in the dysferlin gene and/or dysferlin deficiency causes proximal and distal forms of muscular dystrophy, which are known by the term dysferlinopathy. We describe a case of severe weakness of both limb-girdle and respiratory muscles in a patient who was carrier of the dysferlin gene mutation and who also had COPD. We suggest that the systemic inflammatory response of COPD and the dysferlin deficit interact and are responsible for both the skeletal and respiratory muscle impairment

Rational design of the inlet configuration of flow systems for enhanced mixing

Funder: Chinese Government Scholarship; doi: http://dx.doi.org/10.13039/501100010890Funder: Cambridge Overseas Trust; doi: http://dx.doi.org/10.13039/501100003341AbstractHigh mass transfer rate is a key advantage of microreactors however, under their characteristic laminar flow, it is dominated by slow diffusion rather than fast convection. In this paper, we demonstrate how the configuration of the inlet, i.e. mixers, can promote different flow patterns to greatly enhance mixing efficiency downstream. A systematic evaluation and comparison of different widely adopted mixers as well as advanced designs is presented using a combination of computational fluid dynamics (CFD) and backward particle tracking to accurately calculate diffusion, in the absence of numerical diffusion (false diffusion). In the method, the convection contributed concentration profile is obtained by tracking sampling points from a cross-sectional plane to the inlet point, and diffusion is estimated subsequently. In conventional T- and Y-mixers, the shape of channel, circular or square, is key with only the latter promoting engulfment flow. In cyclone mixers, the resulting average inlet velocity, independent of Reynolds number or geometry, is the dominating design parameter to predict mixing efficiency. This work will serve as a guideline for the design of efficient flow systems with predicted mixing as a way of maximising selectivity and product quality.</jats:p

Advancements in stem cells treatment of skeletal muscle wasting

Muscular dystrophies (MDs) are a heterogeneous group of inherited disorders, in which progressive muscle wasting and weakness is often associated with exhaustion of muscle regeneration potential. Although physiological properties of skeletal muscle tissue are now well known, no treatments are effective for these diseases. Muscle regeneration was attempted by means transplantation of myogenic cells (from myoblast to embryonic stem cells) and also by interfering with the malignant processes that originate in pathological tissues, such as uncontrolled fibrosis and inflammation. Taking into account the advances in the isolation of new subpopulation of stem cells and in the creation of artificial stem cell niches, we discuss how these emerging technologies offer great promises for therapeutic approaches to muscle diseases and muscle wasting associated with aging

CD133+ cells isolated from various sources and their role in future clinical perspective

Background. CD133 is a member of a novel family of cell surface glycoproteins. Initially, the expression of CD133 antigen was seen only in the hematopoietic derived CD34+ stem cells. At present, CD133 expression is demonstrated in undifferentiated epithelium, different types of tumors and myogenic cells. CD133+ neurosphere cells isolated from brain are able to differentiate into both neurons and glial cells. These data suggested that CD133 could be a specific marker for various stem and progenitor cell populations. Objectives. The main goal would be to describe the role for CD133 as a marker of stem cells able to engraft and differentiate, to form functional non-hematopoietic adult lineages and contribute to disease amelioration via tissue regeneration. Results/conclusion. In conclusion, since the rise of CD133 antigen as a suitable stem cell marker, the possible use of CD133+ stem cells in therapeutic applications has opened a new promising field in the treatment of degenerating diseases. The human circulating cells expressing the CD133 antigen behave as a stem cell population capable of commitment to hematopoietic, endothelial and myogenic lineages. CD133 cell therapy may represent a promising treatment for many diseases

Duchenne muscular dystrophy caused by a frame-shift mutation in the acceptor splice site of intron 26

Background: The dystrophin gene is the one of the largest described in human beings and mutations associated to this gene are responsible for Duchenne or Becker muscular dystrophies. Case Presentation: Here we describe a nucleotide substitution in the acceptor splice site of intron 26 (c.3604-1G > C) carried by a 6-year-old boy who presented with a history of progressive proximal muscle weakness and elevated serum creatine kinase levels. RNA analysis showed that the first two nucleotides of the mutated intron 26 (AC) were not recognized by the splicing machinery and a new splicing site was created within exon 27, generating a premature stop codon and avoiding protein translation. Conclusions: The evaluation of the pathogenic effect of the mutation by mRNA analysis will be useful in the optics of an antisense oligonucleotides (AON)-based therapy

A Special Amino-Acid Formula Tailored to Boosting Cell Respiration Prevents Mitochondrial Dysfunction and Oxidative Stress Caused by Doxorubicin in Mouse Cardiomyocytes

Anthracycline anticancer drugs, such as doxorubicin (DOX), can induce cardiotoxicity supposed to be related to mitochondrial damage. We have recently demonstrated that a branchedchain amino acid (BCAA)-enriched mixture (BCAAem), supplemented with drinking water to middle-aged mice, was able to promote mitochondrial biogenesis in cardiac and skeletal muscle. To maximally favor and increase oxidative metabolism and mitochondrial function, here we tested a new original formula, composed of essential amino acids, tricarboxylic acid cycle precursors and co-factors (named \uf0615), in HL-1 cardiomyocytes and mice treated with DOX. We measured mitochondrial biogenesis, oxidative stress, and BCAA catabolic pathway. Moreover, the molecular relevance of endothelial nitric oxide synthase (eNOS) and mechanistic/mammalian target of rapamycin complex 1 (mTORC1) was studied in both cardiac tissue and HL-1 cardiomyocytes. Finally, the role of Kr\ufcppel-like factor 15 (KLF15), a critical transcriptional regulator of BCAA oxidation and eNOS-mTORC1 signal, was investigated. Our results demonstrate that the \uf0615 mixture prevents the DOX-dependent mitochondrial damage and oxidative stress better than the previous BCAAem, implying a KLF15/eNOS/mTORC1 signaling axis. These results could be relevant for the prevention of cardiotoxicity in the DOX-treated patients

A neutrino mass matrix with seesaw mechanism and two-loop mass splitting

We propose a model which uses the seesaw mechanism and the lepton number $\bar L = L_e - L_\mu - L_\tau$ to achieve the neutrino mass spectrum $m_1 = m_2$ and $m_3 = 0$, together with a lepton mixing matrix $U$ with $U_{e3} = 0$. In this way, we accommodate atmospheric neutrino oscillations. A small mass splitting $m_1 > m_2$ is generated by breaking $\bar L$ spontaneously and using Babu's two-loop mechanism. This allows us to incorporate ``just so'' solar-neutrino oscillations with maximal mixing into the model. The resulting mass matrix has three parameters only, since $\bar L$ breaking leads exclusively to a non-zero $ee$ matrix element.Comment: 8 pages, Late

Explicit SO(10) Supersymmetric Grand Unified Model for the Higgs and Yukawa Sectors

A complete set of fermion and Higgs superfields is introduced with well-defined SO(10) properties and U(1) x Z_2 x Z_2 family charges from which the Higgs and Yukawa superpotentials are constructed. The structures derived for the four Dirac fermion and right-handed Majorana neutrino mass matrices coincide with those previously obtained from an effective operator approach. Ten mass matrix input parameters accurately yield the twenty masses and mixings of the quarks and leptons with the bimaximal atmospheric and solar neutrino vacuum solutions favored in this simplest version.Comment: Published version appearing in PRL in which small modifications to original submission and a paragraph concerning proton decay appea