Effect of systemic administration of granulocyte-colony stimulating factor on rate of fracture healing of bone defect in goats as animal model

Granulocyte-colony stimulating factor (G-CSF) serves as an important cytokine in haematopoiesis; released at both physiological and pathological conditions by a range of cells. We hypothesized that the systemic administration of G-CSF would produce an accelerated fracture-healing rate in non-union bone defects; thus, potentially leading to useful clinical applications. Ten male adult Katjang goats, weighing about 15-26 kilograms were randomly chosen and a tibial bone defect was induced in each animal. The defect was maintained by internal fixation with a titanium plate and reinforced by an external fiberglass cast. Post-operative radiographs were performed twice weekly and radiographic assessments were performed by evaluating the bridging and union measurements through a validated method. In the treatment group, the time for bridging and union exhibited statistically significant differences when compared with a control group. The outcomes of the present study establishing a notion that administration of G-CSF besides inducing haematopoiesis, promotes healing of fractures and non-union bone defects as well

Folded Supersymmetry and the LEP Paradox

We present a new class of models that stabilize the weak scale against radiative corrections up to scales of order 5 TeV without large corrections to precision electroweak observables. In these `folded supersymmetric' theories the one loop quadratic divergences of the Standard Model Higgs field are cancelled by opposite spin partners, but the gauge quantum numbers of these new particles are in general different from those of the conventional superpartners. This class of models is built around the correspondence that exists in the large N limit between the correlation functions of supersymmetric theories and those of their non-supersymmetric orbifold daughters. By identifying the mechanism which underlies the cancellation of one loop quadratic divergences in these theories, we are able to construct simple extensions of the Standard Model which are radiatively stable at one loop. Ultraviolet completions of these theories can be obtained by imposing suitable boundary conditions on an appropriate supersymmetric higher dimensional theory compactified down to four dimensions. We construct a specific model based on these ideas which stabilizes the weak scale up to about 20 TeV and where the states which cancel the top loop are scalars not charged under Standard Model color. Its collider signatures are distinct from conventional supersymmetric theories and include characteristic events with hard leptons and missing energy.Comment: 18 pages, 5 figures, references correcte

Pressure tunable quantum anomalous Hall states in a topological antiferromagnet

Mechanical modulation of the lattice parameter can modify the electronic structure and manipulate the magnetic coupling of a material without introducing impurities. Inspired by success in pressure-controlled magnetism, we investigate the effect of hydrostatic pressure on quantized Chern states in the antiferromagnetic topological insulator MnBi2Te4, using transport as a probe. We show that pressure can enhance the robustness of quantum anomalous Hall (QAH) phases that are otherwise delicate in 7SL MnBi2Te4 and in the spin-flop (SF) state of 8SL MnBi2Te4. We explain our findings using a coupled Dirac cone model of MnBi2Te4, which identifies stronger hybridization between van der Waals layers as the driver of topological states. We further demonstrate that moderate pressures readily available in laboratory systems can provide reversible control of magnetic and topological phases. Our results reveal a strong connection between the mechanical engineering of band topology and magnetism.Comment: 11 pages, 4 figure

Physical measurement of the expansion rate of anisotropic tissue expander in the skin of the horse

Tissue expansion technique is one of the most important innovations in skin reconstructive surgery. In this study, anisotropic self-inflating hydrogel tissue expanders were implanted subcutaneously at different anatomical locations; frontal, right shoulder and right forelimb of horses. The resulting skin expansion were observed and recorded daily for the duration of 28 days by manual physical measurements. The rate of height growth and swelling that were recorded are 164.25% at the frontal region of the head, 189.13% at the shoulder region and 122.42% at the forelimb region. The growth of the tissue expander in the three sites could be summarized in three phases; biodegradable in week one, the peak of anisotropic expansion in week two and three, and final degree of swelling in week four

Adeno-associated viral vector serotype 9-based gene therapy for Niemann-Pick disease type A

Niemann-Pick disease type A (NPD-A) is a lysosomal storage disorder characterized by neurodegeneration and early death. It is caused by loss-of-function mutations in the gene encoding for acid sphingomyelinase (ASM), which hydrolyzes sphingomyelin into ceramide. Here, we evaluated the safety of cerebellomedullary (CM) cistern injection of adeno-associated viral vector serotype 9 encoding human ASM (AAV9-hASM) in nonhuman primates (NHP). We also evaluated its therapeutic benefit in a mouse model of the disease (ASM-KO mice). We found that CM injection in NHP resulted in widespread transgene expression within brain and spinal cord cells without signs of toxicity. CM injection in the ASM-KO mouse model resulted in hASM expression in cerebrospinal fluid and in different brain areas without triggering an inflammatory response. In contrast, direct cerebellar injection of AAV9-hASM triggered immune response. We also identified a minimally effective therapeutic dose for CM injection of AAV9-hASM in mice. Two months after administration, the treatment prevented motor and memory impairment, sphingomyelin (SM) accumulation, lysosomal enlargement, and neuronal death in ASM-KO mice. ASM activity was also detected in plasma from AAV9-hASM CM-injected ASM-KO mice, along with reduced SM amount and decreased inflammation in the liver. Our results support CM injection for future AAV9-based clinical trials in NPD-A as well as other lysosomal storage brain disorders.Nation Foundation and by grants from the Spanish Ministry of Economy and Competitivity (SAF-2014-57539-R and SAF2017-87698-R) to M.D.L. and from NIH-NINDS (R01NS073940) to K.S.B. A.P.-C. was a recipient of the FPU predoctoral fellowship from the Spanish Ministry of Economy and Competitivity and Fundación Ramón Areces to the Centro Biología Molecular Severo Ochoa

The role of doxorubicin in non-viral gene transfer in the lung

a b s t r a c t Proteasome inhibitors have been shown to increase adeno-associated virus (AAV)-mediated transduction in vitro and in vivo. To assess if proteasome inhibitors also increase lipid-mediated gene transfer with relevance to cystic fibrosis (CF), we first assessed the effects of doxorubicin and N-acetyl-L-leucinyl-L-leucinal-L-norleucinal in non-CF (A549) and CF (CFTE29o-) airway epithelial cell lines. CFTE29o-cells did not show a response to Dox or LLnL; however, gene transfer in A549 cells increased in a dose-related fashion (p < 0.05), up to approximately 20-fold respectively at the optimal dose (no treatment: 9.3 Â 10 4 AE 1.5 Â 10 3 , Dox: 1.6 Â 10 6 AE 2.6 Â 10 5 , LLnL: 1.9 Â 10 6 AE 3.2 Â 10 5 RLU/mg protein). As Dox is used clinically in cancer chemotherapy we next assessed the effect of this drug on non-viral lung gene transfer in vivo. CF knockout mice were injected intraperitoneally (IP) with Dox (25-100 mg/kg) immediately before nebulisation with plasmid DNA carrying a luciferase reporter gene under the control of a CMV promoter/ enhancer (pCIKLux) complexed to the cationic lipid GL67A. Dox also significantly (p < 0.05) increased expression of a plasmid regulated by an elongation factor 1a promoter (hCEFI) approximately 8-fold. Although administration of Dox before lung gene transfer may not be a clinically viable option, understanding how Dox increases lung gene expression may help to shed light on intracellular bottle-necks to gene transfer, and may help to identify other adjuncts that may be more appropriate for use in man

Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.

To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry

Increased Hepatic Insulin Action in Diet-Induced Obese Mice Following Inhibition of Glucosylceramide Synthase

Obesity is characterized by the accumulation of fat in the liver and other tissues, leading to insulin resistance. We have previously shown that a specific inhibitor of glucosylceramide synthase, which inhibits the initial step in the synthesis of glycosphingolipids (GSLs), improved glucose metabolism and decreased hepatic steatosis in both ob/ob and diet-induced obese (DIO) mice. Here we have determined in the DIO mouse model the efficacy of a related small molecule compound, Genz-112638, which is currently being evaluated clinically for the treatment of Gaucher disease, a lysosomal storage disorder.DIO mice were treated with the Genz-112638 for 12 to 16 weeks by daily oral gavage. Genz-112638 lowered HbA1c levels and increased glucose tolerance. Whole body adiposity was not affected in normal mice, but decreased in drug-treated obese mice. Drug treatment also significantly lowered liver triglyceride levels and reduced the development of hepatic steatosis. We performed hyperinsulinemic-euglycemic clamps on the DIO mice treated with Genz-112638 and showed that insulin-mediated suppression of hepatic glucose production increased significantly compared to the placebo treated mice, indicating a marked improvement in hepatic insulin sensitivity.These results indicate that GSL inhibition in obese mice primarily results in an increase in insulin action in the liver, and suggests that GSLs may have an important role in hepatic insulin resistance in conditions of obesity

Probing exotic phenomena at the interface of nuclear and particle physics with the electric dipole moments of diamagnetic atoms: A unique window to hadronic and semi-leptonic CP violation

The current status of electric dipole moments of diamagnetic atoms which involves the synergy between atomic experiments and three different theoretical areas -- particle, nuclear and atomic is reviewed. Various models of particle physics that predict CP violation, which is necessary for the existence of such electric dipole moments, are presented. These include the standard model of particle physics and various extensions of it. Effective hadron level combined charge conjugation (C) and parity (P) symmetry violating interactions are derived taking into consideration different ways in which a nucleon interacts with other nucleons as well as with electrons. Nuclear structure calculations of the CP-odd nuclear Schiff moment are discussed using the shell model and other theoretical approaches. Results of the calculations of atomic electric dipole moments due to the interaction of the nuclear Schiff moment with the electrons and the P and time-reversal (T) symmetry violating tensor-pseudotensor electron-nucleus are elucidated using different relativistic many-body theories. The principles of the measurement of the electric dipole moments of diamagnetic atoms are outlined. Upper limits for the nuclear Schiff moment and tensor-pseudotensor coupling constant are obtained combining the results of atomic experiments and relativistic many-body theories. The coefficients for the different sources of CP violation have been estimated at the elementary particle level for all the diamagnetic atoms of current experimental interest and their implications for physics beyond the standard model is discussed. Possible improvements of the current results of the measurements as well as quantum chromodynamics, nuclear and atomic calculations are suggested.Comment: 46 pages, 19 tables and 16 figures. A review article accepted for EPJ

CpG-free plasmids confer reduced inflammation and sustained pulmonary gene expression.

Pulmonary delivery of plasmid DNA (pDNA)/cationic liposome complexes is associated with an acute unmethylated CG dinucleotide (CpG)-mediated inflammatory response and brief duration of transgene expression. We demonstrate that retention of even a single CpG in pDNA is sufficient to elicit an inflammatory response, whereas CpG-free pDNA vectors do not. Using a CpG-free pDNA expression vector, we achieved sustained (≥56 d) in vivo transgene expression in the absence of lung inflammation