Immunomodulatory Effects of Bone Marrow-Derived Mesenchymal Stem Cells in a Swine Hemi-Facial Allotransplantation Model

BACKGROUND: In this study, we investigated whether the infusion of bone marrow-derived mesenchymal stem cells (MSCs), combined with transient immunosuppressant treatment, could suppress allograft rejection and modulate T-cell regulation in a swine orthotopic hemi-facial composite tissue allotransplantation (CTA) model. METHODOLOGY/PRINCIPAL FINDINGS: Outbred miniature swine underwent hemi-facial allotransplantation (day 0). Group-I (n = 5) consisted of untreated control animals. Group-II (n = 3) animals received MSCs alone (given on days -1, +1, +3, +7, +14, and +21). Group-III (n = 3) animals received CsA (days 0 to +28). Group-IV (n = 5) animals received CsA (days 0 to +28) and MSCs (days -1, +1, +3, +7, +14, and +21). The transplanted face tissue was observed daily for signs of rejection. Biopsies of donor tissues and recipient blood sample were obtained at specified predetermined times (per 2 weeks post-transplant) or at the time of clinically evident rejection. Our results indicated that the MSC-CsA group had significantly prolonged allograft survival compared to the other groups (P<0.001). Histological examination of the MSC-CsA group displayed the lowest degree of rejection in alloskin and lymphoid gland tissues. TNF-α expression in circulating blood revealed significant suppression in the MSC and MSC-CsA treatment groups, as compared to that in controls. IHC staining showed CD45 and IL-6 expression were significantly decreased in MSC-CsA treatment groups compared to controls. The number of CD4+/CD25+ regulatory T-cells and IL-10 expressions in the circulating blood significantly increased in the MSC-CsA group compared to the other groups. IHC staining of alloskin tissue biopsies revealed a significant increase in the numbers of foxp3(+)T-cells and TGF-β1 positive cells in the MSC-CsA group compared to the other groups. CONCLUSIONS: These results demonstrate that MSCs significantly prolong hemifacial CTA survival. Our data indicate the MSCs did not only suppress inflammation and acute rejection of CTA, but also modulate T-cell regulation and related cytokines expression

Sensing electric fields using single diamond spins

The ability to sensitively detect charges under ambient conditions would be a fascinating new tool benefitting a wide range of researchers across disciplines. However, most current techniques are limited to low-temperature methods like single-electron transistors (SET), single-electron electrostatic force microscopy and scanning tunnelling microscopy. Here we open up a new quantum metrology technique demonstrating precision electric field measurement using a single nitrogen-vacancy defect centre(NV) spin in diamond. An AC electric field sensitivity reaching ~ 140V/cm/\surd Hz has been achieved. This corresponds to the electric field produced by a single elementary charge located at a distance of ~ 150 nm from our spin sensor with averaging for one second. By careful analysis of the electronic structure of the defect centre, we show how an applied magnetic field influences the electric field sensing properties. By this we demonstrate that diamond defect centre spins can be switched between electric and magnetic field sensing modes and identify suitable parameter ranges for both detector schemes. By combining magnetic and electric field sensitivity, nanoscale detection and ambient operation our study opens up new frontiers in imaging and sensing applications ranging from material science to bioimaging

Quantitative Understanding of Probabilistic Behavior of Living Cells Operated by Vibrant Intracellular Networks

For quantitative understanding of probabilistic behaviors of living cells, it is essential to construct a correct mathematical description of intracellular networks interacting with complex cell environments, which has been a formidable task. Here, we present a novel model and stochastic kinetics for an intracellular network interacting with hidden cell environments, employing a complete description of cell state dynamics and its coupling to the system network. Our analysis reveals that various environmental effects on the product number fluctuation of intracellular reaction networks can be collectively characterized by Laplace transform of the time-correlation function of the product creation rate fluctuation with the Laplace variable being the product decay rate. On the basis of the latter result, we propose an efficient method for quantitative analysis of the chemical fluctuation produced by intracellular networks coupled to hidden cell environments. By applying the present approach to the gene expression network, we obtain simple analytic results for the gene expression variability and the environment-induced correlations between the expression levels of mutually noninteracting genes. The theoretical results compose a unified framework for quantitative understanding of various gene expression statistics observed across a number of different systems with a small number of adjustable parameters with clear physical meanings.open1143sciescopu

Inhibition of the tyrosine phosphatase SHP-2 suppresses angiogenesis in vitro and in vivo

Endothelial cell survival is indispensable to maintain endothelial integrity and initiate new vessel formation. We investigated the role of SHP-2 in endothelial cell survival and angiogenesis in vitro as well as in vivo. SHP-2 function in cultured human umbilical vein and human dermal microvascular endothelial cells was inhibited by either silencing the protein expression with antisense-oligodesoxynucleotides or treatment with a pharmacological inhibitor (PtpI IV). SHP-2 inhibition impaired capillary-like structure formation (p < 0.01; n = 8) in vitro as well as new vessel growth ex vivo (p < 0.05; n = 10) and in vivo in the chicken chorioallantoic membrane (p < 0.01, n = 4). Additionally, SHP-2 knock-down abrogated fibroblast growth factor 2 (FGF-2)-dependent endothelial proliferation measured by MTT reduction ( p ! 0.01; n = 12). The inhibitory effect of SHP-2 knock-down on vessel growth was mediated by increased endothelial apoptosis ( annexin V staining, p ! 0.05, n = 9), which was associated with reduced FGF-2-induced phosphorylation of phosphatidylinositol 3-kinase (PI3-K), Akt and extracellular regulated kinase 1/2 (ERK1/2) and involved diminished ERK1/2 phosphorylation after PI3-K inhibition (n=3). These results suggest that SHP-2 regulates endothelial cell survival through PI3-K-Akt and mitogen-activated protein kinase pathways thereby strongly affecting new vessel formation. Thus, SHP-2 exhibits a pivotal role in angiogenesis and may represent an interesting target for therapeutic approaches controlling vessel growth. Copyright (C) 2007 S. Karger AG, Basel

Variable dose interplay effects across radiosurgical apparatus in treating multiple brain metastases

PURPOSE: Normal brain tissue doses have been shown to be strongly apparatus dependent for multi-target stereotactic radiosurgery. In this study, we investigated whether inter-target dose interplay effects across contemporary radiosurgical treatment platforms are responsible for such an observation. METHODS: For the study, subsets ([Formula: see text] and 12) of a total of 12 targets were planned at six institutions. Treatment platforms included the (1) Gamma Knife Perfexion (PFX), (2) CyberKnife, (3) Novalis linear accelerator equipped with a 3.0-mm multi-leaf collimator (MLC), and the (4) Varian Truebeam flattening-filter-free (FFF) linear accelerator also equipped with a 2.5 mm MLC. Identical dose–volume constraints for the targets and critical structures were applied for each apparatus. All treatment plans were developed at individual centers, and the results were centrally analyzed. RESULTS: We found that dose–volume constraints were satisfied by each apparatus with some differences noted in certain structures such as the lens. The peripheral normal brain tissue doses were lowest for the PFX and highest for TrueBeam FFF and CyberKnife treatment plans. Comparing the volumes of normal brain receiving 12 Gy, TrueBeam FFF, Novalis, and CyberKnife were 180–290 % higher than PFX. The mean volume of normal brain-per target receiving 4-Gy increased by approximately 3.0 cc per target for TrueBeam, 2.7 cc per target for CyberKnife, 2.0 cc per target for Novalis, and 0.82 cc per target for PFX. The beam-on time was shortest with the TrueBeam FFF (e.g., 6–9 min at a machine output rate of 1,200 MU/min) and longest for the PFX (e.g., 50–150 mins at a machine output rate of 350 cGy/min). CONCLUSION: The volumes of normal brain receiving 4 and 12 Gy were higher, and increased more swiftly per target, for Linac-based SRS platforms than for PFX. Treatment times were shortest with TrueBeam FFF

Genome-wide association study for acute otitis media in children identifies FNDC1 as disease contributing gene

Acute otitis media (AOM) is among the most common pediatric diseases, and the most frequent reason for antibiotic treatment in children. Risk of AOM is dependent on environmental and host factors, as well as a significant genetic component. We identify genome-wide significance at a locus on 6q25.3 (rs2932989, P(meta)=2.15 × 10(−09)), and show that the associated variants are correlated with the methylation status of the FNDC1 gene (cg05678571, P=1.43 × 10(−06)), and further show it is an eQTL for FNDC1 (P=9.3 × 10(−05)). The mouse homologue, Fndc1, is expressed in middle ear tissue and its expression is upregulated upon lipopolysaccharide treatment. In this first GWAS of AOM and the largest OM genetic study to date, we identify the first genome-wide significant locus associated with AOM

Serum amyloid A primes microglia for ATP-dependent interleukin-1\u3b2 release

Acute-phase response is a systemic reaction to environmental/inflammatory insults and involves production of acute-phase proteins, including serum amyloid A (SAA). Interleukin-1\u3b2 (IL-1\u3b2), a master regulator of neuroinflammation produced by activated inflammatory cells of the myeloid lineage, in particular microglia, plays a key role in the pathogenesis of acute and chronic diseases of the peripheral nervous system and CNS. IL-1\u3b2 release is promoted by ATP acting at the purinergic P2X7 receptor (P2X7R) in cells primed with toll-like receptor (TLR) ligands

Risk factors for severe hand foot mouth disease in Singapore: a case control study

BACKGROUND: Hand foot mouth disease (HFMD) is a common childhood infection that can potentially lead to serious complications. The aim of this study is to identify risk factors of acquiring severe HFMD in our population. METHODS: We performed a case control study using patients admitted to our hospital from August 2004 to July 2014. Cases were patients with severe HFMD disease while controls were age-matched patients obtained from the same year, in a 2:1 ratio. Data comprising demographic characteristics, clinical symptoms and signs, and lab findings were collected. Conditional univariable logistic regression was performed to determine risk factors for severe disease. RESULTS: A total of 24 cases of severe HFMD were identified and matched with 48 controls. Seventeen (70.8 %) cases had central nervous system complications. Seven (29.2 %) had cardiovascular complications without evidence of myocarditis. One patient died of encephalitis. The overall mortality of severe disease is 4 %. Evidence of hypoperfusion, seizure, altered mentation, meningeal irritation, tachycardia, tachypnea, raised absolute neutrophil count and EV-A71 (Enterovirus A71) positivity were significantly associated with a severe course of HFMD. CONCLUSION: In managing children with HFMD, physicians should consider these factors to help identify patients at risk for severe disease

Collective Dynamics of Specific Gene Ensembles Crucial for Neutrophil Differentiation: The Existence of Genome Vehicles Revealed

Cell fate decision remarkably generates specific cell differentiation path among the multiple possibilities that can arise through the complex interplay of high-dimensional genome activities. The coordinated action of thousands of genes to switch cell fate decision has indicated the existence of stable attractors guiding the process. However, origins of the intracellular mechanisms that create “cellular attractor” still remain unknown. Here, we examined the collective behavior of genome-wide expressions for neutrophil differentiation through two different stimuli, dimethyl sulfoxide (DMSO) and all-trans-retinoic acid (atRA). To overcome the difficulties of dealing with single gene expression noises, we grouped genes into ensembles and analyzed their expression dynamics in correlation space defined by Pearson correlation and mutual information. The standard deviation of correlation distributions of gene ensembles reduces when the ensemble size is increased following the inverse square root law, for both ensembles chosen randomly from whole genome and ranked according to expression variances across time. Choosing the ensemble size of 200 genes, we show the two probability distributions of correlations of randomly selected genes for atRA and DMSO responses overlapped after 48 hours, defining the neutrophil attractor. Next, tracking the ranked ensembles' trajectories, we noticed that only certain, not all, fall into the attractor in a fractal-like manner. The removal of these genome elements from the whole genomes, for both atRA and DMSO responses, destroys the attractor providing evidence for the existence of specific genome elements (named “genome vehicle”) responsible for the neutrophil attractor. Notably, within the genome vehicles, genes with low or moderate expression changes, which are often considered noisy and insignificant, are essential components for the creation of the neutrophil attractor. Further investigations along with our findings might provide a comprehensive mechanistic view of cell fate decision