Franck-Condon Factors and Radiative Lifetime of the A^{2}\Pi_{1/2} - X^{2}\Sigma^{+} Transition of Ytterbium Monoflouride, YbF

The fluorescence spectrum resulting from laser excitation of the A^{2}\Pi_{1/2} - X^{2}\Sigma^{+} (0,0) band of ytterbium monofluoride, YbF, has been recorded and analyzed to determine the Franck-Condon factors. The measured values are compared with those predicted from Rydberg-Klein-Rees (RKR) potential energy curves. From the fluorescence decay curve the radiative lifetime of the A^{2}\Pi_{1/2} state is measured to be 28\pm2 ns, and the corresponding transition dipole moment is 4.39\pm0.16 D. The implications for laser cooling YbF are discussed.Comment: 5 pages, 5 figure

Transplantation of Autologous Adipose Stem Cells Lacks Therapeutic Efficacy in the Experimental Autoimmune Encephalomyelitis Model

Multiple sclerosis (MS), characterized by chronic inflammation, demyelination, and axonal damage, is a complicated neurological disease of the human central nervous system. Recent interest in adipose stromal/stem cell (ASCs) for the treatment of CNS diseases has promoted further investigation in order to identify the most suitable ASCs. To investigate whether MS affects the biologic properties of ASCs and whether autologous ASCs from MS-affected sources could serve as an effective source for stem cell therapy, cells were isolated from subcutaneous inguinal fat pads of mice with established experimental autoimmune encephalomyelitis (EAE), a murine model of MS. ASCs from EAE mice and their syngeneic wildtype mice were cultured, expanded, and characterized for their cell morphology, surface antigen expression, osteogenic and adipogenic differentiation, colony forming units, and inflammatory cytokine and chemokine levels in vitro. Furthermore, the therapeutic efficacy of the cells was assessed in vivo by transplantation into EAE mice. The results indicated that the ASCs from EAE mice displayed a normal phenotype, typical MSC surface antigen expression, and in vitro osteogenic and adipogenic differentiation capacity, while their osteogenic differentiation capacity was reduced in comparison with their unafflicted control mice. The ASCs from EAE mice also demonstrated increased expression of pro-inflammatory cytokines and chemokines, specifically an elevation in the expression of monocyte chemoattractant protein-1 and keratin chemoattractant. In vivo, infusion of wild type ASCs significantly ameliorate the disease course, autoimmune mediated demyelination and cell infiltration through the regulation of the inflammatory responses, however, mice treated with autologous ASCs showed no therapeutic improvement on the disease progression

The Neuroanatomical Basis of Two Subcomponents of Rumination: A VBM Study

Rumination is a trait that includes two subcomponents, namely brooding and reflective pondering, respectively construed as maladaptive and adaptive response styles to negative experiences. Existing evidence indicates that rumination in general is associated with structural and functional differences in the anterior cingulate cortex (ACC) and the dorsal lateral prefrontal cortex (DLPFC). However, conclusive evidence on the specific neural structural basis of each of the two subcomponents is lacking. In this voxel-based morphometry study, we investigated the independent and specific neural structural basis of brooding and reflective pondering in 30 healthy young adults, who belonged to high or low brooding or reflective pondering groups. Consistent with past research, modest but significant positive correlation was found between brooding and reflective pondering. When controlling for reflective pondering, high-brooding group showed increased gray matter volumes in the left DLPFC and ACC. Further analysis on extracted gray matter values showed that gray matter of the same DLPFC and ACC regions also showed significant negative effects of reflective pondering. Taken together, our findings indicate that the two subcomponents of rumination might share some common processes yet also have distinct neural basis. In view of the significant roles of the left DLPFC and ACC in attention and self-related emotional processing/regulation, our findings provide insight into how the potentially shared and distinct cognitive, affective and neural processes of brooding and reflective pondering can be extended to clinical populations to further elucidate the neurobehavioral relationships between rumination and prefrontal abnormality

Age of the Donor Reduces the Ability of Human Adipose-Derived Stem Cells to Alleviate Symptoms in the Experimental Autoimmune Encephalomyelitis Mouse Model

There is a significant clinical need for effective therapies for primary progressive multiple sclerosis, which presents later in life (i.e., older than 50 years) and has symptoms that increase in severity without remission. With autologous mesenchymal stem cell therapy now in the early phases of clinical trials for all forms of multiple sclerosis (MS), it is necessary to determine whether autologous stem cells from older donors have therapeutic effectiveness. In this study, the therapeutic efficacy of human adipose-derived mesenchymal stem cells (ASCs) from older donors was directly compared with that of cells from younger donors for disease prevention. Mice were induced with chronic experimental autoimmune encephalomyelitis (EAE) using the myelin oligodendrocyte glycoprotein35-55 peptide and treated before disease onset with ASCs derived from younger ( \u3c 35 years) or older ( \u3e 60 years) donors. ASCs from older donors failed to ameliorate the neurodegeneration associated with EAE, and mice treated with older donor cells had increased central nervous system inflammation, demyelination, and splenocyte proliferation in vitro compared with the mice receiving cells from younger donors. Therefore, the results of this study demonstrated that donor age significantly affects the ability of human ASCs to provide neuroprotection, immunomodulation, and/or remyelination in EAE mice. The age-related therapeutic differences corroborate recent findings that biologic aging occurs in stem cells, and the differences are supported by evidence in this study that older ASCs, compared with younger donor cells, secrete less hepatocyte growth factor and other bioactive molecules when stimulated in vitro. These results highlight the need for evaluation of autologous ASCs derived from older patients when used as therapy for MS

nature biotechnology VOLUME

To better understand the molecular mechanisms and genetic basis of human disease, we systematically examine relationships between 3,949 genes, 62,663 mutations and 3,453 associated disorders by generating a three-dimensional, structurally resolved human interactome. This network consists of 4,222 high-quality binary protein-protein interactions with their atomic-resolution interfaces. We find that in-frame mutations (missense point mutations and in-frame insertions and deletions) are enriched on the interaction interfaces of proteins associated with the corresponding disorders, and that the disease specificity for different mutations of the same gene can be explained by their location within an interface. We also predict 292 candidate genes for 694 unknown disease-to-gene associations with proposed molecular mechanism hypotheses. This work indicates that knowledge of how in-frame disease mutations alter specific interactions is critical to understanding pathogenesis. Structurally resolved interaction networks should be valuable tools for interpreting the wealth of data being generated by large-scale structural genomics and disease association studies. Over the past few decades, a tremendous amount of resources and effort have been invested in mapping human disease loci genetically and later physically 1 . Since the completion of the human genome sequence, especially with advances in genome-wide association studies and ongoing cancer genome sequencing projects, an impressive list of disease-associated genes and their mutations have been produced 2 . However, it has rarely been possible to translate this wealth of information on individual mutations and their association with disease into biological or therapeutic insights 3 . Most of the drugs approved by the US Food and Drug Administration today are palliative 4 -they merely treat symptoms, rather than targeting specific genes or pathways responsible, even if associated genes are known. One main reason for this lack of success is the complex genotype-tophenotype relationships among diseases and their associated genes and mutations. In particular, (i) the same gene can be associated with multiple disorders (gene pleiotropy); and (ii) mutations in any one of many genes can cause the same clinical disorder (locus heterogeneity). For example, mutations in TP53 are linked to 32 clinically distinguishable forms of cancer and cancer-related disorders, whereas mutations in any of at least 12 different genes can lead to long QT syndrome. With the publication of several large-scale protein-protein interaction networks in human 5-8 , researchers have recently begun to use complex cellular networks to explore these genotype-to-phenotype relationships 2,9 , on the basis that many proteins function by interacting with other proteins. However, most analyses model proteins as graph-theoretical nodes, ignoring the structural details of individual proteins and the spatial constraints of their interactions. Here, we investigate on a large-scale the underlying molecular mechanisms for the complex genotype-to-phenotype relationships by integrating three-dimensional (3D) atomic-level protein structure information with high-quality large-scale protein-protein interaction data. Within the framework of this structurally resolved protein interactome, we examine the relationships among human diseases and their associated genes and mutations. RESULTS Structurally resolved protein interactome for human disease We first combined 12,577 reliable literature-curated binary interactions filtered from six widely used databases 10-15 (Online Methods) and 8,173 well-verified, high-throughput, yeast two-hybrid (Y2H) interactions Next, we structurally resolved the interfaces of these interactions using a homology modeling approach 16 . We used both iPfam 17 and 3did 18 to identify the interfaces of two interacting proteins by mapping them to known atomic-resolution 3D structures of interactions in the Protein Data Bank (PDB) Finally, to compile a comprehensive list of disease-associated genes and their mutations, we combined information from both Online Mendelian Inheritance in Man (OMIM

Obesity Associated Alterations in the Biology of Adipose Stem Cells Mediate Enhanced Tumorigenesis by Estrogen Dependent Pathways

Introduction: Obesity has been associated with increased incidence and mortality of breast cancer. While the precise correlation between obesity and breast cancer remains to be determined, recent studies suggest that adipose tissue and adipose stem cells (ASCs) influence breast cancer tumorigenesis and tumor progression. Methods: Breast cancer cells lines were co-cultured with ASCs (n = 24), categorized based on tissue site of origin and body mass index (BMI), and assessed for enhanced proliferation, alterations in gene expression profile with PCR arrays, and enhanced tumorigenesis in immunocompromised mice. The gene expression profile of ASCs was assess with PCR arrays and qRT-PCR and confirmed with Western blot analysis. Inhibitory studies were conducted by delivering estrogen antagonist ICI182,780, leptin neutralizing antibody, or aromatase inhibitor letrozole and assessing breast cancer cell proliferation. To assess the role of leptin in human breast cancers, Oncomine and Kaplan Meier plot analyses were conducted. Results: ASCs derived from the abdominal subcutaneous adipose tissue of obese subjects (BMI \u3e 30) enhanced breast cancer cell proliferation in vitro and tumorigenicity in vivo . These findings were correlated with changes in the gene expression profile of breast cancer cells after co-culturing with ASCs, particularly in estrogen receptor-alpha (ESR1) and progesterone receptor (PGR) expression. Analysis of the gene expression profile of the four groups of ASCs revealed obesity induced alterations in several key genes, including leptin (LEP). Blocking estrogen signaling with ICI182,780, leptin neutralizing antibody, or letrozole diminished the impact of ASCs derived from obese subjects. Women diagnosed with estrogen receptor/progesterone receptor positive (ER+/PR+) breast cancers that also expressed high levels of leptin had poorer prognosis than women with low leptin expression. Conclusion: ASCs isolated from the abdomen of obese subjects demonstrated increased expression of leptin, through estrogen stimulation, which increased breast cancer cell proliferation. The results from this study demonstrate that abdominal obesity induces significant changes in the biological properties of ASCs and that these alterations enhance ER+/PR+ breast cancer tumorigenesis through estrogen dependent pathways

Comparison of Human Adult Stem Cells from Adipose Tissue and Bone Marrow in the Treatment of Experimental Autoimmune Encephalomyelitis

Introduction. While administration of ex vitro culture-expanded stem cells has been used to study immunosuppressive mechanisms in multiple models of autoimmune diseases, less is known about the uncultured, nonexpanded stromal vascular fraction (SVF)-based therapy. The SVF is composed of a heterogeneous population of cells and has been used clinically to treat acute and chronic diseases, alleviating symptoms in a range of tissues and organs. Methods. In this study, the ability of human SVF cells was compared with culture-expanded adipose stem cells (ASCs) and bone-derived marrow stromal cells (BMSCs) as a treatment of myelin oligodendrocyte glycoprotein (35-55)-induced experimental autoimmune encephalitis in C57Bl/6J mice, a well-studied multiple sclerosis model (MS). A total of 1 x 106 BMSCs, ASCs, or SVF cells were administered intraperitoneally concomitantly with the induction of disease. Mice were monitored daily for clinical signs of disease by three independent, blinded investigators and rated on a scale of 0 to 5. Spinal cords were obtained after euthanasia at day 30 and processed for histological staining using luxol fast blue, toluidine blue, and hematoxylin and eosin to measure myelin and infiltrating immune cells. Blood was collected from mice at day 30 and analyzed by enzyme-linked immunosorbent assay to measure serum levels of inflammatory cytokines. Results: The data indicate that intraperitoneal administration of all cell types significantly ameliorates the severity of disease. Furthermore, the data also demonstrate, for the first time, that the SVF was as effective as the more commonly cultured BMSCs and ASCs in an MS model. All cell therapies also demonstrated a similar reduction in tissue damage, inflammatory infiltrates, and sera levels of IFNγ and IL-12. While IFNγ levels were reduced to comparable levels between treatment groups, levels of IL-12 were significantly lower in SVF-treated than BMSC-treated or ASC-treated mice. Conclusions: Based on these data, it is evident that SVF cells have relevant therapeutic potential in an animal model of chronic MS and might represent a valuable tool for stem cell-based therapy in chronic inflammatory disease of the central nervous system. SVF offers advantages of direct and rapid isolation procedure in a xenobiotic-free environment

Administration of Murine Stromal Vascular Fraction Ameliorates Chronic Experimental Autoimmune Encephalomyelitis

Administration of adipose-derived stromal/stem cells (ASCs) represents a promising therapeutic approach for autoimmune diseases since they have been shown to have immunomodulatory properties. The uncultured, nonexpanded counterpart of ASCs, the stromal vascular fraction (SVF), is composed of a heterogeneous mixture of cells. Although administration of ex vivo culture-expanded ASCs has been used to study immunomodulatory mechanisms in multiple models of autoimmune diseases, less is known about SVF-based therapy. The ability of murine SVF cells to treat myelin oligodendrocyte glycoprotein35-55-induced experimental autoimmune encephalitis (EAE) was compared with that of culture-expanded ASCs in C57Bl/6J mice. A total of 1 x 106 SVF cells or ASCs were administered intraperitoneally concomitantly with the induction of disease. The data indicate that intraperitoneal administration of ASCs significantly ameliorated the severity of disease course. They also demonstrate, for the first time, that the SVF effectively inhibited disease severity and was statistically more effective than ASCs. Both cell therapies also demonstrated a reduction in tissue damage, a decrease in inflammatory infiltrates, and a reduction in sera levels of interferon-γ and interleukin-12. Based on these data, SVF cells effectively inhibited EAE disease progression more than culture-expanded ASCs

<i>APETALA2</i> functions as a temporal factor together with <i>BLADE-ON-PETIOLE2</i> and <i>MADS29</i> to control flower and grain development in barley

Cereal grain develops from fertilised florets. Alterations in floret and grain development greatly influence grain yield and quality. Despite this, little is known about the underlying genetic control of these processes, especially in key temperate cereals such as barley and wheat. Using a combination of near-isogenic mutant comparisons, gene editing and genetic analyses, we reveal that HvAPETALA2 (HvAP2) controls floret organ identity, floret boundaries, and maternal tissue differentiation and elimination during grain development. These new roles of HvAP2 correlate with changes in grain size and HvAP2-dependent expression of specific HvMADS-box genes, including the B-sister gene, HvMADS29 Consistent with this, gene editing demonstrates that HvMADS29 shares roles with HvAP2 in maternal tissue differentiation. We also discovered that a gain-of-function HvAP2 allele masks changes in floret organ identity and grain size due to loss of barley LAXATUM.A/ BLADE-ON-PETIOLE2 (HvBOP2) gene function. Taken together, we reveal novel, pleiotropic roles and regulatory interactions for an APETALA2-like gene controlling floret and grain development in a temperate cereal.Jennifer R. Shoesmith, Charles Ugochukwu Solomon, Xiujuan Yang, Laura G. Wilkinson, Scott Sheldrick, Ewan van Eijden ... et al