The Λp\bf{\Lambda p} interaction studied via femtoscopy in p + Nb reactions at sNN=3.18 GeV\mathbf{\sqrt{s_{NN}}=3.18} ~\mathrm{\bf{GeV}}

We report on the first measurement of $p\Lambda$ and $pp$ correlations via the femtoscopy method in p+Nb reactions at $\mathrm{\sqrt{s_{NN}}=3.18} ~\mathrm{GeV}$, studied with the High Acceptance Di-Electron Spectrometer (HADES). By comparing the experimental correlation function to model calculations, a source size for $pp$ pairs of $r_{0,pp}=2.02 \pm 0.01(\mathrm{stat})^{+0.11}_{-0.12} (\mathrm{sys}) ~\mathrm{fm}$ and a slightly smaller value for $p\Lambda$ of $r_{0,\Lambda p}=1.62 \pm 0.02(\mathrm{stat})^{+0.19}_{-0.08}(\mathrm{sys}) ~\mathrm{fm}$ is extracted. Using the geometrical extent of the particle emitting region, determined experimentally with $pp$ correlations as reference together with a source function from a transport model, it is possible to study different sets of scattering parameters. The $p\Lambda$ correlation is proven sensitive to predicted scattering length values from chiral effective field theory. We demonstrate that the femtoscopy technique can be used as valid alternative to the analysis of scattering data to study the hyperon-nucleon interaction.Comment: 12 pages, 11 figure

Developmental Stage, Phenotype, and Migration Distinguish Naive- and Effector/Memory-like CD4+ Regulatory T Cells

Regulatory T cells (Tregs) fulfill a central role in immune regulation. We reported previously that the integrin αEβ7 discriminates distinct subsets of murine CD4+ regulatory T cells. Use of this marker has now helped to unravel a fundamental dichotomy among regulatory T cells. αE−CD25+ cells expressed L-selectin and CCR7, enabling recirculation through lymphoid tissues. In contrast, αE-positive subsets (CD25+ and CD25−) displayed an effector/memory phenotype expressing high levels of E/P-selectin–binding ligands, multiple adhesion molecules as well as receptors for inflammatory chemokines, allowing efficient migration into inflamed sites. Accordingly, αE-expressing cells were found to be the most potent suppressors of inflammatory processes in disease models such as antigen-induced arthritis

Ectopic Expression of Neurogenin 2 Alone is Sufficient to Induce Differentiation of Embryonic Stem Cells into Mature Neurons

Recent studies show that combinations of defined key developmental transcription factors (TFs) can reprogram somatic cells to pluripotency or induce cell conversion of one somatic cell type to another. However, it is not clear if single genes can define a cell̀s identity and if the cell fate defining potential of TFs is also operative in pluripotent stem cells in vitro. Here, we show that ectopic expression of the neural TF Neurogenin2 (Ngn2) is sufficient to induce rapid and efficient differentiation of embryonic stem cells (ESCs) into mature glutamatergic neurons. Ngn2-induced neuronal differentiation did not require any additional external or internal factors and occurred even under pluripotency-promoting conditions. Differentiated cells displayed neuron-specific morphology, protein expression, and functional features, most importantly the generation of action potentials and contacts with hippocampal neurons. Gene expression analyses revealed that Ngn2-induced in vitro differentiation partially resembled neurogenesis in vivo, as it included specific activation of Ngn2 target genes and interaction partners. These findings demonstrate that a single gene is sufficient to determine cell fate decisions of uncommitted stem cells thus giving insights into the role of key developmental genes during lineage commitment. Furthermore, we present a promising tool to improve directed differentiation strategies for applications in both stem cell research and regenerative medicine

Conditional Expression of Wnt4 during Chondrogenesis Leads to Dwarfism in Mice

Wnts are expressed in the forming long bones, suggesting roles in skeletogenesis. To examine the action of Wnts in skeleton formation, we developed a genetic system to conditionally express Wnt4 in chondrogenic tissues of the mouse. A mouse Wnt4 cDNA was introduced into the ubiquitously expressed Rosa26 (R26) locus by gene targeting in embryonic stem (ES) cells. The expression of Wnt4 from the R26 locus was blocked by a neomycin selection cassette flanked by loxP sites (floxneo) that was positioned between the Rosa26 promoter and the Wnt4 cDNA, creating the allele designated R26(floxneoWnt4). Wnt4 expression was activated during chondrogenesis using Col2a1-Cre transgenic mice that express Cre recombinase in differentiating chondrocytes. R26(floxneoWnt4); Col2a1-Cre double heterozygous mice exhibited a growth deficiency, beginning approximately 7 to 10 days after birth, that resulted in dwarfism. In addition, they also had craniofacial abnormalities, and delayed ossification of the lumbar vertebrae and pelvic bones. Histological analysis revealed a disruption in the organization of the growth plates and a delay in the onset of the primary and secondary ossification centers. Molecular studies showed that Wnt4 overexpression caused decreased proliferation and altered maturation of chondrocytes. In addition, R26(floxneoWnt4); Col2a1-Cre mice had decreased expression of vascular endothelial growth factor (VEGF). These studies demonstrate that Wnt4 overexpression leads to dwarfism in mice. The data indicate that Wnt4 levels must be regulated in chondrocytes for normal growth plate development and skeletogenesis. Decreased VEGF expression suggests that defects in vascularization may contribute to the dwarf phenotype

B1 SOX Coordinate Cell Specification with Patterning and Morphogenesis in the Early Zebrafish Embryo

The B1 SOX transcription factors SOX1/2/3/19 have been implicated in various processes of early embryogenesis. However, their regulatory functions in stages from the blastula to early neurula remain largely unknown, primarily because loss-of-function studies have not been informative to date. In our present study, we systematically knocked down the B1 sox genes in zebrafish. Only the quadruple knockdown of the four B1 sox genes sox2/3/19a/19b resulted in very severe developmental abnormalities, confirming that the B1 sox genes are functionally redundant. We characterized the sox2/3/19a/19b quadruple knockdown embryos in detail by examining the changes in gene expression through in situ hybridization, RT–PCR, and microarray analyses. Importantly, these phenotypic analyses revealed that the B1 SOX proteins regulate the following distinct processes: (1) early dorsoventral patterning by controlling bmp2b/7; (2) gastrulation movements via the regulation of pcdh18a/18b and wnt11, a non-canonical Wnt ligand gene; (3) neural differentiation by regulating the Hes-class bHLH gene her3 and the proneural-class bHLH genes neurog1 (positively) and ascl1a (negatively), and regional transcription factor genes, e.g., hesx1, zic1, and rx3; and (4) neural patterning by regulating signaling pathway genes, cyp26a1 in RA signaling, oep in Nodal signaling, shh, and mdkb. Chromatin immunoprecipitation analysis of the her3, hesx1, neurog1, pcdh18a, and cyp26a1 genes further suggests a direct regulation of these genes by B1 SOX. We also found an interesting overlap between the early phenotypes of the B1 sox quadruple knockdown embryos and the maternal-zygotic spg embryos that are devoid of pou5f1 activity. These findings indicate that the B1 SOX proteins control a wide range of developmental regulators in the early embryo through partnering in part with Pou5f1 and possibly with other factors, and suggest that the B1 sox functions are central to coordinating cell fate specification with patterning and morphogenetic processes occurring in the early embryo

ZIC1 Is Downregulated through Promoter Hypermethylation, and Functions as a Tumor Suppressor Gene in Colorectal Cancer

The transcription factor, Zinc finger of the cerebellum (ZIC1), plays a crucial role in vertebrate development. Recently, ZIC1 has also been found to participate in the progression of human cancers, including medulloblastomas, endometrial cancers, and mesenchymal neoplasms. However, the function of ZIC1 in colon cancer progression has not been defined. In this study, we demonstrate ZIC1 to be silenced or significantly downregulated in colon cancer cell lines. These effects were reversed by demethylation treatment with 5-aza-2′-deoxycytidine (Aza). ZIC1 expression is also significantly downregulated in primary colorectal cancer tissues relative to adjacent non-tumor tissues (p = 0.0001). Furthermore, methylation of ZIC1 gene promoter is frequently detected in primary tumor tissues (85%, 34/40), but not in adjacent non-tumor tissues. Ectopic expression of ZIC1 suppresses cell proliferation and induces apoptosis, which is associated with MAPK and PI3K/Akt pathways, as well as the Bcl-xl/Bad/Caspase3 cascade. To identify target candidates of ZIC1, we employed cDNA microarray and found that 337 genes are downregulated and 95 genes upregulated by ectopic expression of ZIC1, which were verified by 10 selected gene expressions by qRT-PCR. Taken together, our results suggest that ZIC1 may potentially function as a tumor suppressor gene, which is downregulated through promoter hypermethylation in colorectal cancers

Measurement of global polarization of {\Lambda} hyperons in few-GeV heavy-ion collisions

The global polarization of {\Lambda} hyperons along the total orbital angular momentum of a relativistic heavy-ion collision is presented based on the high statistics data samples collected in Au+Au collisions at \sqrt{s_{NN}} = 2.4 GeV and Ag+Ag at 2.55 GeV with the High-Acceptance Di-Electron Spectrometer (HADES) at GSI, Darmstadt. This is the first measurement below the strangeness production threshold in nucleon-nucleon collisions. Results are reported as a function of the collision centrality as well as a function of the hyperon transverse momentum (p_T) and rapidity (y_{CM}) for the range of centrality 0--40%. We observe a strong centrality dependence of the polarization with an increasing signal towards peripheral collisions. For mid-central (20--40%) collisions the polarization magnitudes are (%) = 6.0 \pm 1.3 (stat.) \pm 2.0 (syst.) for Au+Au and (%) = 4.6 \pm 0.4 (stat.) \pm 0.5 (syst.) for Ag+Ag, which are the largest values observed so far. This observation thus provides a continuation of the increasing trend previously observed by STAR and contrasts expectations from recent theoretical calculations predicting a maximum in the region of collision energies about 3 GeV. The observed polarization is of a similar magnitude as predicted by 3D fluid dynamics and the UrQMD plus thermal vorticity model and significantly above results from the AMPT model.Comment: 8 pages, 4 figure

Inclusive e+^+e−^- production in collisions of pions with protons and nuclei in the second resonance region of baryons

Inclusive e$^+$e$^-$ production has been studied with HADES in $\pi^-$ + p, $\pi^-$ + C and $\pi^- + \mathrm{CH}_2$ reactions, using the GSI pion beam at $\sqrt{s_{\pi p}}$ = 1.49 GeV. Invariant mass and transverse momentum distributions have been measured and reveal contributions from Dalitz decays of $\pi^0$, $\eta$ mesons and baryon resonances. The transverse momentum distributions are very sensitive to the underlying kinematics of the various processes. The baryon contribution exhibits a deviation up to a factor seven from the QED reference expected for the dielectron decay of a hypothetical point-like baryon with the production cross section constrained from the inverse $\gamma$ n$\rightarrow \pi^-$ p reaction. The enhancement is attributed to a strong four-momentum squared dependence of the time-like electromagnetic transition form factors as suggested by Vector Meson Dominance (VMD). Two versions of the VMD, that differ in the photon-baryon coupling, have been applied in simulations and compared to data. VMD1 (or two-component VMD) assumes a coupling via the $\rho$ meson and a direct coupling of the photon, while in VMD2 (or strict VMD) the coupling is only mediated via the $\rho$ meson. The VMD2 model, frequently used in transport calculations for dilepton decays, is found to overestimate the measured dielectron yields, while a good description of the data can be obtained with the VMD1 model assuming no phase difference between the two amplitudes. Similar descriptions have also been obtained using a time-like baryon transition form factor model where the pion cloud plays the major role.Comment: (HADES collaboration