Suppression of ILC2 differentiation from committed T cell precursors by E protein transcription factors

Current models propose that group 2 innate lymphoid cells (ILC2s) are generated in the bone marrow. Here, we demonstrate that subsets of these cells can differentiate from multipotent progenitors and committed T cell precursors in the thymus, both in vivo and in vitro. These thymic ILC2s exit the thymus, circulate in the blood, and home to peripheral tissues. Ablation of E protein transcription factors greatly promotes the ILC fate while impairing B and T cell development. Consistently, a transcriptional network centered on the ZBTB16 transcription factor and IL-4 signaling pathway is highly up-regulated due to E protein deficiency. Our results show that ILC2 can still arise from what are normally considered to be committed T cell precursors, and that this alternative cell fate is restrained by high levels of E protein activity in these cells. Thymus-derived lung ILC2s of E protein-deficient mice show different transcriptomes, proliferative properties, and cytokine responses from wild-type counterparts, suggesting potentially distinct functions

The effect of 14 weeks of vitamin D3 supplementation on antimicrobial peptides and proteins in athletes

Heavy training is associated with increased respiratory infection risk and antimicrobial proteins are important in defence against oral and respiratory tract infections. We examined the effect of 14 weeks of vitamin D3 supplementation (5000 IU/day) on the resting plasma cathelicidin concentration and the salivary secretion rates of secretory immunoglobulin A (SIgA), cathelicidin, lactoferrin and lysozyme in athletes during a winter training period. Blood and saliva were obtained at the start of the study from 39 healthy men who were randomly allocated to vitamin D3 supplement or placebo. Blood samples were also collected at the end of the study; saliva samples were collected after 7 and 14 weeks. Plasma total 25(OH)D concentration increased by 130% in the vitamin D3 group and decreased by 43% in the placebo group (both P=0.001). The percentage change of plasma cathelicidin concentration in the vitamin D3 group was higher than in the placebo group (P=0.025). Only in the vitamin D3 group, the saliva SIgA and cathelicidin secretion rates increased over time (both P=0.03). A daily 5000 IU vitamin D3 supplement has a beneficial effect in up-regulating the expression of SIgA and cathelicidin in athletes during a winter training period which could improve resistance to respiratory infections

Disrupted CXCR2 Signaling in Oligodendroglia Lineage Cells Enhances Myelin Repair in a Viral Model of Multiple Sclerosis.

CXCR2 is a chemokine receptor expressed on oligodendroglia that has been implicated in the pathogenesis of neuroinflammatory demyelinating diseases as well as enhancement of the migration, proliferation, and myelin production by oligodendroglia. Using an inducible proteolipid protein (Plp) promoter-driven Cre-loxP recombination system, we were able to assess how timed ablation of Cxcr2 in oligodendroglia affected disease following intracranial infection with the neurotropic JHM strain of mouse hepatitis virus (JHMV). Generation of Plp-Cre-ER(T)::Cxcr2flox/flox transgenic mice (termed Cxcr2-CKO mice) allows for Cxcr2 to be silenced in oligodendrocytes in adult mice following treatment with tamoxifen. Ablation of oligodendroglia Cxcr2 did not influence clinical severity in response to intracranial infection with JHMV. Infiltration of activated T cells or myeloid cells into the central nervous system (CNS) was not affected, nor was the ability to control viral infection. In addition, the severity of demyelination was similar between tamoxifen-treated mice and vehicle-treated controls. Notably, deletion of Cxcr2 resulted in increased remyelination, as assessed by g-ratio (the ratio of the inner axonal diameter to the total outer fiber diameter) calculation, compared to that in vehicle-treated control mice. Collectively, our findings argue that CXCR2 signaling in oligodendroglia is dispensable with regard to contributing to neuroinflammation, but its deletion enhances remyelination in a preclinical model of the human demyelinating disease multiple sclerosis (MS).IMPORTANCE Signaling through the chemokine receptor CXCR2 in oligodendroglia is important for developmental myelination in rodents, while chemical inhibition or nonspecific genetic deletion of CXCR2 appears to augment myelin repair in animal models of the human demyelinating disease multiple sclerosis (MS). To better understand the biology of CXCR2 signaling on oligodendroglia, we generated transgenic mice in which Cxcr2 is selectively ablated in oligodendroglia upon treatment with tamoxifen. Using a viral model of neuroinflammation and demyelination, we demonstrate that genetic silencing of CXCR2 on oligodendroglia did not affect clinical disease, neuroinflammation, or demyelination, yet there was increased remyelination. These findings support and extend previous findings suggesting that targeting CXCR2 may offer a therapeutic avenue for enhancing remyelination in patients with demyelinating diseases

A Durable, Realistic, Low-Cost Training Model for Percutaneous Renal Access Using Ballistic Gelatin

The purpose of this study was to design and implement a durable, realistic, and low-cost phantom kidney model for percutaneous renal access that could improve a novice surgeon’s technical skills without compromising patient safety

Deuterium Chemodynamics of Massive Pre-Stellar Cores

High levels of deuterium fractionation of $\rm N_2H^+$ (i.e., $\rm D_{frac}^{N_2H^+} \gtrsim 0.1$) are often observed in pre-stellar cores (PSCs) and detection of $\rm N_2D^+$ is a promising method to identify elusive massive PSCs. However, the physical and chemical conditions required to reach such high levels of deuteration are still uncertain, as is the diagnostic utility of $\rm N_2H^+$ and $\rm N_2D^+$ observations of PSCs. We perform 3D magnetohydrodynamics simulations of a massive, turbulent, magnetised PSC, coupled with a sophisticated deuteration astrochemical network. Although the core has some magnetic/turbulent support, it collapses under gravity in about one freefall time, which marks the end of the simulations. Our fiducial model achieves relatively low $\rm D_{frac}^{N_2H^+} \sim 0.002$ during this time. We then investigate effects of initial ortho-para ratio of $\rm H_2$ ($\rm OPR^{H_2}$), temperature, cosmic ray (CR) ionization rate, CO and N-species depletion factors and prior PSC chemical evolution. We find that high CR ionization rates and high depletion factors allow the simulated $\rm D_{frac}^{N_2H^+}$ and absolute abundances to match observational values within one freefall time. For $\rm OPR^{H_2}$, while a lower initial value helps the growth of $\rm D_{frac}^{N_2H^+}$, the spatial structure of deuteration is too widespread compared to observed systems. For an example model with elevated CR ionization rates and significant heavy element depletion, we then study the kinematic and dynamic properties of the core as traced by its $\rm N_2D^+$ emission. The core, undergoing quite rapid collapse, exhibits disturbed kinematics in its average velocity map. Still, because of magnetic support, the core often appears kinematically sub-virial based on its $\rm N_2D^+$ velocity dispersion.Comment: 25 pages, 20 figures, 2 tables, accepted for publication in MNRAS, comments welcom

Selectron Studies at e-e- and e+e- Colliders

Selectrons may be studied in both e-e- and e+e- collisions at future linear colliders. Relative to e+e-, the e-e- mode benefits from negligible backgrounds and \beta threshold behavior for identical selectron pair production, but suffers from luminosity degradation and increased initial state radiation and beamstrahlung. We include all of these effects and compare the potential for selectron mass measurements in the two modes. The virtues of the e-e- collider far outweigh its disadvantages. In particular, the selectron mass may be measured to 100 MeV with a total integrated luminosity of 1 fb^-1, while more than 100 fb^-1 is required in e+e- collisions for similar precision.Comment: 16 pages, 11 figure

Probing Lepton Flavor Violation at Future Colliders

Supersymmetric theories with significant lepton flavor violation have $\tilde{e}$ and $\tilde{\mu}$ nearly degenerate. In this case, pair production of $\tilde{e}^+ \tilde{e}^-$ and $\tilde{\mu}^+ \tilde{\mu}^-$ at LEPII and at the Next Linear Collider leads to the phenomenon of slepton oscillations, which is analogous to neutrino oscillations. The reach in $\Delta m^2$ and $\sin^2 2 \theta$ gives a probe of lepton flavor violation which is significantly more powerful than the current bounds from rare processes, such as $\mu \to e\gamma$. Polarizable $e^-$ beams and the $e^-e^-$ mode at the NLC are found to be promising options.Comment: 10 pages, 3 figures, RevTeX, minor corrections, published versio

FAP-overexpressing fibroblasts produce an extracellular matrix that enhances invasive velocity and directionality of pancreatic cancer cells

<p>Abstract</p> <p>Background</p> <p>Alterations towards a permissive stromal microenvironment provide important cues for tumor growth, invasion, and metastasis. In this study, Fibroblast activation protein (FAP), a serine protease selectively produced by tumor-associated fibroblasts in over 90% of epithelial tumors, was used as a platform for studying tumor-stromal interactions.</p> <p>We tested the hypothesis that FAP enzymatic activity locally modifies stromal ECM (extracellular matrix) components thus facilitating the formation of a permissive microenvironment promoting tumor invasion in human pancreatic cancer.</p> <p>Methods</p> <p>We generated a tetracycline-inducible FAP overexpressing fibroblastic cell line to synthesize an <it>in vivo</it>-like 3-dimensional (3D) matrix system which was utilized as a stromal landscape for studying matrix-induced cancer cell behaviors. A FAP-dependent topographical and compositional alteration of the ECM was characterized by measuring the relative orientation angles of fibronectin fibers and by Western blot analyses. The role of FAP in the matrix-induced permissive tumor behavior was assessed in Panc-1 cells in assorted matrices by time-lapse acquisition assays. Also, FAP⁺matrix-induced regulatory molecules in cancer cells were determined by Western blot analyses.</p> <p>Results</p> <p>We observed that FAP remodels the ECM through modulating protein levels, as well as through increasing levels of fibronectin and collagen fiber organization. FAP-dependent architectural/compositional alterations of the ECM promote tumor invasion along characteristic parallel fiber orientations, as demonstrated by enhanced directionality and velocity of pancreatic cancer cells on FAP⁺matrices. This phenotype can be reversed by inhibition of FAP enzymatic activity during matrix production resulting in the disorganization of the ECM and impeded tumor invasion. We also report that the FAP⁺ matrix-induced tumor invasion phenotype is β₁-integrin/FAK mediated.</p> <p>Conclusion</p> <p>Cancer cell invasiveness can be affected by alterations in the tumor microenvironment. Disruption of FAP activity and β₁-integrins may abrogate the invasive capabilities of pancreatic and other tumors by disrupting the FAP-directed organization of stromal ECM and blocking β₁-integrin dependent cell-matrix interactions. This provides a novel preclinical rationale for therapeutics aimed at interfering with the architectural organization of tumor-associated ECM. Better understanding of the stromal influences that fuel progressive tumorigenic behaviors may allow the effective future use of targeted therapeutics aimed at disrupting specific tumor-stromal interactions.</p

B→DsπB \to D_s \pi and the tree amplitude in B→π+π−B \to \pi^+ \pi^-

The recently-observed decay $B^0 \to D_s^+ \pi^-$ is expected to proceed mainly by means of a tree amplitude in the factorization limit: $B^0 \to \pi^- {(W^+)}^*$, ${(W^+)}^* \to D_s^+$. Under this assumption, we predict the corresponding contribution of the tree amplitude to $B^0 \to \pi^+ \pi^-$. We indicate the needed improvements in data that will allow a useful estimate of this amplitude with errors comparable to those accompanying other methods. Since the factorization hypothesis for this process goes beyond that proved in most approaches, we also discuss independent tests of this hypothesis.Comment: 7 pages, LaTeX, 1 figure, to be submitted to Phys. Rev. D (Brief Reports