Interleukin-12 bypasses common gamma-chain signalling in emergency natural killer cell lymphopoiesis

Differentiation and homeostasis of natural killer (NK) cells relies on common gamma-chain (γc)-dependent cytokines, in particular IL-15. Consequently, NK cells do not develop in mice with targeted γc deletion. Herein we identify an alternative pathway of NK-cell development driven by the proinflammatory cytokine IL-12, which can occur independently of γc-signalling. In response to viral infection or upon exogenous administration, IL-12 is sufficient to elicit the emergence of a population of CD122+CD49b+ cells by targeting NK-cell precursors (NKPs) in the bone marrow (BM). We confirm the NK-cell identity of these cells by transcriptome-wide analyses and their ability to eliminate tumour cells. Rather than using the conventional pathway of NK-cell development, IL-12-driven CD122+CD49b+ cells remain confined to a NK1.1lowNKp46low stage, but differentiate into NK1.1+NKp46+ cells in the presence of γc-cytokines. Our data reveal an IL-12-driven hard-wired pathway of emergency NK-cell lymphopoiesis bypassing steady-state γc-signalling

The Quark Beam Function at NNLL

In hard collisions at a hadron collider the most appropriate description of the initial state depends on what is measured in the final state. Parton distribution functions (PDFs) evolved to the hard collision scale Q are appropriate for inclusive observables, but not for measurements with a specific number of hard jets, leptons, and photons. Here the incoming protons are probed and lose their identity to an incoming jet at a scale \mu_B << Q, and the initial state is described by universal beam functions. We discuss the field-theoretic treatment of beam functions, and show that the beam function has the same RG evolution as the jet function to all orders in perturbation theory. In contrast to PDF evolution, the beam function evolution does not mix quarks and gluons and changes the virtuality of the colliding parton at fixed momentum fraction. At \mu_B, the incoming jet can be described perturbatively, and we give a detailed derivation of the one-loop matching of the quark beam function onto quark and gluon PDFs. We compute the associated NLO Wilson coefficients and explicitly verify the cancellation of IR singularities. As an application, we give an expression for the next-to-next-to-leading logarithmic order (NNLL) resummed Drell-Yan beam thrust cross section.Comment: 54 pages, 9 figures; v2: notation simplified in a few places, typos fixed; v3: journal versio

Parton Fragmentation within an Identified Jet at NNLL

The fragmentation of a light parton i to a jet containing a light energetic hadron h, where the momentum fraction of this hadron as well as the invariant mass of the jet is measured, is described by "fragmenting jet functions". We calculate the one-loop matching coefficients J_{ij} that relate the fragmenting jet functions G_i^h to the standard, unpolarized fragmentation functions D_j^h for quark and gluon jets. We perform this calculation using various IR regulators and show explicitly how the IR divergences cancel in the matching. We derive the relationship between the coefficients J_{ij} and the quark and gluon jet functions. This provides a cross-check of our results. As an application we study the process e+ e- to X pi+ on the Upsilon(4S) resonance where we measure the momentum fraction of the pi+ and restrict to the dijet limit by imposing a cut on thrust T. In our analysis we sum the logarithms of tau=1-T in the cross section to next-to-next-to-leading-logarithmic accuracy (NNLL). We find that including contributions up to NNLL (or NLO) can have a large impact on extracting fragmentation functions from e+ e- to dijet + h.Comment: expanded introduction, typos fixed, journal versio

Protein versus DNA as a marker for peripheral blood mononuclear cell counting

Quantitative analysis of intracellular analytes requires an accurate and precise assay not only for the quantitation of the analytes, but also for the quantitation of the number of cells in which they were determined. In this technical note we compare protein and DNA as markers for the number of peripheral blood mononuclear cells (PBMCs) isolated from whole blood. The protein content of samples was highly influenced by red blood cell contamination and was, therefore, a less suitable marker. The DNA-based method was unaffected by red blood cell contamination and was finally validated over a range from 10 × 106 to 300 × 106 PBMCs/mL

Intratumoral IL-12 delivery empowers CAR-T cell immunotherapy in a pre-clinical model of glioblastoma

Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain cancer, for which effective therapies are urgently needed. Chimeric antigen receptor (CAR)-based immunotherapy represents a promising therapeutic approach, but it is often impeded by highly immunosuppressive tumor microenvironments (TME). Here, in an immunocompetent, orthotopic GBM mouse model, we show that CAR-T cells targeting tumor-specific epidermal growth factor receptor variant III (EGFRvIII) alone fail to control fully established tumors but, when combined with a single, locally delivered dose of IL-12, achieve durable anti-tumor responses. IL-12 not only boosts cytotoxicity of CAR-T cells, but also reshapes the TME, driving increased infiltration of proinflammatory CD4+ T cells, decreased numbers of regulatory T cells (Treg), and activation of the myeloid compartment. Importantly, the immunotherapy-enabling benefits of IL-12 are achieved with minimal systemic effects. Our findings thus show that local delivery of IL-12 may be an effective adjuvant for CAR-T cell therapy for GBM

Second order QCD corrections to inclusive semileptonic b \to Xc l \bar \nu_l decays with massless and massive lepton

We extend previous computations of the second order QCD corrections to semileptonic b \to c inclusive transitions, to the case where the charged lepton in the final state is massive. This allows accurate description of b \to c \tau \bar \nu_\tau decays. We review techniques used in the computation of O(\alpha_s^2) corrections to inclusive semileptonic b \to c transitions and present extensive numerical studies of O(\alpha_s^2) QCD corrections to b \to c l \bar \nu_l decays, for l =e, \tau.Comment: 30 pages, 4 figures, 5 table

Open Problems on Central Simple Algebras

We provide a survey of past research and a list of open problems regarding central simple algebras and the Brauer group over a field, intended both for experts and for beginners.Comment: v2 has some small revisions to the text. Some items are re-numbered, compared to v

The relationship between spasticity in young children (18 months of age) with cerebral palsy and their gross motor function development

<p>Abstract</p> <p>Background</p> <p>It is thought that spasticity has an influence on the development of functional motor abilities among children with cerebral palsy (CP). The extent to which spasticity is associated with the change in motor abilities in young children with CP has not been established. The objective of this study is to evaluate the relationship of initial spasticity in young children with CP and their gross motor function development over one year.</p> <p>Methods</p> <p>Fifty children with CP aged 18 months, GMFCS-levels I-V participated in a longitudinal observational study. Change in gross motor functioning (GMFM-66) was measured over one year. The level of spasticity measured at the first assessment was determined with the Modified Tardieu Scale in three muscle groups of the lower extremity (adductor muscles, the hamstrings and the m. gastrocnemius). The Spasticity Total Score per child was calculated with a maximum score of 12 points.</p> <p>Results</p> <p>Spearman's Rho Correlation (-0.28) revealed a statistically significant relationship (p < 0.05) of small strength between the Spasticity Total Score and the change score of the GMFM-66.</p> <p>Conclusion</p> <p>Our findings indicate that when measured over one year, spasticity is marginally related to gross motor function development in infants with CP. The initial level of spasticity is only one of the many child, environmental and family factors that determines gross motor development of a young child with CP.</p