Double real radiation corrections to ttˉt\bar{t} production at the LHC: the all-fermion processes

We present the double real radiation corrections to the hadronic $t \bar{t}$ production stemming from partonic processes with fermions only. For this purpose, we extend the NNLO antenna subtraction formalism developed originally for the computation of jet observables in $e^+e^-$ annihilation to include the evaluation of hadronic observables involving a massive pair of particles. In all partonic processes, we checked the validity of our subtraction terms given for leading and subleading colour contributions numerically by showing that the ratio between real radiation matrix elements and subtraction terms approaches unity in all single and double unresolved configurations.Comment: 68 pages, 9 figure

Gravity-driven instabilities: interplay between state-and-velocity dependent frictional sliding and stress corrosion damage cracking

We model the progressive maturation of a heterogeneous mass towards a gravity-driven instability, characterized by the competition between frictional sliding and tension cracking, using array of slider blocks on an inclined basal surface, which interact via elastic-brittle springs. A realistic state- and rate-dependent friction law describes the block-surface interaction. The inner material damage occurs via stress corrosion. Three regimes, controlling the mass instability and its precursory behavior, are classified as a function of the ratio $T_c/T_f$ of two characteristic time scales associated with internal damage/creep and with frictional sliding. For $T_c/T_f \gg 1$, the whole mass undergoes a series of internal stick and slip events, associated with an initial slow average downward motion of the whole mass, and progressively accelerates until a global coherent runaway is observed. For $T_c/T_f \ll 1$, creep/damage occurs sufficiently fast compared with nucleation of sliding, causing bonds to break, and the bottom part of the mass undergoes a fragmentation process with the creation of a heterogeneous population of sliding blocks. For the intermediate regime $T_c/T_f \sim 1$, a macroscopic crack nucleates and propagates along the location of the largest curvature associated with the change of slope from the stable frictional state in the upper part to the unstable frictional sliding state in the lower part. The other important parameter is the Young modulus $Y$ which controls the correlation length of displacements in the system.Comment: 40 pages, 13 figure

The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia : design, results and future prospects

The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.Peer reviewe

Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located nearNEDD4LandSLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (R(g)ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.Author summary Although twin studies have shown that body mass index (BMI) is highly heritable, many common genetic variants involved in the development of BMI have not yet been identified, especially in children. We studied associations of more than 40 million genetic variants with childhood BMI in 61,111 children aged between 2 and 10 years. We identified 25 genetic variants that were associated with childhood BMI. Two of these have not been implicated for BMI previously, located close to the genesNEDD4LandSLC45A3. We also show that the genetic background of childhood BMI overlaps with that of birth weight, adult BMI, waist-to-hip-ratio, diastolic blood pressure, type 2 diabetes, and age at menarche. Our results suggest that the biological processes underlying childhood BMI largely overlap with those underlying adult BMI. However, the overlap is not complete. Additionally, the genetic backgrounds of childhood BMI and other cardio-metabolic phenotypes are overlapping. This may mean that the associations of childhood BMI and later cardio-metabolic outcomes are partially explained by shared genetics, but it could also be explained by the strong association of childhood BMI with adult BMI

The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia: design, results and future prospects

The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites

Molecular Mechanisms of T Cells Activation by Dendritic Cells in Autoimmune Diseases

The interaction between T cell and dendritic cells (DCs) that leads to T cell activation affects the progression of the immune response including autoimmune diseases. Antigen presentation on immune cell surface, formation of an immunological synapse (IS), and specific identification of complex by T cells including two activating signals are necessary steps that lead to T cell activation. The formation of stimulatory IS involves the inclusion of costimulatory molecules, such as ICAM-1/LFA-1 and CD28/B7-1, and so on. Some fusion proteins and monoclonal antibodies targeting costimulatory molecules have been developed and approved to treat autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), type I diabetes (T1D), inflammatory bowel disease (IBD), and psoriasis. These biological agents, including CTLA-4- and LFA-3-Ig, anti-CD3 monoclonal antibody, could prevent the successful engagement of DCs by T cell with significant efficacy and safety profile. In this article, we reviewed the molecular mechanisms of T cell activation during the interaction between T cells and DCs, and summarized some biological agents that target costimulatory molecules involved in the regulation of T cell activation

Tumor necrosis factor α stimulates expression of adenovirus early region 3 proteins: implications for viral persistence

Human adenovirus (Ad) can cause persistent infections in humans. Early region 3 (E3) of the virus appears to be implicated in this phenomenon. This transcription unit encodes proteins that interfere in various ways with host cell functions, including (i) cell-surface expression of histocompat- ibility class I antigens (HLA), (ih) cell-surface expression of the epidermal growth factor receptor (EGF-R), and (iii) the bio- logical activity of tumor necrosis factor a (TNF-a). We trans- fected the human cell line 293 with the entire E3 region of Ad2 and investigated the influence of the cytokines TNF-a and interferon y (IFN-y) on cell-surface expression of HLA class I and the EGF-R. Whereas IFN-y treatment induced expression of HLA to some extent but not that of the EGF-R, TNF-a treatment augmented the reduction of these cell-surface mol- ecules. Subsequent studies on the mechanism of this effect showed a TNF-a-dependent upregulation of E3 protein (E3/19K) and mRNA. The significance of this phenomenon was confirmed in infection experiments. A dramatic increase in the amount of E3/19K, even after short induction with low doses of TNF-o! could be demonstrated. The study provides evidence for an interaction between the immune system and Ad in which the virus takes advantage of an immune mediator to escape immunosurveillance of the host

Analysis of the maturation process of dendritic cells deficient for TNF and lymphotoxin-alpha reveals an essential role for TNF.

Dendritic cells (DCs) generated from bone marrow (BM) precursor cells of C57BL/6 (B6.WT) mice and cultured in the presence of granulocyte macrophage-colony stimulating factor differentiate to mature BM-DCs spontaneously. These mature DCs are characterized by high levels of major histocompatibility complex (MHC) class II, CD40, and CD86 on their surface. To analyze the involvement of tumor necrosis factor (TNF) and the related cytokine lymphotoxin (LT)alpha in DC maturation, we studied the development of DCs from the BM of B6.TNF(-/-), B6.LTalpha(-/-), and B6.TNF/LTalpha(-/-) mice and compared it to B6.WT mice. Although the development of BM precursor cells to the level of immature DCs (CD11c(+), MHC class II(low), CD40(low), and CD86(low)) was equivalent in all genotypes, B6.TNF(-/-) and B6.TNF/LTalpha(-/-) cells showed an impaired capacity to differentiate to mature DCs. In contrast, mature BM-DCs generated from LTalpha-negative, immature DCs developed like B6.WT cells. Further studies revealed that once matured, the phenotype of all tested genotypes was comparable. They expressed high levels of CD40 and CD86, were exclusively positive for the chemokine receptor (CCR)7 but negative for CCR5 and CCR2, and were able to enter the paracortex of draining lymph nodes. The limited maturation of TNF-deficient BM-DCs could be restored by mixing TNF-negative with TNF-positive Ly5.1 BM cells, and maturation of B6.WT DCs could be blocked with an anti-TNF monoclonal antibody. The substitution of B6.TNF(-/-) BM cells with recombinant TNF revealed promotion or suppression of BM-DC maturation depending on the point of time of TNF addition