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The aims of this study were to (a) examine the effects of a 6-week sand training program including both sprint and jump exercises on the speed-related and vertical jump performance of elite young soccer players and (b) compare the changes induced by a sand training scheme with those induced by a similar training program (in volume, intensity, and exercise types) performed on grass. Twenty-four under-20 soccer players were randomly allocated to 2 training groups, as follows: "sand" (n = 12) or "grass" (n = 12) groups. Athletes performed squat and countermovement jumps, linear sprints, and Zigzag change-of-direction speed tests at pre-, mid- (after 6 training sessions), and postintervention (after 12 training sessions). Both groups exhibited similar increases in the vertical jump and Zigzag performance after the 6-week training period (p values ranging from 0.0001 to 0.025; effect size ranging from 1.05 to 3.78, for main effect of time). No significant changes were detected for the linear sprint velocity for both the groups (p values ranging from 0.079 to 1.00; effect size ranging from 0.07 to 0.65, for main effect of time). In summary, training on sand or grass surfaces resulted in similar improvements in the physical performance of elite young soccer players. This study confirms the current evidence on the effectiveness of both soft and harder training surfaces in improving the sprint and jump performance of team-sport athletes. [ABSTRACT FROM AUTHOR]

Several systems, including contractile tail bacteriophages, the type VI secretion system and R-type pyocins, use a multiprotein tubular apparatus to attach to and penetrate host cell membranes. This macromolecular machine resembles a stretched, coiled spring (or sheath) wound around a rigid tube with a spike-shaped protein at its tip. A baseplate structure, which is arguably the most complex part of this assembly, relays the contraction signal to the sheath. Here we present the atomic structure of the approximately 6-megadalton bacteriophage T4 baseplate in its pre- and post- host attachment states and explain the events that lead to sheath contraction in atomic detail. We establish the identity and function of a minimal set of components that is conserved in all contractile injection systems and show that the triggering mechanism is universally conserved., Bacteriophages (viruses of bacteria) use a specialized organelle called a tail to deliver their genetic material and proteins across the cell envelope during infection (1-4). In phages with the most [...]

A study to ascertain if the development of systemic lupus erythematosus (SLE) is influenced by the presence of certain genes is conducted. Results confirm that the hereditary genes play a role in the development as also reduced expression of BLK and increase depression of C8orf13 and variants in the ITGAM-ITGAX region.

Ig class switch recombination (CSR) and somatic hypermutation serve to diversify antibody responses and are orchestrated by the activity of activation-induced cytidine deaminase and many proteins involved in DNA repair and genome surveillance. Msh5, a gene encoded in the central MHC class III region, and its obligate heterodimerization partner Msh4 have a critical role in regulating meiotic homologous recombination and have not been implicated in CSR. Here, we show that MRL/Ipr mice carrying a congenic [H-2.sup.b/b] MHC interval exhibit several abnormalities regarding CSR, including a profound deficiency of IgG3 in most mice and long micro-homologies at Ig switch (S) joints. We found that Msh5 is expressed at low levels on the [H-2.sup.b] haplotype and, importantly, a similar long S joint microhomology phenotype was observed in both Msh5 and Msh4-null mice. We also present evidence that genetic variation in MSH5 is associated with IgA deficiency and common variable immune deficiency (CVID) in humans. One of the human MSH5 alleles identified contains two nonsynonymous polymorphisms, and the variant protein encoded by this allele shows impaired binding to MSH4. Similar to the mice, Ig S joints from CVID and IgA deficiency patients carrying disease-associated MSH5 alleles show increased donor/acceptor microhomology, involving pentameric DNA repeat sequences and lower mutation rates than controls. Our findings suggest that Msh4/5 heterodimers contribute to CSR and support a model whereby Msh4/5 promotes the resolution of DNA breaks with low or no terminal microhomology by a classical nonhomologous end-joining mechanism while possibly suppressing an alternative microhomology-mediated pathway. immunoglobulin subclass deficiency | mismatch repair | Msh4

Background Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4.sup.+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4.sup.+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs. Methods and Findings To define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3.sup.+ CD4.sup.+ CD25.sup.high CD127.sup.low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 x 10.sup.6 to 1.5 x 10.sup.6 IU/m.sup.2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 x 10.sup.6 IU/m.sup.2 (standard error [SE] = 0.078, 95% CI = -0.052, 0.254) and 0.497 x 10.sup.6 IU/m.sup.2 (SE = 0.092, 95% CI = 0.316, 0.678), respectively. On analysis of secondary outcomes, using a highly sensitive IL-2 assay, the observed plasma concentrations of the drug at 90 min exceeded the hypothetical Treg-specific therapeutic window determined in vitro (0.015-0.24 IU/ml), even at the lowest doses (0.040 x 10.sup.6 and 0.045 x 10.sup.6 IU/m.sup.2) administered. A rapid decrease in Treg frequency in the circulation was observed at 90 min and at day 1, which was dose dependent (mean decrease 11.6%, SE = 2.3%, range 10.0%-48.2%, n = 37), rebounding at day 2 and increasing to frequencies above baseline over 7 d. Teffs, natural killer cells, and eosinophils also responded, with their frequencies rapidly and dose-dependently decreased in the blood, then returning to, or exceeding, pretreatment levels. Furthermore, there was a dose-dependent down modulation of one of the two signalling subunits of the IL-2 receptor, the [beta] chain (CD122) (mean decrease = 58.0%, SE = 2.8%, range 9.8%-85.5%, n = 33), on Tregs and a reduction in their sensitivity to aldesleukin at 90 min and day 1 and 2 post-treatment. Due to blood volume requirements as well as ethical and practical considerations, the study was limited to adults and to analysis of peripheral blood only. Conclusions The DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2-3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%-50%, with the eventual goal of preventing T1D. Trial Registration ISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735, Author(s): John A. Todd 1,*, Marina Evangelou 2, Antony J. Cutler 1, Marcin L. Pekalski 1, Neil M. Walker 1, Helen E. Stevens 1, Linsey Porter 1, Deborah J. Smyth [...]

Abstract Background CD4+CD25+ regulatory T cells play an essential role in maintaining immune homeostasis and preventing autoimmunity. Therefore, defects in Treg development, maintenance or function have been associated with several human autoimmune diseases including Systemic Lupus Erythematosus (SLE), a systemic autoimmune disease characterized by loss of tolerance to nuclear components and significantly more frequent in females. Results To investigate the involvement of Treg in SLE pathogenesis, we determined the frequency of CD4+CD25+CD45RO+ T cells, which encompass the majority of Treg activity, in the PBMC of 148 SLE patients (76 patients were part of 54 families), 166 relatives and 117 controls. SLE patients and their relatives were recruited in several Portuguese hospitals and through the Portuguese Lupus Association. Control individuals were blood donors recruited from several regional blood donor centers. Treg frequency was significantly lower in SLE patients than healthy controls (z = -6.161, P < 0.00001) and intermediate in the relatives' group. Remarkably, this T cell subset was also lower in females, most strikingly in the control population (z = 4.121, P < 0.001). We further ascertained that the decreased frequency of Treg in SLE patients resulted from the specific reduction of bona fide FOXP3+CD4+CD25+ Treg. Treg frequency was negatively correlated with SLE activity index (SLEDAI) and titers of serum anti-dsDNA antibodies. Both Treg frequency and disease activity were modulated by IVIg treatment in a documented SLE case. The segregation of Treg frequency within the SLE families was indicative of a genetic trait. Candidate gene analysis revealed that specific variants of CTLA4 and TGFβ were associated with the decreased frequency of Treg in PBMC, while FOXP3 gene variants were associated with affection status, but not with Treg frequency. Conclusion SLE patients have impaired Treg production or maintenance, a trait strongly associated with SLE disease activity and autoantibody titers, and possibly resulting from the inability to convert FOXP3+CD25- into FOXP3+CD25+ T cells. Treg frequency is highly heritable within SLE families, with specific variants of the CTLA4 and TGFβ genes contributing to this trait, while FOXP3 contributes to SLE through mechanisms not involving a modulation of Treg frequency. These findings establish that the genetic components in SLE pathogenesis include genes related to Treg generation or maintenance.