Complex exon-intron marking by histone modifications is not determined solely by nucleosome distribution

It has recently been shown that nucleosome distribution, histone modifications and RNA polymerase II (Pol II) occupancy show preferential association with exons (“exon-intron marking”), linking chromatin structure and function to co-transcriptional splicing in a variety of eukaryotes. Previous ChIP-sequencing studies suggested that these marking patterns reflect the nucleosomal landscape. By analyzing ChIP-chip datasets across the human genome in three cell types, we have found that this marking system is far more complex than previously observed. We show here that a range of histone modifications and Pol II are preferentially associated with exons. However, there is noticeable cell-type specificity in the degree of exon marking by histone modifications and, surprisingly, this is also reflected in some histone modifications patterns showing biases towards introns. Exon-intron marking is laid down in the absence of transcription on silent genes, with some marking biases changing or becoming reversed for genes expressed at different levels. Furthermore, the relationship of this marking system with splicing is not simple, with only some histone modifications reflecting exon usage/inclusion, while others mirror patterns of exon exclusion. By examining nucleosomal distributions in all three cell types, we demonstrate that these histone modification patterns cannot solely be accounted for by differences in nucleosome levels between exons and introns. In addition, because of inherent differences between ChIP-chip array and ChIP-sequencing approaches, these platforms report different nucleosome distribution patterns across the human genome. Our findings confound existing views and point to active cellular mechanisms which dynamically regulate histone modification levels and account for exon-intron marking. We believe that these histone modification patterns provide links between chromatin accessibility, Pol II movement and co-transcriptional splicing

Physics of leptoquarks in precision experiments and at particle colliders

We present a comprehensive review of physics effects generated by leptoquarks (LQs), i.e., hypothetical particles that can turn quarks into leptons and vice versa, of either scalar or vector nature. These considerations include discussion of possible completions of the Standard Model that contain LQ fields. The main focus of the review is on those LQ scenarios that are not problematic with regard to proton stability. We accordingly concentrate on the phenomenology of light leptoquarks that is relevant for precision experiments and particle colliders. Important constraints on LQ interactions with matter are derived from precision low-energy observables such as electric dipole moments, (g-2) of charged leptons, atomic parity violation, neutral meson mixing, Kaon, B, and D meson decays, etc. We provide a general analysis of indirect constraints on the strength of LQ interactions with the quarks and leptons to make statements that are as model independent as possible. We address complementary constraints that originate from electroweak precision measurements, top, and Higgs physics. The Higgs physics analysis we present covers not only the most recent but also expected results from the Large Hadron Collider (LHC). We finally discuss direct LQ searches. Current experimental situation is summarized and self-consistency of assumptions that go into existing accelerator-based searches is discussed. A progress in making next-to-leading order predictions for both pair and single LQ productions at colliders is also outlined.Comment: 136 pages, 22 figures, typographical errors fixed, the Physics Reports versio

Immunization with Single-Cycle SIV Significantly Reduces Viral Loads After an Intravenous Challenge with SIVmac239

Strains of simian immunodeficiency virus (SIV) that are limited to a single cycle of infection were evaluated for the ability to elicit protective immunity against wild-type SIVmac239 infection of rhesus macaques by two different vaccine regimens. Six animals were inoculated at 8-week intervals with 6 identical doses consisting of a mixture of three different envelope variants of single-cycle SIV (scSIV). Six additional animals were primed with a mixture of cytoplasmic domain-truncated envelope variants of scSIV and boosted with two doses of vesicular stomatitis virus glycoprotein (VSV G) trans-complemented scSIV. While both regimens elicited detectable virus-specific T cell responses, SIV-specific T cell frequencies were more than 10-fold higher after boosting with VSV G trans-complemented scSIV (VSV G scSIV). Broad T cell recognition of multiple viral antigens and Gag-specific CD4+ T cell responses were also observed after boosting with VSV G scSIV. With the exception of a single animal in the repeated immunization group, all of the animals became infected following an intravenous challenge with SIVmac239. However, significantly lower viral loads and higher memory CD4+ T cell counts were observed in both immunized groups relative to an unvaccinated control group. Indeed, both scSIV immunization regimens resulted in containment of SIVmac239 replication after challenge that was as good as, if not better than, what has been achieved by other non-persisting vaccine vectors that have been evaluated in this challenge model. Nevertheless, the extent of protection afforded by scSIV was not as good as typically conferred by persistent infection with live, attenuated SIV. These observations have potentially important implications to the design of an effective AIDS vaccine, since they suggest that ongoing stimulation of virus-specific immune responses may be essential to achieving the degree of protection afforded by live, attenuated SIV

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

The effect of rehabilitation interventions on physical function and immobility-related complications in severe stroke—protocol for a systematic review

Abstract Background Stroke rehabilitation aims to optimise function and reduce complications post-stroke. Rehabilitation to optimise physical function post-stroke has beneficial effects for survivors of mild to moderate stroke. However, little is known about the effectiveness of interventions to rehabilitate physical function or manage immobility-related complications for survivors of severe stroke. The systematic review aims to evaluate the effectiveness of rehabilitation interventions on physical function and immobility-related complications in severe stroke and identify topics for future research in this area. Methods A systematic review of relevant electronic databases (MEDLINE, Embase, CINAHL, AMED, PEDro, DORIS and CENTRAL) between January 1987 and July 2017 will be undertaken to identify eligible published randomised controlled trials (RCTs) in any language. Ongoing RCTs will be identified by searching health-care trial registers (Stroke Trials Registry, ClinicalTrials.gov). Hand searches of identified study reference lists will also be performed. The PRISMA statement will be used to guide the systematic review. Two reviewers will screen search results, select studies using pre-defined selection criteria, extract data from and assess risk of bias for selected studies. Studies comparing the effect of one type of rehabilitation intervention to another or usual care on physical function and immobility-related complications for patients with severe stroke will be included. Studies may include participants with all levels of stroke severity but must provide sub-group analysis based on stroke severity. Studies will focus on any phase of the stroke rehabilitation pathway and will be grouped and analysed according to their timeframe post-stroke into acute and early sub-acute (up to 3 months post-stroke), early sub-acute to late sub-acute (from 3 to 6 months post-stroke) and chronic (greater than 6 months post-stroke). If sufficient studies demonstrate homogeneity, a meta-analysis will pool results of individual outcomes. The GRADE approach will be used to assess the evidence strength. Discussion The results of this systematic review will summarise the strength of evidence for rehabilitation interventions used in the rehabilitation of physical function and immobility-related complications in severe stroke and identify gaps in evidence. Systematic review registration The systematic review was registered with the International Prospective Register of Systematic Reviews (PROSPERO)—registration number CRD77737