Effi cacy of a Russian-backbone live attenuated infl uenza vaccine among children in Senegal: a randomised, double-blind, placebo-controlled trial

Background Live attenuated infl uenza vaccines have been shown to signifi cantly reduce infl uenza in diverse populations of children, but no effi cacy studies have been done in resource-poor tropical settings. In Senegal, we assessed the effi cacy and safety of a live attenuated infl uenza vaccine based on Russian-derived master donor viruses and licensed as a single dose. Methods In this double-blind, placebo-controlled, parallel group, single-centre trial done near Niakhar, Senegal, generally healthy children aged 2–5 years were randomly allocated (2:1) to receive a single intranasal dose of masked trivalent live attenuated infl uenza vaccine or placebo. The allocation sequence was computer-generated by PATH with block sizes of three. The manufacturer provided vaccine and placebo in coded vials to preserve blinding. Participants were monitored through the predictable infl uenza season in Senegal for adverse events and signs and symptoms of infl uenza using weekly home visits and surveillance in clinics. The primary outcome was symptomatic laboratoryconfi rmed infl uenza caused by any strain and occurring from 15 days post-vaccination to the end of the study. The primary analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT01854632. Findings Between May 23, and July 1, 2013, 1761 children were randomly assigned, 1174 to receive live attenuated infl uenza vaccine and 587 to receive placebo. The per-protocol set included 1173 vaccinees and 584 placebo recipients followed up to Dec 20, 2013. Symptomatic infl uenza was laboratory-confi rmed in 210 (18%) of 1173 recipients of live attenuated infl uenza vaccine and 105 (18%) of placebo recipients, giving a vaccine effi cacy of 0·0% (95% CI –26·4 to 20·9). Adverse events were balanced between the study groups. Two girls who had received live attenuated infl uenza vaccine died, one due to anasarca 12 days postvaccination and one due to malnutrition 70 days postvaccination. Interpretation Live attenuated infl uenza vaccine was well tolerated in young children in Senegal, but did not provide protection against infl uenza. Further study in such populations, which might experience extended periods of infl uenza circulation, is warranted

Lysosome-mediated processing of chromatin in senescence

Cellular senescence is a stable proliferation arrest, a potent tumor suppressor mechanism, and a likely contributor to tissue aging. Cellular senescence involves extensive cellular remodeling, including of chromatin structure. Autophagy and lysosomes are important for recycling of cellular constituents and cell remodeling. Here we show that an autophagy/lysosomal pathway processes chromatin in senescent cells. In senescent cells, lamin A/C–negative, but strongly γ-H2AX–positive and H3K27me3-positive, cytoplasmic chromatin fragments (CCFs) budded off nuclei, and this was associated with lamin B1 down-regulation and the loss of nuclear envelope integrity. In the cytoplasm, CCFs were targeted by the autophagy machinery. Senescent cells exhibited markers of lysosomal-mediated proteolytic processing of histones and were progressively depleted of total histone content in a lysosome-dependent manner. In vivo, depletion of histones correlated with nevus maturation, an established histopathologic parameter associated with proliferation arrest and clinical benignancy. We conclude that senescent cells process their chromatin via an autophagy/lysosomal pathway and that this might contribute to stability of senescence and tumor suppression

Linking Yeast Gcn5p Catalytic Function and Gene Regulation Using a Quantitative, Graded Dominant Mutant Approach

Establishing causative links between protein functional domains and global gene regulation is critical for advancements in genetics, biotechnology, disease treatment, and systems biology. This task is challenging for multifunctional proteins when relying on traditional approaches such as gene deletions since they remove all domains simultaneously. Here, we describe a novel approach to extract quantitative, causative links by modulating the expression of a dominant mutant allele to create a function-specific competitive inhibition. Using the yeast histone acetyltransferase Gcn5p as a case study, we demonstrate the utility of this approach and (1) find evidence that Gcn5p is more involved in cell-wide gene repression, instead of the accepted gene activation associated with HATs, (2) identify previously unknown gene targets and interactions for Gcn5p-based acetylation, (3) quantify the strength of some Gcn5p-DNA associations, (4) demonstrate that this approach can be used to correctly identify canonical chromatin modifications, (5) establish the role of acetyltransferase activity on synthetic lethal interactions, and (6) identify new functional classes of genes regulated by Gcn5p acetyltransferase activity—all six of these major conclusions were unattainable by using standard gene knockout studies alone. We recommend that a graded dominant mutant approach be utilized in conjunction with a traditional knockout to study multifunctional proteins and generate higher-resolution data that more accurately probes protein domain function and influence

Physical and chemical impacts of a major storm on a temperate lake: a taste of things to come?

Extreme weather can have a substantial influence on lakes and is expected to become more frequent with climate change. We explored the influence of one particular extreme event, Storm Ophelia, on the physical and chemical environment of England's largest lake, Windermere. We found that the substantial influence of Ophelia on meteorological conditions at Windermere, in particular wind speed, resulted in a 25-fold increase (relative to the study-period average) in the wind energy flux at the lake-air interface. Following Ophelia, there was a short-lived mixing event in which the Schmidt stability decreased by over 100 Jm-2 and the thermocline deepened by over 10 m during a 12-hour period. As a result of changes to the strength of stratification, Ophelia also changed the internal seiche regime of Windermere with the dominant seiche period increasing from ~17 h pre-storm to ~21 h post-storm. Following Ophelia, there was an upwelling of cold and low-oxygenated waters at the southern-end of the lake. This had a substantial influence on the main outflow of Windermere, the River Leven, where dissolved oxygen concentrations decreased by ~48 %, from 9.3 mg L-1 to 4.8 mg L-1, while at the mid-lake monitoring station in Windermere, it decreased by only ~3%. This study illustrates that the response of a lake to extreme weather can cause important effects downstream, the influence of which may not be evident at the lake surface. To understand the impact of future extreme events fully, the whole lake and downstream-river system need to be studied together

Latent autoimmunity across disease-specific boundaries in at-risk first-degree relatives of SLE and RA patientsResearch in context

Background: Autoimmune disease prevention requires tools to assess an individual's risk of developing a specific disease. One tool is disease-associated autoantibodies, which accumulate in an asymptomatic preclinical period. However, patients sometimes exhibit autoantibodies associated with a different disease classification. When and how these alternative autoantibodies first appear remain unknown. This cross-sectional study characterizes alternative autoimmunity, and associated genetic and environmental factors, in unaffected first-degree relatives (FDRs) of patients, who exhibit increased future risk for the same disease. Methods: Samples (n = 1321) from disease-specific autoantibody-positive (aAb+) systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 1 diabetes (T1D) patients; and unaffected aAb+ and autoantibody-negative (aAb–) SLE and RA FDRs were tested for SLE, RA, and T1D aAbs, as well as anti-tissue transglutaminase, anti-cardiolipin and anti-thyroperoxidase. FDR SLE and RA genetic risk scores (GRS) were calculated. Findings: Alternative autoimmunity occurred in SLE patients (56%) and FDRs (57·4%), RA patients (32·6%) and FDRs (34·8%), and T1D patients (43%). Expanded autoimmunity, defined as autoantibodies spanning at least two other diseases, occurred in 18·5% of SLE patients, 16·4% of SLE FDRs, 7·8% of RA patients, 5·3% of RA FDRs, and 10·8% of T1D patients. SLE FDRs were more likely to have alternative (odds ratio [OR] 2·44) and expanded (OR 3·27) autoimmunity than RA FDRs. Alternative and expanded autoimmunity were associated with several environmental exposures. Alternative autoimmunity was associated with a higher RA GRS in RA FDRs (OR 1·41), and a higher SLE GRS in aAb+ RA FDRs (OR 1·87), but not in SLE FDRs. Interpretation: Autoimmunity commonly crosses disease-specific boundaries in systemic (RA, SLE) and organ-specific (T1D) autoimmune diseases. Alternative autoimmunity is more common in SLE FDRs than RA FDRs, and is influenced by genetic and environmental factors. These findings have substantial implications for preclinical disease pathogenesis and autoimmune disease prevention studies. Fund: NIH U01AI101981, R01AR051394, U19AI082714, P30AR053483, P30GM103510, U54GM104938, U01AI101934, R01AI024717, U01AI130830, I01BX001834, & U01HG008666. Keywords: Autoantibodies, Lupus, Rheumatoid arthritis, Type I diabetes, Relatives, Genetic ris