Protein kinase C theta is required for efficient induction of IL-10-secreting T cells

<div><p>Secretion of interleukin-10 (IL-10) by CD4⁺ T cells is an essential immunoregulatory mechanism. The work presented here assesses the role of the signaling molecule protein kinase C theta (PKCθ) in the induction of IL-10 expression in CD4⁺ T cells. Using wildtype and PKCθ-deficient Tg4 T cell receptor transgenic mice, we implemented a well-described protocol of repeated doses of myelin basic protein (MBP)Ac1-9[4Y] antigen to induce Tr1-like IL-10⁺ T cells. We find that PKCθ is required for the efficient induction of IL-10 following antigen administration. Both serum concentrations of IL-10 and the proportion of IL-10⁺ T cells were reduced in PKCθ-deficient mice relative to wildtype mice following [4Y] treatment. We further characterized the T cells of [4Y] treated PKCθ-deficient Tg4 mice and found reduced expression of the transcription factors cMaf, Nfil3 and FoxP3 and the surface receptors PD-1 and Tim3, all of which have been associated with the differentiation or function of IL-10⁺ T cells. Finally, we demonstrated that, unlike [4Y] treated wildtype Tg4 T cells, cells from PKCθ-deficient mice were unable to suppress the priming of naïve T cells <i>in vitro</i> and <i>in vivo</i>. In summary, we present data demonstrating a role for PKCθ in the induction of suppressive, IL-10-secreting T cells induced in TCR-transgenic mice following chronic antigen administration. This should be considered when contemplating PKCθ as a suitable drug target for inducing immune suppression and graft tolerance.</p></div

Little evidence for an effect of smoking on multiple sclerosis risk:A Mendelian Randomization study

The causes of multiple sclerosis (MS) remain unknown. Smoking has been associated with MS in observational studies and is often thought of as an environmental risk factor. We used two-sample Mendelian randomization (MR) to examine whether this association is causal using genetic variants identified in genome-wide association studies (GWASs) as associated with smoking. We assessed both smoking initiation and lifetime smoking behaviour (which captures smoking duration, heaviness, and cessation). There was very limited evidence for a meaningful effect of smoking on MS susceptibility as measured using summary statistics from the International Multiple Sclerosis Genetics Consortium (IMSGC) meta-analysis, including 14,802 cases and 26,703 controls. There was no clear evidence for an effect of smoking on the risk of developing MS (smoking initiation: odds ratio [OR] 1.03, 95% confidence interval [CI] 0.92-1.61; lifetime smoking: OR 1.10, 95% CI 0.87-1.40). These findings suggest that smoking does not have a detrimental consequence on MS susceptibility. Further work is needed to determine the causal effect of smoking on MS progression

Unexpected diversity and complexity of the Guerrero Negro hypersaline microbial mat

Author Posting. © The Author(s), 2006. This is the author's version of the work. It is posted here by permission of American Society for Microbiology for personal use, not for redistribution. The definitive version was published in Applied and Environmental Microbiology 72 (2006): 3685-3695, doi:10.1128/AEM.72.5.3685-3695.2006.We applied nucleic acids-based molecular methods, combined with estimates of biomass (ATP), pigments and microelectrode measurements of chemical gradients, to map microbial diversity vertically on the mm-scale in a hypersaline microbial mat from Guerrero Negro, Baja California Sur, Mexico. To identify the constituents of the mat, small-subunit ribosomal RNA genes were amplified by PCR from community genomic DNA extracted from layers, cloned and sequenced. Bacteria dominated the mat and displayed unexpected and unprecedented diversity. The majority (1336) of 1586 bacterial 16S rRNA sequences generated were unique, representing 752 species (≥97% rRNA sequence identity) in 42 of the main bacterial phyla, including 15 novel candidate phyla. The diversity of the mat samples differentiated according to the chemical milieu defined by concentrations of O2 and H2S. Chloroflexi formed the majority of the biomass by percentage of bulk rRNA and of clones in rRNA gene libraries. This result contradicts the general belief that Cyanobacteria dominate these communities. Although Cyanobacteria constituted a large fraction of the biomass in the upper few mm (>80% of total rRNA and photosynthetic pigments), Chloroflexi sequences were conspicuous throughout the mat. Filamentous Chloroflexi were identified by fluorescent in-situ hybridization within the polysaccharide sheaths of the prominent cyanobacterium Microcoleus chthonoplastes in addition to free-living in the mat. The biological complexity of the mat far exceeds that observed in other polysaccharide-rich microbial ecosystems, such as human and mouse distal guts, and suggests that positive feedbacks exist between chemical complexity and biological diversity.R. Ley was supported in part by an NRC- NASA Astrobiology Institutes Post Doctoral Associateship, J. Spear by an Agouron Institute postdoctoral fellowship. This work was supported by the NASA Cooperative Agreement with the University of Colorado Center for Astrobiology to N. R. Pace

The Lantern Vol. 3, No. 2, March 1935

• Puppets of Propaganda • Reluctance • Reflections From My Diary • Reverie • Bash Turner Enters the Limelight • The College Students\u27 Obligation • The Schwenkfelders • Love\u27s Desire • Verse • On the Squirt of a Grapefruit • Pioneers! • Whither Fraternities? • Mary Peters: A Book Review • Different as Night and Day • Ode to an Alley Cathttps://digitalcommons.ursinus.edu/lantern/1005/thumbnail.jp

Cumulative impact assessments of multiple host species loss from plant diseases show disproportionate reductions in associated biodiversity

Non-native plant pests and pathogens are increasing exponentially, causing extirpation of foundation species. The impact of large-scale declines in a single host on associated biodiversity is widely documented. However, the impact of multiple host loss on biodiversity and whether these impacts are multiplicative has not been assessed. Ecological theory suggests that systems with greater functional redundancy (alternative hosts) will be more resilient to the loss of sympatric hosts. We test this theory and show its importance in relation to pest/pathogen impact assessments. We assessed the potential impact on biodiversity of the loss of two widely occurring sympatric European tree species, Fraxinus excelsior and Quercus petraea/robur, both of which are currently threatened by a range of pests and pathogens. At the UK scale, the total number of associated species at risk of extirpation from plant diseases affecting these two sympatric hosts is greater than the sum of the associated species at risk from declines in either host alone. F. excelsior hosts 45 obligate species (species only found on that host) and Q. petraea/robur hosts 326. However, a decline in both these trees would impact 512 associated species, across multiple taxon groups, a 38% increase. Assessments at a local scale, 24 mixed F. excelsior–Q. petraea/robur woodlands revealed that these impacts may be even greater due to a lack of functional redundancy. Only 21% of sites were able to provide functional redundancy for F. excelsior and Q. petraea/robur associated species which can use other tree species. In most woodlands, the tree species required to provide functional redundancy were not present, although the site conditions were often suitable for them to grow. Synthesis. Understanding of functional redundancy should be applied to assessments of pests/pathogens impact on biodiversity. In risk assessments, higher impact scores should be given to pests/pathogens affecting hosts occurring with other host plant species already impacted by pests/pathogens. Current pest/pathogen risk assessment approaches that ignore the cumulative, cascading effects shown in this study may allow an insidious, mostly overlooked, driver of biodiversity loss to continue.Biotechnology and Biological Sciences Research Council, Grant/Award Number: BB/N022831/1; Rural and Environment Science and Analytical Services Division.info:eu-repo/semantics/publishedVersio

The effectiveness, implementation, and experiences of peer support approaches for mental health: A systematic umbrella review

Background: Peer support for mental health is recommended across international policy guidance and provision. Our systematic umbrella review summarises evidence on the effectiveness, implementation, and experiences of paid peer support approaches for mental health. Methods: We searched MEDLINE, EMBASE, PsycINFO, The Campbell Collaboration, and The Cochrane Database of Systematic Reviews (2012–2022) for reviews of paid peer support interventions for mental health. The AMSTAR2 assessed quality. Results were synthesised narratively, with implementation reported using the CFIR (Consolidated Framework for Implementation Research). The protocol was registered with PROSPERO (registration number: CRD42022362099). Results: We included 35 reviews (426 primary studies, n = 95–40,927 participants): systematic reviews with (n = 13) or without (n = 13) meta-analysis, or with qualitative synthesis (n = 3), scoping reviews (n = 6). Most reviews were low or critically low (97%) quality, one review was high quality. Effectiveness was investigated in 23 reviews. Results were mixed; there was some evidence from meta-analyses that peer support may improve depression symptoms (particularly perinatal depression), self-efficacy, and recovery. Factors promoting successful implementation, investigated in 9 reviews, included adequate training and supervision, a recovery-oriented workplace, strong leadership, and a supportive and trusting workplace culture with effective collaboration. Barriers included lack of time, resources and funding, and lack of recognised peer support worker (PSW) certification. Experiences of peer support were explored in 11 reviews, with 3 overarching themes: (i) what the PSW role can bring, including recovery and improved wellbeing for service users and PSWs; (ii) confusion over the PSW role, including role ambiguity and unclear boundaries; and (iii) organisational challenges and impact, including low pay, negative non-peer staff attitudes, and lack of support and training. Conclusions: Peer support may be effective at improving some clinical outcomes, self-efficacy, and recovery. Certain populations, e.g. perinatal populations, may especially benefit from peer support. Potential strategies to successfully implement PSWs include co-production, clearly defined PSW roles, a receptive hierarchical structure and staff, appropriate PSW and staff training with clinical and/or peer supervision alongside safeguarding. Services could benefit from clear, coproduced, setting specific implementation guidelines for PSW. PSW roles tend to be poorly defined and associations between PSW intervention content and impacts need further investigation. Future research should reflect the priorities of providers/service users involved in peer support

Improved Search for Muon-Neutrino to Electron-Neutrino Oscillations in MINOS

We report the results of a search for ν_e appearance in a ν_μ beam in the MINOS long-baseline neutrino experiment. With an improved analysis and an increased exposure of 8.2×10^(20) protons on the NuMI target at Fermilab, we find 2sin^2(θ_(23))sin^2(2θ_(13))<0.12(0.20) at 90% confidence level for δ=0 and the normal (inverted) neutrino mass hierarchy, with a best-fit of 2sin^2(θ_(23))sin^2(2θ_(13))=0.041^(+0.047)_(-0.031)(0.079^(+0.071)_(-0.053). The θ_(13)= 0 hypothesis is disfavored by the MINOS data at the 89% confidence level

New constraints on muon-neutrino to electron-neutrino transitions in MINOS

This paper reports results from a search for ν_μ → ν_e transitions by the MINOS experiment based on a 7×10^(20) protons-on-target exposure. Our observation of 54 candidate ν_e events in the far detector with a background of 49.1±7.0(stat)±2.7(syst) events predicted by the measurements in the near detector requires 2sin^2(2θ_(13))sin^2θ_(23)<0.12(0.20) at the 90% C.L. for the normal (inverted) mass hierarchy at δ_(CP)=0. The experiment sets the tightest limits to date on the value of θ_(13) for nearly all values of δ_(CP) for the normal neutrino mass hierarchy and maximal sin^2(2θ_(23))

Search for sterile neutrino mixing in the MINOS long-baseline experiment

A search for depletion of the combined flux of active neutrino species over a 735 km baseline is reported using neutral-current interaction data recorded by the MINOS detectors in the NuMI neutrino beam. Such a depletion is not expected according to conventional interpretations of neutrino oscillation data involving the three known neutrino flavors. A depletion would be a signature of oscillations or decay to postulated noninteracting sterile neutrinos, scenarios not ruled out by existing data. From an exposure of 3.18×10^(20) protons on target in which neutrinos of energies between ∼500  MeV and 120 GeV are produced predominantly as ν_μ, the visible energy spectrum of candidate neutral-current reactions in the MINOS far detector is reconstructed. Comparison of this spectrum to that inferred from a similarly selected near-detector sample shows that of the portion of the ν_μ flux observed to disappear in charged-current interaction data, the fraction that could be converting to a sterile state is less than 52% at 90% confidence level (C.L.). The hypothesis that active neutrinos mix with a single sterile neutrino via oscillations is tested by fitting the data to various models. In the particular four-neutrino models considered, the mixing angles θ_(24) and θ_(34) are constrained to be less than 11° and 56° at 90% C.L., respectively. The possibility that active neutrinos may decay to sterile neutrinos is also investigated. Pure neutrino decay without oscillations is ruled out at 5.4 standard deviations. For the scenario in which active neutrinos decay into sterile states concurrently with neutrino oscillations, a lower limit is established for the neutrino decay lifetime τ_3/m_3>2.1×10^(-12) s/eV at 90% C.L