High-throughput screen identifies non inflammatory small molecule inducers of trained immunity

Trained immunity is characterized by epigenetic and metabolic reprogramming in response to specific stimuli. This rewiring can result in increased cytokine and effector responses to pathogenic challenges, providing nonspecific protection against disease. It may also improve immune responses to established immunotherapeutics and vaccines. Despite its promise for next-generation therapeutic design, most current understanding and experimentation is conducted with complex and heterogeneous biologically derived molecules, such as β-glucan or the Bacillus Calmette-Guérin (BCG) vaccine. This limited collection of training compounds also limits the study of the genes most involved in training responses as each molecule has both training and nontraining effects. Small molecules with tunable pharmacokinetics and delivery modalities would both assist in the study of trained immunity and its future applications. To identify small molecule inducers of trained immunity, we screened a library of 2,000 drugs and drug-like compounds. Identification of well-defined compounds can improve our understanding of innate immune memory and broaden the scope of its clinical applications. We identified over two dozen small molecules in several chemical classes that induce a training phenotype in the absence of initial immune activation—a current limitation of reported inducers of training. A surprising result was the identification of glucocorticoids, traditionally considered immunosuppressive, providing an unprecedented link between glucocorticoids and trained innate immunity. We chose seven of these top candidates to characterize and establish training activity in vivo. In this work, we expand the number of compounds known to induce trained immunity, creating alternative avenues for studying and applying innate immune training

Predator-Induced Vertical Behavior of a Ctenophore

Although many studies have focused on Mnemiopsis leidyi predation, little is known about the role of this ctenophore as prey when abundant in native and invaded pelagic systems. We examined the response of the ctenophore M. leidyi to the predatory ctenophore Beroe ovata in an experiment in which the two species could potentially sense each other while being physically separated. On average, M. leidyi responded to the predator’s presence by increasing variability in swimming speeds and by lowering their vertical distribution. Such behavior may help explain field records of vertical migration, as well as stratified and near-bottom distributions of M. leidyi

The GSK-3β-FBXL21 Axis Contributes to Circadian TCAP Degradation and Skeletal Muscle Function.

FBXL21 is a clock-controlled E3 ligase modulating circadian periodicity via subcellular-specific CRYPTOCHROME degradation. How FBXL21 regulates tissue-specific circadian physiology and what mechanism operates upstream is poorly understood. Here we report the sarcomere component TCAP as a cytoplasmic substrate of FBXL21. FBXL21 interacts with TCAP in a circadian manner antiphasic to TCAP accumulation in skeletal muscle, and circadian TCAP oscillation is disrupted in Psttm mice with an Fbxl21 hypomorph mutation. GSK-3β phosphorylates FBXL21 and TCAP to activate FBXL21-mediated, phosphodegron-dependent TCAP degradation. GSK-3β inhibition or knockdown diminishes FBXL21-Cul1 complex formation and delays FBXL21-mediated TCAP degradation. Finally, Psttm mice show significant skeletal muscle defects, including impaired fiber size, exercise tolerance, grip strength, and response to glucocorticoid-induced atrophy, in conjunction with cardiac dysfunction. These data highlight a circadian regulatory pathway where a GSK-3β-FBXL21 functional axis controls TCAP degradation via SCF complex formation and regulates skeletal muscle function

The auditory cortex of the bat Phyllostomus discolor: Localization and organization of basic response properties

<p>Abstract</p> <p>Background</p> <p>The mammalian auditory cortex can be subdivided into various fields characterized by neurophysiological and neuroarchitectural properties and by connections with different nuclei of the thalamus. Besides the primary auditory cortex, echolocating bats have cortical fields for the processing of temporal and spectral features of the echolocation pulses. This paper reports on location, neuroarchitecture and basic functional organization of the auditory cortex of the microchiropteran bat <it>Phyllostomus discolor </it>(family: Phyllostomidae).</p> <p>Results</p> <p>The auditory cortical area of <it>P. discolor </it>is located at parieto-temporal portions of the neocortex. It covers a rostro-caudal range of about 4800 μm and a medio-lateral distance of about 7000 μm on the flattened cortical surface.</p> <p>The auditory cortices of ten adult <it>P. discolor </it>were electrophysiologically mapped in detail. Responses of 849 units (single neurons and neuronal clusters up to three neurons) to pure tone stimulation were recorded extracellularly. Cortical units were characterized and classified depending on their response properties such as best frequency, auditory threshold, first spike latency, response duration, width and shape of the frequency response area and binaural interactions.</p> <p>Based on neurophysiological and neuroanatomical criteria, the auditory cortex of <it>P. discolor </it>could be subdivided into anterior and posterior ventral fields and anterior and posterior dorsal fields. The representation of response properties within the different auditory cortical fields was analyzed in detail. The two ventral fields were distinguished by their tonotopic organization with opposing frequency gradients. The dorsal cortical fields were not tonotopically organized but contained neurons that were responsive to high frequencies only.</p> <p>Conclusion</p> <p>The auditory cortex of <it>P. discolor </it>resembles the auditory cortex of other phyllostomid bats in size and basic functional organization. The tonotopically organized posterior ventral field might represent the primary auditory cortex and the tonotopically organized anterior ventral field seems to be similar to the anterior auditory field of other mammals. As most energy of the echolocation pulse of <it>P. discolor </it>is contained in the high-frequency range, the non-tonotopically organized high-frequency dorsal region seems to be particularly important for echolocation.</p

Exercise mitigates sleep-loss-induced changes in glucose tolerance, mitochondrial function, sarcoplasmic protein synthesis, and diurnal rhythms

Objective Sleep loss has emerged as a risk factor for the development of impaired glucose tolerance. The mechanisms underpinning this observation are unknown; however, both mitochondrial dysfunction and circadian misalignment have been proposed. Because exercise improves glucose tolerance and mitochondrial function, and alters circadian rhythms, we investigated whether exercise may counteract the effects induced by inadequate sleep. Methods To minimize between-group differences of baseline characteristics, 24 healthy young males were allocated into one of the three experimental groups: a Normal Sleep (NS) group (8 h time in bed (TIB) per night, for five nights), a Sleep Restriction (SR) group (4 h TIB per night, for five nights), and a Sleep Restriction and Exercise group (SR+EX) (4 h TIB per night, for five nights and three high-intensity interval exercise (HIIE) sessions). Glucose tolerance, mitochondrial respiratory function, sarcoplasmic protein synthesis (SarcPS), and diurnal measures of peripheral skin temperature were assessed pre- and post-intervention. Results We report that the SR group had reduced glucose tolerance post-intervention (mean change ± SD, P value, SR glucose AUC: 149 ± 115 A.U., P = 0.002), which was also associated with reductions in mitochondrial respiratory function (SR: -15.9 ± 12.4 pmol O2.s−1.mg−1, P = 0.001), a lower rate of SarcPS (FSR%/day SR: 1.11 ± 0.25%, P < 0.001), and reduced amplitude of diurnal rhythms. These effects were not observed when incorporating three sessions of HIIE during this period (SR+EX: glucose AUC 67 ± 57, P = 0.239, mitochondrial respiratory function: 0.6 ± 11.8 pmol O2.s−1.mg−1, P = 0.997, and SarcPS (FSR%/day): 1.77 ± 0.22%, P = 0.971). Conclusions A five-night period of sleep restriction leads to reductions in mitochondrial respiratory function, SarcPS, and amplitude of skin temperature diurnal rhythms, with a concurrent reduction in glucose tolerance. We provide novel data demonstrating that these same detrimental effects are not observed when HIIE is performed during the period of sleep restriction. These data therefore provide evidence in support of the use of HIIE as an intervention to mitigate the detrimental physiological effects of sleep loss

Phylogenomic evidence for a common ancestor of mitochondria and the SAR11 clade

Mitochondria share a common ancestor with the Alphaproteobacteria, but determining their precise origins is challenging due to inherent difficulties in phylogenetically reconstructing ancient evolutionary events. Nonetheless, phylogenetic accuracy improves with more refined tools and expanded taxon sampling. We investigated mitochondrial origins with the benefit of new, deeply branching genome sequences from the ancient and prolific SAR11 clade of Alphaproteobacteria and publicly available alphaproteobacterial and mitochondrial genome sequences. Using the automated phylogenomic pipeline Hal, we systematically studied the effect of taxon sampling and missing data to accommodate small mitochondrial genomes. The evidence supports a common origin of mitochondria and SAR11 as a sister group to the Rickettsiales. The simplest explanation of these data is that mitochondria evolved from a planktonic marine alphaproteobacterial lineage that participated in multiple inter-specific cell colonization events, in some cases yielding parasitic relationships, but in at least one case producing a symbiosis that characterizes modern eukaryotic life

Seasonal changes and population dynamics of the ctenophore Mnemiopsis leidyi after its first year of invasion in the Kiel Fjord, Western Baltic Sea

We analyzed the seasonal variations of the ctenophore Mnemiopsis leidyi weekly collected since its first record in the western Baltic Sea in October 2006. The distribution pattern together with the seasonal dynamics and population outbreaks in late summer 2007 indicate recent successfully establishment of M. leidyi in this area. Seasonal changes showed two periods of high reproductive activity characterized by a population structure dominated by small size classes, followed by an increase of larger ones. These results further revealed that the bulk of the population remains in deep layers during the periods of low population density, whereas it appeared situated in upper layers during the proliferation of the species. We further emphasized the strength of the population outbreaks, which can reach abundances >10-fold higher in time periods shorter than a week. The predatory impact this species may have in pelagic ecosystems warns on the importance of its recent range of expansion

TRY plant trait database - enhanced coverage and open access

Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns