Abstract
Despite many behavioral and neuroimaging investigations, it remains unclear how the human cortex represents spectrotemporal sound features during auditory imagery, and how this ...representation compares to auditory perception. To assess this, we recorded electrocorticographic signals from an epileptic patient with proficient music ability in 2 conditions. First, the participant played 2 piano pieces on an electronic piano with the sound volume of the digital keyboard on. Second, the participant replayed the same piano pieces, but without auditory feedback, and the participant was asked to imagine hearing the music in his mind. In both conditions, the sound output of the keyboard was recorded, thus allowing precise time-locking between the neural activity and the spectrotemporal content of the music imagery. This novel task design provided a unique opportunity to apply receptive field modeling techniques to quantitatively study neural encoding during auditory mental imagery. In both conditions, we built encoding models to predict high gamma neural activity (70-150 Hz) from the spectrogram representation of the recorded sound. We found robust spectrotemporal receptive fields during auditory imagery with substantial, but not complete overlap in frequency tuning and cortical location compared to receptive fields measured during auditory perception.
The suppression of tumorigenicity 2/IL-33 (ST2/IL-33) pathway has been implicated in several immune and inflammatory diseases. ST2 is produced as 2 isoforms. The membrane-bound isoform (ST2L) induces ...an immune response when bound to its ligand, IL-33. The other isoform is a soluble protein (sST2) that is thought to be a decoy receptor for IL-33 signaling. Elevated sST2 levels in serum are associated with an increased risk for cardiovascular disease. We investigated the determinants of sST2 plasma concentrations in 2,991 Framingham Offspring Cohort participants. While clinical and environmental factors explained some variation in sST2 levels, much of the variation in sST2 production was driven by genetic factors. In a genome-wide association study (GWAS), multiple SNPs within IL1RL1 (the gene encoding ST2) demonstrated associations with sST2 concentrations. Five missense variants of IL1RL1 correlated with higher sST2 levels in the GWAS and mapped to the intracellular domain of ST2, which is absent in sST2. In a cell culture model, IL1RL1 missense variants increased sST2 expression by inducing IL-33 expression and enhancing IL-33 responsiveness (via ST2L). Our data suggest that genetic variation in IL1RL1 can result in increased levels of sST2 and alter immune and inflammatory signaling through the ST2/IL-33 pathway.
Summary
In a world that will rely increasingly on efficient plant growth for sufficient food, it is important to learn about natural mechanisms of phytohormone action. In this work, the introduction ...of a fluorophore to an auxin molecule represents a sensitive and non‐invasive method to directly visualise auxin localisation with high spatiotemporal resolution.
The state‐of‐the‐art multidisciplinary approaches of genetic and chemical biology analysis together with live cell imaging, liquid chromatography–mass spectrometry (LC‐MS) and surface plasmon resonance (SPR) methods were employed for the characterisation of auxin‐related biological activity, distribution and stability of the presented compounds in Arabidopsis thaliana.
Despite partial metabolisation in vivo, these fluorescent auxins display an uneven and dynamic distribution leading to the formation of fluorescence maxima in tissues known to concentrate natural auxin, such as the concave side of the apical hook. Importantly, their distribution is altered in response to different exogenous stimuli in both roots and shoots. Moreover, we characterised the subcellular localisation of the fluorescent auxin analogues as being present in the endoplasmic reticulum and endosomes.
Our work provides powerful tools to visualise auxin distribution within different plant tissues at cellular or subcellular levels and in response to internal and environmental stimuli during plant development.
De novo lymphangiogenesis influences the course of different human diseases as diverse as chronic renal transplant rejection and tumor metastasis. The cellular mechanisms of lymphangiogenesis in ...human diseases are currently unknown, and could involve division of local preexisting endothelial cells or incorporation of circulating progenitors. We analyzed renal tissues of individuals with gender-mismatched transplants who had transplant rejection and high rates of overall lymphatic endothelial proliferation as well as massive chronic inflammation. Donor-derived cells were detected by in situ hybridization of the Y chromosome. We compared these tissues with biopsies of essentially normal skin and intestine, and two rare carcinomas with low rates of lymphatic endothelial proliferation that were derived from individuals with gender-mismatched bone marrow transplants. Here, we provide evidence for the participation of recipient-derived lymphatic progenitor cells in renal transplants. In contrast, lymphatic vessels of normal tissues and those around post-transplant carcinomas did not incorporate donor-derived progenitors. This indicates a stepwise mechanism of inflammation-associated de novo lymphangiogenesis, implying that potential lymphatic progenitor cells derive from the circulation, transmigrate through the connective tissue stroma, presumably in the form of macrophages, and finally incorporate into the growing lymphatic vessel.
The stereoselective synthesis of a variety of functionalized hydroindoles suitable as building blocks for thiodiketopiperazine natural products such as rostratins B–D is reported. The key precursor ...for all transformations is a previously reported hexahydroindole compound. All functional groups were installed with the desired stereochemistry and the feasibility of the synthetic strategy was exemplified by dimerization of two hydroindole units to form the pentacyclic C2‐symmetric scaffold of rostratin C.
Mycotoxins via dimerization: The stereoselective synthesis of a variety of functionalized hydroindoles suitable as building blocks for thiodiketopiperazine natural products such as the mycotoxins rostratins B–D is reported. All functional groups were successfully installed with the desired stereochemistry, and dimerization of two hydroindole units resulted in the pentacyclic C2‐symmetric scaffold of rostratin C (see scheme).
Reports detailing the prognostic impact of TP53 mutations in medulloblastoma offer conflicting conclusions. We resolve this issue through the inclusion of molecular subgroup profiles.
We determined ...subgroup affiliation, TP53 mutation status, and clinical outcome in a discovery cohort of 397 medulloblastomas. We subsequently validated our results on an independent cohort of 156 medulloblastomas.
TP53 mutations are enriched in wingless (WNT; 16%) and sonic hedgehog (SHH; 21%) medulloblastomas and are virtually absent in subgroups 3 and 4 tumors (P < .001). Patients with SHH/TP53 mutant tumors are almost exclusively between ages 5 and 18 years, dramatically different from the general SHH distribution (P < .001). Children with SHH/TP53 mutant tumors harbor 56% germline TP53 mutations, which are not observed in children with WNT/TP53 mutant tumors. Five-year overall survival (OS; ± SE) was 41% ± 9% and 81% ± 5% for patients with SHH medulloblastomas with and without TP53 mutations, respectively (P < .001). Furthermore, TP53 mutations accounted for 72% of deaths in children older than 5 years with SHH medulloblastomas. In contrast, 5-year OS rates were 90% ± 9% and 97% ± 3% for patients with WNT tumors with and without TP53 mutations (P = .21). Multivariate analysis revealed that TP53 status was the most important risk factor for SHH medulloblastoma. Survival rates in the validation cohort mimicked the discovery results, revealing that poor survival of TP53 mutations is restricted to patients with SHH medulloblastomas (P = .012) and not WNT tumors.
Subgroup-specific analysis reconciles prior conflicting publications and confirms that TP53 mutations are enriched among SHH medulloblastomas, in which they portend poor outcome and account for a large proportion of treatment failures in these patients.
Rain-index insurance is strongly advocated in many parts of the developing world to help farmers to cope with climatic risk that prevails in (semi-)arid rangelands due to low and highly uncertain ...rainfall. We present a modeling analysis of how the availability of rain-index insurance affects the sustainability of rangeland management. We show that a rain-index insurance with frequent payoffs, i.e. a high strike level, leads to the choice of less sustainable grazing management than without insurance available. However, rain-index insurance with a low to medium strike level enhances the farmer's well-being while not impairing the sustainability of rangeland management.
► We study natural and financial insurance against climate risks in rangelands. ► We analyze a dynamic and stochastic coupled ecological–economic model. ► Resting in rainy years acts as natural insurance for managing climate risk. ► Introducing rain-index insurance can have adverse effects on sustainability. ► Adequate insurance design – a low strike level – may reduce negative effects.
In acute inflammatory lung disease in newborn infants, exogenous surfactant only transiently improves lung function. We hypothesized that the transient nature of this protection is in part explained ...by elevated acid sphingomyelinase (a-SMase) activity that may inactivate surfactant and promote proinflammatory responses.
We investigated the intermediate-term effects (>12 h) of a-SMase inhibition in a neonatal piglet model of repeated airway lavage by the intratracheal use of the a-SMase inhibitor imipramine, together with exogenous surfactant as a carrier substance.
After surfactant washout and induction of pulmonary inflammation, lung function was monitored over 24 hours of mechanical ventilation and followed by ex vivo analyses. In addition, we studied the effect of lipopolysaccharide inhalation in a-SMase-deficient mice at 48 hours.
Surfactant washout increased both pulmonary a-SMase activity and ceramide content; this was attenuated by surfactant and prevented in the surfactant plus imipramine group. Compared with surfactant alone, Pa(O(2)), dynamic compliance, and extravascular lung water were improved in the final 12 hours in the surfactant plus imipramine group. At 24 hours, lavage fluid leukocyte counts and IL-8 concentrations decreased, and physical surfactant film properties improved. In the mouse model at 48 hours, a-SMase-deficient mice showed reduced pulmonary ceramide levels and attenuated leukocyte influx into the alveolar space.
We conclude that stabilization of exogenous surfactant by adding imipramine to create a "fortified surfactant preparation" improves lung function in a clinically relevant piglet model, and that this effect can be attributed to the inhibition of a-SMase as evidenced in the mouse model.
Living kidney donor safety requires reliable long-term follow-up of renal function after donation. The current study aimed to define the precision and accuracy of post-donation estimated glomerular ...filtration rate (eGFR) slopes compared with measured GFR (mGFR) slopes.
In 349 donors (age 51 ± 10, 54% female), we analysed eGFR according to the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault/body surface area (CG/BSA), creatinine clearance (CrCl) and mGFR (125I-iothalamate) changes from 3 months until 5 years post-donation.
Donors had a pre-donation mGFR of 116 ± 23 mL/min, at 3 months post-donation mGFR was 73 ± 14 mL/min and at 5 years it was 79 ± 16 mL/min. Between 3 months and 5 years post-donation, 28% of donors had a declining mGFR (-0.82 ± 0.79 mL/min/year), 47% were stable and 25% had an increasing mGFR. Overall, eGFR equations showed good slope estimates (bias eGFRCKD-EPI 0.13 ± 2.16 mL/min/year, eGFRMDRD 0.19 ± 2.10 mL/min/year, eGFRCG/BSA -0.08 ± 2.06 mL/min/year, CrCl -0.12 ± 4.75 mL/min/year), but in donors with a decreasing mGFR the slope was underestimated (bias eGFRCKD-EPI 1.41 ± 2.03 mL/min/year, eGFRMDRD 1.51 ± 1.96 mL/min/year, eGFRCG/BSA 1.20 ± 1.87 mL/min/year). The CrCl had a high imprecision bias interquartile range -1.51-3.41 mL/min/year.
All eGFR equations underestimated GFR slopes in donors with a declining GFR between 3 months and 5 years post-donation. This study underlines the value of mGFR in the follow-up of donors with risk of progressive GFR loss.
The active site of potassium (K+) channels catalyses the transport of K+ ions across the plasma membrane—similar to the catalytic function of the active site of an enzyme—and is inhibited by toxins ...from scorpion venom. On the basis of the conserved structures of K+ pore regions and scorpion toxins, detailed structures for the K+ channel–scorpion toxin binding interface have been proposed. In these models and in previous solution-state nuclear magnetic resonance (NMR) studies using detergent-solubilized membrane proteins, scorpion toxins were docked to the extracellular entrance of the K+ channel pore assuming rigid, preformed binding sites. Using high-resolution solid-state NMR spectroscopy, here we show that high-affinity binding of the scorpion toxin kaliotoxin to a chimaeric K+ channel (KcsA-Kv1.3) is associated with significant structural rearrangements in both molecules. Our approach involves a combined analysis of chemical shifts and proton–proton distances and demonstrates that solid-state NMR is a sensitive method for analysing the structure of a membrane protein–inhibitor complex. We propose that structural flexibility of the K+ channel and the toxin represents an important determinant for the high specificity of toxin–K+ channel interactions.
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