Alfordreimer2544

In mammals, temperature-sensitive TRP channels make membrane conductance of cells extremely temperature dependent, allowing the detection of temperature ranging from noxious cold to noxious heat. We progressively deleted the distal carboxyl terminus domain (CTD) of the cold-activated melastatin receptor channel, TRPM8. We found that the enthalpy change associated with channel gating is proportional to the length of the CTD. https://www.selleckchem.com/products/sb-415286.html Deletion of the last 36 amino acids of the CTD transforms TRPM8 into a reduced temperature-sensitivity channel (Q10 ∼4). Exposing the intracellular domain to a denaturing agent increases the energy required to open the channel indicating that cold drives channel gating by stabilizing the folded state of the CTD. Experiments in the presence of an osmoticant agent suggest that channel gating involves a change in solute-inaccessible volume in the CTD of ∼1,900 Å3 This volume matches the void space inside the coiled coil according to the cryogenic electron microscopy structure of TRPM8. The results indicate that a folding-unfolding reaction of a specialized temperature-sensitive structure is coupled to TRPM8 gating.The structural unit of eukaryotic chromatin is a nucleosome, comprising two histone H2A-H2B heterodimers and one histone (H3-H4)2 tetramer, wrapped around by ∼146 bp of DNA. The N-terminal flexible histone tails stick out from the histone core and have extensive posttranslational modifications, causing epigenetic changes of chromatin. Although crystal and cryogenic electron microscopy structures of nucleosomes are available, the flexible tail structures remain elusive. Using NMR, we have examined the dynamics of histone H3 tails in nucleosomes containing unmodified and tetra-acetylated H4 tails. In unmodified nucleosome, the H3 tail adopts a dynamic equilibrium structure between DNA-contact and reduced-contact states. In acetylated H4 nucleosome, however, the H3 tail equilibrium shifts to a mainly DNA-contact state with a minor reduced-contact state. The acetylated H4 tail is dynamically released from its own DNA-contact state to a reduced-contact state, while the H3 tail DNA-contact state becomes major. Notably, H3 K14 in the acetylated H4 nucleosome is much more accessible to acetyltransferase Gcn5 relative to unmodified nucleosome, possibly due to the formation of a favorable H3 tail conformation for Gcn5. In summary, each histone tail adopts a characteristic dynamic state but regulates one other, probably creating a histone tail network even on a nucleosome.The ribosome translates the genetic code into proteins in all domains of life. Its size and complexity demand long-range interactions that regulate ribosome function. These interactions are largely unknown. Here, we apply a global coevolution method, statistical coupling analysis (SCA), to identify coevolving residue networks (sectors) within the 23S ribosomal RNA (rRNA) of the large ribosomal subunit. As in proteins, SCA reveals a hierarchical organization of evolutionary constraints with near-independent groups of nucleotides forming physically contiguous networks within the three-dimensional structure. Using a quantitative, continuous-culture-with-deep-sequencing assay, we confirm that the top two SCA-predicted sectors contribute to ribosome function. These sectors map to distinct ribosome activities, and their origins trace to phylogenetic divergences across all domains of life. These findings provide a foundation to map ribosome allostery, explore ribosome biogenesis, and engineer ribosomes for new functions. Despite differences in chemical structure, protein and RNA enzymes appear to share a common internal logic of interaction and assembly.Medulloblastoma is the most common malignant brain tumor in children. Here we describe a medulloblastoma model using Induced pluripotent stem (iPS) cell-derived human neuroepithelial stem (NES) cells generated from a Gorlin syndrome patient carrying a germline mutation in the sonic hedgehog (SHH) receptor PTCH1. We found that Gorlin NES cells formed tumors in mouse cerebellum mimicking human medulloblastoma. Retransplantation of tumor-isolated NES (tNES) cells resulted in accelerated tumor formation, cells with reduced growth factor dependency, enhanced neurosphere formation in vitro, and increased sensitivity to Vismodegib. Using our model, we identified LGALS1 to be a GLI target gene that is up-regulated in both Gorlin tNES cells and SHH-subgroup of medulloblastoma patients. Taken together, we demonstrate that NES cells derived from Gorlin patients can be used as a resource to model medulloblastoma initiation and progression and to identify putative targets.Carbon and nitrogen isotope ratios in hair sampled from 65 communities across the central and intermountain regions of the United States and more intensively throughout 29 ZIP codes in the Salt Lake Valley, Utah, revealed a dietary divergence related to socioeconomic status as measured by cost of living, household income, and adjusted gross income. Corn-fed, animal-derived proteins were more common in the diets of lower socioeconomic status populations than were plant-derived proteins, with individual estimates of animal-derived protein diets as high as 75%; United States towns and cities averaged 57%. Similar patterns were seen across the socioeconomic status spectrum in the Salt Lake Valley. It is likely that corn-fed animal proteins were associated with concentrated animal-feeding operations, a common practice for industrial animal production in the United States today. Given recent studies highlighting the negative impacts of animal-derived proteins in our diets, hair carbon isotope ratios could provide an approach for scaling assessments of animal-sourced foods and health risks in communities across the United States.Snow plays a fundamental role in global water resources, climate, and biogeochemical processes; however, no global snow drought assessments currently exist. Changes in the duration and intensity of droughts can significantly impact ecosystems, food and water security, agriculture, hydropower, and the socioeconomics of a region. We characterize the duration and intensity of snow droughts (snow water equivalent deficits) worldwide and differences in their distributions over 1980 to 2018. We find that snow droughts became more prevalent, intensified, and lengthened across the western United States (WUS). Eastern Russia, Europe, and the WUS emerged as hot spots for snow droughts, experiencing ∼2, 16, and 28% longer snow drought durations, respectively, in the latter half of 1980 to 2018. In this second half of the record, these regions exhibited a higher probability (relative to the first half of the record) of having a snow drought exceed the average intensity from the first period by 3, 4, and 15%. The Hindu Kush and Central Asia, extratropical Andes, greater Himalayas, and Patagonia, however, experienced decreases (percent changes) in the average snow drought duration (-4, -7, -8, and -16%, respectively). Although we do not attempt to separate natural and human influences with a detailed attribution analysis, we discuss some relevant physical processes (e.g., Arctic amplification and polar vortex movement) that likely contribute to observed changes in snow drought characteristics. We also demonstrate how our framework can facilitate drought monitoring and assessment by examining two snow deficits that posed large socioeconomic challenges in the WUS (2014/2015) and Afghanistan (2017/2018).The Japanese government developed a strategy for plastics and laid out ambitious targets including the reduction of 25% for single-use plastic waste and the reuse/recycling of 60% for plastic containers and packaging by 2030. However, the current usage situation of single-use plastics including containers and packaging, which should be a basis of the strategy, is unclear. Here, we identify the nationwide material flow of plastics in Japan based on input-output tables. Of the domestic plastic demand of 8.4 Mt in 2015, 1.6 and 2.5 Mt were estimated to be for containers and packaging comprising household and industry inflows, respectively, through the purchase/procurement of products, services, and raw materials. Considering the current amount of recycling collected from households (1.0 Mt) and industries (0.3 to 0.4 Mt), the reuse/recycling target has already been achieved if the goal is limited to household container and packaging waste, as is the focus of Japan's recycling law. Conversely, the results indicate that it will be extremely difficult to reach the target collectively with industries. Therefore, it is essential that efforts be made throughout the entire supply chain. Food containers and packaging that flowed into the food-processing and food service sectors accounted for 15% of the inflow of containers and packaging into industries. Thus, the key to achieving the reuse/recycling target will comprise the collection of plastic food packaging from not only households but also the food industry. Furthermore, the collection of flexible plastic films used between industry sectors will put the target within reach.Nuclear Factor of Activated T cells 5 (NFAT5) is a transcription factor (TF) that mediates protection from adverse effects of hypertonicity by increasing transcription of genes, including those that lead to cellular accumulation of protective organic osmolytes. NFAT5 has three intrinsically ordered (ID) activation domains (ADs). Using the NFAT5 N-terminal domain (NTD), which contains AD1, as a model, we demonstrate by biophysical methods that the NTD senses osmolytes and hypertonicity, resulting in stabilization of its ID regions. In the presence of sufficient NaCl or osmolytes, trehalose and sorbitol, the NFAT5 NTD undergoes a disorder-to-order shift, adopting higher average secondary and tertiary structure. Thus, NFAT5 is activated by the stress that it protects against. In its salt and/or osmolyte-induced more ordered conformation, the NTD interacts with several proteins, including HMGI-C, which is known to protect against apoptosis. These findings raise the possibility that the increased intracellular ionic strength and elevated osmolytes caused by hypertonicity activate and stabilize NFAT5.Strata from the Ediacaran Period (635 million to 538 million years ago [Ma]) contain several examples of enigmatic, putative shell-building metazoan fossils. These fossils may provide insight into the evolution and environmental impact of biomineralization on Earth, especially if their biological affinities and modern analogs can be identified. Recently, apparent morphological similarities with extant coralline demosponges have been used to assign a poriferan affinity to Namapoikia rietoogensis, a modular encrusting construction that is found growing between (and on) microbial buildups in Namibia. Here, we present three-dimensional reconstructions of Namapoikia that we use to assess the organism's proposed affinity. Our morphological analyses, which comprise quantitative measurements of thickness, spacing, and connectivity, reveal that Namapoikia produced approximately millimeter-thick meandering and branching/merging sheets. We evaluate this reconstructed morphology in the context of poriferan biology and determine that Namapoikia likely is not a sponge-grade organism.