Calcineurin (Cn), a Ca2+/calmodulin-dependent Ser/Thr protein phosphatase, is an important participant in signaling pathways that activate T cells. It is the target of the immunosuppressive drugs ...cyclosporin A (CsA) and FK506. These drugs bind proteins known as cyclophilin (Cyp) and FK506-binding protein, respectively, and the drug-protein complexes in turn inhibit Cn. We report the crystal structure of a Cyp/CsA/Cn ternary complex, determined to a resolution of 3.1 Å. Residues 3-9 of CsA, particularly N-methyl leucines 4 and 6, and Trp-121 of Cyp form a composite surface for interaction with Cn. The hydrophobic interface buries two hydrogen bonds. The structure accounts clearly for the effects of mutations in Cn on CsA-resistance and for the way modifications of CsA alter immunosuppressive activity.
Crystal structures of classical cadherins have revealed two dimeric configurations. In the first, N-terminal beta-strands of EC1 domains 'swap' between partner molecules. The second configuration ...(the 'X dimer'), also observed for T-cadherin, is mediated by residues near the EC1-EC2 calcium binding sites, and N-terminal beta-strands of partner EC1 domains, though held adjacent, do not swap. Here we show that strand-swapping mutants of type I and II classical cadherins form X dimers. Mutant cadherins impaired for X-dimer formation show no binding in short-time frame surface plasmon resonance assays, but in long-time frame experiments, they have homophilic binding affinities close to that of wild type. Further experiments show that exchange between monomers and dimers is slowed in these mutants. These results reconcile apparently disparate results from prior structural studies and suggest that X dimers are binding intermediates that facilitate the formation of strand-swapped dimers.
Ras-related small GTP-binding proteins control a wide range of cellular processes by regulating a variety of effector pathways, including prominent roles in the control of mitogen-activated protein ...kinase (MAPK) cascades. Although the regulatory role(s) for many Ras family GTPases are well established, the physiological function for the Rit/Rin subfamily has been lacking. Here, using both knockout mice and Drosophila models, we demonstrate an evolutionarily conserved role for Rit subfamily GTPases (mammalian Rit and Rin, and the Drosophila RIC homologue) in governing survival in response to oxidative stress. Primary embryonic fibroblasts derived from Rit knockout mice display increased apoptosis and selective disruption of MAPK signaling following reactive oxygen species (ROS) exposure but not in response to endoplasmic reticulum stress or DNA damage. These deficits include a reduction in ROS-mediated stimulation of a p38-MK2-HSP27 signaling cascade that controls Akt activation, directing Bad phosphorylation to promote cell survival. Furthermore, D-RIC null flies display increased susceptibility to environmental stresses and reduced stress-dependent p38 signaling, extending the Rit-p38 survival pathway to Drosophila. Together, our studies establish the Rit GTPases as critical regulators of an evolutionarily conserved, p38 MAPK-dependent signaling cascade that functions as an important survival mechanism for cells in response to oxidative stress.
During the endosymbiosis formed between plants and arbuscular mycorrhizal (AM) fungi, the root cortical cells are colonized by branched hyphae called arbuscules, which function in nutrient exchange ...with the plant 1. Despite their positive function, arbuscules are ephemeral structures, and their development is followed by a degeneration phase, in which the arbuscule and surrounding periarbuscular membrane and matrix gradually disappear from the root cell 2, 3. Currently, the root cell’s role in this process and the underlying regulatory mechanisms are unknown. Here, by using a Medicago truncatula pt4 mutant in which arbuscules degenerate prematurely 4, we identified arbuscule degeneration-associated genes, of which 38% are predicted to encode secreted hydrolases, suggesting a role in disassembly of the arbuscule and interface. Through RNAi and analysis of an insertion mutant, we identified a symbiosis-specific MYB-like transcription factor (MYB1) that suppresses arbuscule degeneration in mtpt4. In myb1, expression of several degeneration-associated genes is reduced. Conversely, in roots constitutively overexpressing MYB1, expression of degeneration-associated genes is increased and subsequent development of symbiosis is impaired. MYB1-regulated gene expression is enhanced by DELLA proteins and is dependent on NSP1 5, but not NSP2 6. Furthermore, MYB1 interacts with DELLA and NSP1. Our data identify a transcriptional program for arbuscule degeneration and reveal that its regulators include MYB1 in association with two transcriptional regulators, NSP1 and DELLA, both of which function in preceding phases of the symbiosis. We propose that the combinatorial use of transcription factors enables the sequential expression of transcriptional programs for arbuscule development and degeneration.
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•A transcriptional program associated with arbuscule degeneration during AM symbiosis•Arbuscule degeneration-associated genes encoding hydrolases are regulated by MYB1•della double and triple mutants reveal that DELLAs influence arbuscule degeneration•MYB1-regulated gene expression requires NSP1 and is enhanced by DELLAs
During AM symbiosis, the root cortical cells construct and later disassemble a membrane and matrix around the fungal symbiont. Floss et al. identify a transcriptional program associated with arbuscule degeneration and reveal that expression of degeneration-associated hydrolase genes is regulated by MYB1 in association with NSP1 and DELLAs.
Anxiety is one of the most common mental states of humans. Although it drives us to avoid frightening situations and to achieve our goals, it may also impose significant suffering and burden if it ...becomes extreme. Because we experience anxiety in a variety of forms, previous studies investigated neural substrates of anxiety in a variety of ways. These studies revealed that individuals with high state, trait, or pathological anxiety showed altered neural substrates. However, no studies have directly investigated whether the different dimensions of anxiety share a common neural substrate, despite its theoretical and practical importance. Here, we investigated a brain network of anxiety shared by different dimensions of anxiety in a unified analytical framework using functional magnetic resonance imaging (fMRI). We analyzed different datasets in a single scale, which was defined by an anxiety-related brain network derived from whole brain. We first conducted the anxiety provocation task with healthy participants who tended to feel anxiety related to obsessive-compulsive disorder (OCD) in their daily life. We found a common state anxiety brain network across participants (1585 trials obtained from 10 participants). Then, using the resting-state fMRI in combination with the participants' behavioral trait anxiety scale scores (879 participants from the Human Connectome Project), we demonstrated that trait anxiety shared the same brain network as state anxiety. Furthermore, the brain network between common to state and trait anxiety could detect patients with OCD, which is characterized by pathological anxiety-driven behaviors (174 participants from multi-site datasets). Our findings provide direct evidence that different dimensions of anxiety have a substantial biological inter-relationship. Our results also provide a biologically defined dimension of anxiety, which may promote further investigation of various human characteristics, including psychiatric disorders, from the perspective of anxiety.
•Common brain networks among different dimensions of anxiety were investigated.•The state anxiety brain network was similarly represented across participants.•There was a common brain network for trait anxiety and state anxiety.•This common brain network was generalized to pathological anxiety.
Parameter identification for wildfire forecasting models often relies on case-by-case tuning or posterior diagnosis/analysis, which can be computationally expensive due to the complexity of the ...forward prediction model. In this paper, we introduce an efficient parameter flexible fire prediction algorithm based on machine learning and reduced order modelling techniques. Using a training dataset generated by physics-based fire simulations, the method forecasts burned area at different time steps with a low computational cost. We then address the bottleneck of efficient parameter estimation by developing a novel inverse approach relying on data assimilation techniques (latent assimilation) in the reduced order space. The forward and the inverse modellings are tested on two recent large wildfire events in California. Satellite observations are used to validate the forward prediction approach and identify the model parameters. By combining these forward and inverse approaches, the system manages to integrate real-time observations for parameter adjustment, leading to more accurate future predictions.
Securing food and energy supplies presents a significant challenge to human survival and progress. The rice-wheat rotation is one of the main food crop systems in China. However, no comprehensive ...assessment of the water footprint (WF), carbon footprint (CF), carbon production efficiency (CPE), and net ecosystem economic benefits (NEEB) of different rice-wheat rotation systems has been reported.
This study was conducted to assess the productivity, WF, CF, CPE, and NEEB of dry direct-seeded, wet direct-seeded, and transplanted rice-wheat (TR-W) rotation systems. The objective was to provide theoretical guidance for the development of clean and sustainable rice-wheat rotation production technology systems.
We used a split-plot design, with the main plots being the dry direct-seeded, wet direct-seeded, and transplanted rice planting methods, and the subplots consisting of two rice genotypes. Dry direct-seeded rice was mainly rainfed, ensuring that the soil remained relatively dry so that the soil is kept aerobic during the whole reproductive period of rice. Wet direct-seeded rice continues to keep the soil moist after sowing; the plots were maintained under a water layer of 3–10 cm following the emergence of 4.5 leaves, a condition that persisted until two weeks prior to the rice harvest. Transplanted rice was maintained under a water layer of 3–10 cm following transplanting until 2 weeks prior to the rice harvest. Subsequent to the rice harvest, the above-ground rice stubble was removed, and the ground was tilled with a rotary tiller in preparation for the subsequent wheat planting.
Results demonstrated that the annual yield from the dry direct-seeded rice-wheat (DR-W) rotation system was comparable to the wet direct-seeded rice-wheat (WR-W) rotation system, while significantly lower than that of the TR-W rotation system. However, the WF of DR-W rotation system was 45.96% and 33.94% lower than that of WR-W and TR-W rotation systems, respectively, and the CF was 35.57% and 25.87% lower than that of WR-W and TR-W rotation systems, respectively. Therefore, its water and carbon production efficiencies were higher than those of WR-W and TR-W rotation systems. In addition, NEEB in DR-W and TR-W was comparable and significantly higher than that in WR-W.
The DR-W rotation was a promising rotation system according to the comparable annual yield, lower water and carbon footprints, higher CPE, and comparable or higher NEEB in comparison with other rice-wheat rotation systems.
We suggest that the DR-W rotation should be promoted as the primary production mode for the rice-wheat rotation.
•The annual yield of the DR-W was not lower than that of the WR-W and TR-W.•The DR-W has a lower water and carbon footprint than WR-W and TR-W.•The DR-W has higher carbon production efficiency than WR-W and TR-W.•The DR-W and TR-W had higher net ecosystem economic benefits than the WR-W.•The comprehensive advantage of the DR-W was greater than that of the WR-W and TR-W.
Recently, practitioners and researchers met to discuss the role of requirements, and AI and SE. We offer here notes on that fascinating discussion. Also, have you considered writing for this column? ...This “SE for AI” column publishes commentaries on the growing field of SE for AI. Submissions are welcomed and encouraged (1,000–2,400 words, each figure and table counts as 250 words, try to use fewer than 12 references, and keep the discussion practitioner focused). Please submit your ideas to me at timm@ieee.org.—Tim Menzies
The exocyst complex regulates the last steps of exocytosis, which is essential to organisms across kingdoms. In humans, its dysfunction is correlated with several significant diseases, such as ...diabetes and cancer progression. Investigation of the dynamic regulation of the evolutionarily conserved exocyst-related processes using mutants in genetically tractable organisms such as Arabidopsis thaliana is limited by the lethality or the severity of phenotypes. We discovered that the small molecule Endosidin2 (ES2) binds to the EXO70 (exocyst component of 70 kDa) subunit of the exocyst complex, resulting in inhibition of exocytosis and endosomal recycling in both plant and human cells and enhancement of plant vacuolar trafficking. An EXO70 protein with a C-terminal truncation results in dominant ES2 resistance, uncovering possible distinct regulatory roles for the N terminus of the protein. This study not only provides a valuable tool in studying exocytosis regulation but also offers a potentially new target for drugs aimed at addressing human disease.
Resistance to androgen deprivation therapies is a major driver of mortality in advanced prostate cancer. Therefore, there is a need to develop new preclinical models that allow the investigation of ...resistance mechanisms and the assessment of drugs for the treatment of castration-resistant prostate cancer.
We generated two novel cell line models (LAPC4-CR and VCaP-CR) which were derived by passaging LAPC4 and VCaP cells in vivo and in vitro under castrate conditions. We performed detailed transcriptomic (RNA-seq) and proteomic analyses (SWATH-MS) to delineate expression differences between castration-sensitive and castration-resistant cell lines. Furthermore, we characterized the in vivo and in vitro growth characteristics of these novel cell line models.
The two cell line derivatives LAPC4-CR and VCaP-CR showed castration-resistant growth in vitro and in vivo which was only minimally inhibited by AR antagonists, enzalutamide, and bicalutamide. High-dose androgen treatment resulted in significant growth arrest of VCaP-CR but not in LAPC4-CR cells. Both cell lines maintained AR expression, but exhibited distinct expression changes on the mRNA and protein level. Integrated analyses including data from LNCaP and the previously described castration-resistant LNCaP-abl cells revealed an expression signature of castration resistance.
The two novel cell line models LAPC4-CR and VCaP-CR and their comprehensive characterization on the RNA and protein level represent important resources to study the molecular mechanisms of castration resistance.
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