Potentiation of neuronal nicotinic receptors by 17β-estradiol: Roles of the carboxy-terminal and the amino-terminal extracellular domains

The endogenous steroid 17β-estradiol (βEST) potentiates activation of neuronal nicotinic receptors containing α4 subunits. Previous work has shown that the final 4 residues of the α4 subunit are required for potentiation. However, receptors containing the α2 subunit are not potentiated although it has these 4 residues, and only one amino acid difference in the C-terminal tail (FLAGMI vs. WLAGMI). Previous work had indicated that the tryptophan residue was involved in binding an analog of βEST, but not in potentiation by βEST. To determine the structural basis for the loss of potentiation we analyzed data from chimeric subunits, which indicated that the major factor underlying the difference between α2 and α4 is the tryptophan/phenylalanine difference, while the N-terminal extracellular domain is a less significant factor. When the tryptophan in α4 was mutated, both phenylalanine and tyrosine conferred lower potentiation while lysine and leucine did not. The reduction reflected a reduced maximal magnitude of potentiation, indicating that the tryptophan is involved in transduction of steroid effects. The regions of the α4 N-terminal extracellular domain involved in potentiation lie near the agonist-binding pocket, rather than close to the membrane or the C-terminal tail, and appear to be involved in transduction rather than binding. These observations indicate that the C-terminal region is involved in both steroid binding (AGMI residues) and transduction (W). The role of the N-terminus appears to be independent of the C-terminal tryptophan and likely reflects an influence on conformational changes caused during channel activation by agonist and potentiation by estradiol

A portable site: a binding element for 17β-estradiol can be placed on any subunit of a nicotinic α4β2 receptor

Endogenous steroids can modulate the activity of transmitter-gated channels by directly interacting with the receptor. 17β-Estradiol potentiates activation of neuronal nicotinic α4β2 receptors by interacting with a 4 amino-acid sequence at the extreme carboxy-terminus of the α4 subunit, but it is not known whether potentiation requires that the sequence be placed on a specific subunit (e.g. an α4 subunit which is involved in forming an acetylcholine-binding site). By using concatemers of subunits and chimeric subunits, we have found that the carboxy-terminal domain can be moved from the α4 to the β2 subunit and still result in potentiation. In addition, the sequence can be placed on a subunit which contributes to an acetylcholine-binding site or on the structural subunit. The data indicate that this estradiol-binding element is a discrete sequence, and suggest that the effect of 17β-estradiol is mediated by actions on single subunits and that the overall consequences for gating occur due to the summation of independent energetic contributions to overall gating of this receptor

AN INTEGRATED GEOMECHANICS AND PETROPHYSICS STUDY OF HYDRAULIC FRACTURING IN NATURALLY FRACTURED RESERVOIRS

Production enhancement of tight reservoirs requires in-depth analysis of mechanisms governing hydraulic fracturing, especially in naturally fractured reservoirs. This study is dedicated to the optimization of hydraulic fracturing and drilling by integrating both rock fracture mechanics and petrophysics study. Fracture twist near the borehole adversely impair production rate or induce premature screenout, and is analyzed in terms of mixed-mode fracture propagation. The best fracture propagation criterion is selected by comparing experimental and theoretical fracture initiation angles, suggestions regarding the alleviation of fracture twist are summarized by sensitivity analysis. Accurate estimation of fracture gradient is critical for both drilling and hydraulic fracturing. Fracture gradient by traditional methods is greatly overestimated due to the ignorance of preexisting fractures, nonlinear near wellbore stress concentration acting on fracture surfaces, and nonlinear fluid pressure distribution inside fractures. A weight function method is firstly introduced to petroleum engineering for the calculation of stress intensity factor where there are preexisting fractures intersecting borehole. Weight function parameters of a pair of symmetrical fractures emanating from borehole are derived and verified against existing models. The weight function parameters are applied to predict breakdown pressure of preexisting fractures. The simulation results are compared against both measured breakdown pressure in both fields and laboratory and results of classical fracture models. The proven weight function method shows a great potential in improving the accuracy of breakdown pressure prediction. Screening fracture candidates plays a central role in hydraulic fracturing design. Identification of fracture barrier helps prevent freshwater aquifer from contamination and undesirable water breakthrough due to unintentional cross of fracture barriers. New definition of brittleness is developed and benchmarked for unconventional shale. Correlations of brittleness with neutron porosity and compressional slowness are built for predicting brittleness in the fields lacking specific logging data, and saving cost of logging service. Fracability index model is firstly developed for screening fracturing candidates and fracture barrier identification by integrating brittleness and fracture energy (or fracture toughness, Young’s modulus, tensile strength). Its interpretation result is proven by logging interpretation. It is found that it is not always right that formations with high brittleness are good fracturing candidates. The fracability index model refines the formation evaluation and narrows the thickness of target interval. This research establishes a comprehensive understanding regarding fracture twist, mixed-mode fracture propagation, fracture gradient prediction, fracturing candidate selection by integrating theoretical modeling, experimental efforts, and logging interpretation. The methodologies will not only help engineers improve hydraulic fracturing design, but also provide evidence and theoretical support for explaining previously failed cases

Chat-UniVi: Unified Visual Representation Empowers Large Language Models with Image and Video Understanding

Large language models have demonstrated impressive universal capabilities across a wide range of open-ended tasks and have extended their utility to encompass multimodal conversations. However, existing methods encounter challenges in effectively handling both image and video understanding, particularly with limited visual tokens. In this work, we introduce Chat-UniVi, a unified vision-language model capable of comprehending and engaging in conversations involving images and videos through a unified visual representation. Specifically, we employ a set of dynamic visual tokens to uniformly represent images and videos. This representation framework empowers the model to efficiently utilize a limited number of visual tokens to simultaneously capture the spatial details necessary for images and the comprehensive temporal relationship required for videos. Moreover, we leverage a multi-scale representation, enabling the model to perceive both high-level semantic concepts and low-level visual details. Notably, Chat-UniVi is trained on a mixed dataset containing both images and videos, allowing direct application to tasks involving both mediums without requiring any modifications. Extensive experimental results demonstrate that Chat-UniVi, as a unified model, consistently outperforms even existing methods exclusively designed for either images or videos.Comment: 26 page

Improving Lake Mixing Process Simulations in the Community Land Model by Using K Profile Parameterization

We improved lake mixing process simulations by applying a vertical mixing scheme, K profile parameterization (KPP), in the Community Land Model (CLM) version 4.5, developed by the National Center for Atmospheric Research. Vertical mixing of the lake water column can significantly affect heat transfer and vertical temperature profiles. However, the current vertical mixing scheme in CLM requires an arbitrarily enlarged eddy diffusivity to enhance water mixing. The coupled CLM-KPP considers a boundary layer for eddy development, and in the lake interior water mixing is associated with internal wave activity and shear instability. We chose a lake in Arctic Alaska and a lake on the Tibetan Plateau to evaluate this improved lake model. Results demonstrated that CLM-KPP reproduced the observed lake mixing and significantly improved lake temperature simulations when compared to the original CLM. Our newly improved model better represents the transition between stratification and turnover. This improved lake model has great potential for reliable physical lake process predictions and better ecosystem services

The Nicotinic a5 Subunit Can Replace Either an Acetylcholine-Binding or Nonbinding Subunit in the a4b2* Neuronal Nicotinic Receptor

ABSTRACT Heteropentameric neuronal nicotinic receptors assemble so that the canonical acetylcholine-binding sites are located at the interfaces between two pairs of subunits, while the fifth subunit does not participate in a canonical transmitter-binding site. Several subunits are considered to be unable to participate in forming a functional receptor when they occupy a position that would contribute to such a site, including the a5 subunit. The a5 subunit is of interest because of its apparent involvement in nicotine dependence and in the control of dopamine release. We have examined this question using a4 and b2 subunits in concatemeric constructs with the a5 subunit, expressed in Xenopus oocytes. Using dimeric constructs of a4 and b2 subunits expressed with free a5 and pentameric constructs incorporating a single copy of a5, we find that the a5 subunit can occupy the position of a nonbinding subunit, or replace a b2 subunit participating in a canonical binding site. The resulting receptors functionally resemble pentamers assembled with two copies of a4 and three copies of b2. Functional receptors apparently cannot be formed with a5 subunits in both canonical binding sites. These observations extend the present ideas on the possible positions in the pentamer that may be occupied by the a5 subunit, and suggest that additional physiologic or pharmacological subtypes of neuronal nicotinic receptors may be present in neurons

Evaluation of Arctic sea ice simulation of CMIP6 models from China

Nine coupled climate models from China participating in the Coupled Model Intercomparison Project Phase 6 (CMIP6) were evaluated in terms of their capability in ensemble historical Arctic sea ice simulation in the context of 56 CMIP6 models. We evaluated these nine models using satellite observations from 1980 to 2014. This evaluation was conducted comprehensively using 12 metrics covering different aspects of the seasonal cycle and long-term trend of sea ice extent (SIE) and sea ice concentration (SIC). The nine Chinese models tended to overestimate SIE, especially in March, and underestimate its long-term decline trend. There was less spread in model skill in reproducing the spatial pattern of March SIC than in reproducing the spatial pattern of September SIC. The error of March SIC simulation was distributed at the margins of sea ice cover, such as in the Nordic Seas, the Barents Sea, the Labrador Sea, the Bering Sea, and the Sea of Okhotsk. However, the error of September SIC was distributed both at the margins of sea ice cover and in the central part of the Arctic Basin. Five of these nine models had capabilities comparable with the majority of the CMIP6 models in reproducing the seasonal cycle and long-term trend of Arctic sea ice

Analysis of gene expression profiles in response to Sporisorium reilianum f. sp. zeae in maize ( Zea mays L.)

Background: Head smut of maize, which is caused by Sporisorium reilianum f. sp. zeae (K\ufchn), is a serious disease in maize. In order to reveal the molecular mechanism of the resistance to head smut in maize, a microarray containing ~14,850 probes was used to monitor the gene expression profiles between a disease resistant near isogenic line (NIL) and a highly susceptible inbred line after S. reilianum was injected with an artificial inoculation method. Results: Levels of expression for 3,532 genes accounting for 23.8% of the total probes changed after inoculation. Gene Ontology analysis revealed that the differentially expressed genes participated in physiological and biochemical pathways. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that plant\u2013pathogen interaction, natural killer cell mediated cytotoxicity and benzoxazinoid biosynthesis pathways play important roles in resistance to head smut. Three head smut resistance-related candidate genes, CLAVATA1, bassinosteroid insensitive 1-associated receptor kinase 1 and LOC100217307 with leucine-rich repeat (LRR) conserved domains were identified, each of which is in maize mapping bin 2.09, a region previously shown to include a major QTL for head smut resistance. Furthermore, LOC100217307 was validated by quantitative real-time (qRT)-PCR inferring that this gene may be involved in the resistance to head smut of maize. Conclusions: This study provided valuable information for cloning, functional analysis and marker assisted breeding of head smut resistance genes