Miracle-dz/UniFAR-FTUs huggingface dataset:
Flapping loops : roles for hinges in a ligand-binding domain of the nicotinic receptor ( A perspective for " Glycine hinges with opposing actions at the acetylcholine receptor-channel transmitter binding site "

One of the goals of molecular pharmacology is to understand the machinery that converts information about the presence of a chemical (binding) to a functional consequence. Agonists are drugs which bind to their molecular targets and cause conformational changes underlying activation of the target. Inevitably, therefore, it can be difficult to disentangle the affinity of the agonist for the target from its efficacy in producing the ensuing conformational change. Efficacy depends on two factors: the intrinsic equilibrium between active and inactive states in the absence of agonist, and the energy contributed by the agonist due to the relative affinities of agonist for the active and inactive states. These difficulties are particularly frustrating when the goal is to determine the role(s) that particular residues in a target protein have in shaping the overall efficacy of a drug: how is it possible to unambiguously distinguish a role in determining intrinsic efficacy from one in determining relative affinity? This perspective highlights a research article in this issue (p.___) which demonstrates a quantitative approach to the resolution of this problem in the case of activation of the muscle nicotinic receptor. This elegant (if demanding) approach involves determining, separately, the consequences of specific mutations on gating in the unliganded and liganded states. 4 The evolution of our thinking about how drug effects are mediated received a strong impetus when Langley (Langley, 1905) proposed that nicotine combines with a specific receptive substance in striated muscle (see Figure 1A) and shortly afterwards Hill (Hill, 1909) derived a simple binding equation. However, further advances in understanding agonist activity were slow in coming. In 1956 Stephenson (Stephenson, 1956) introduced the concept that "affinity," the binding interaction between drug and target, and "efficacy," the ability of the drug to produce an effect, are separable. del Castillo and Katz (del Castillo and Katz, 1957) were the first to propose a specific kinetic scheme with separate steps for binding and activation (Figure 1B), again for the muscle nicotinic receptor to explain the nature of partial agonists. Subsequent work demonstrated that almost all of the active nicotinic receptors had 2 bound agonist molecules. The advent of high resolution single channel recordings then provided evidence that the receptors could be active, albeit rarely, when only a single agonist was bound (Colquhoun and Sakmann, 1985), or even in the absence of agonist (Jackson, 1984). At present the core activation scheme for the nicotinic receptor shows …
Nervous System Defects of Ankyrin B ( Ϫ / Ϫ ) Mice Suggest Functional Overlap between the Cell Adhesion Molecule L1 and 440-kd Ankyrin B in Premyelinated Axons

The L1 CAM family of cell adhesion molecules and the ankyrin family of spectrin-binding proteins are candidates to collaborate in transcellular complexes used in diverse contexts in nervous systems of vertebrates and invertebrates. This report presents evidence for functional coupling between L1 and 440-kD ankyrin B in premyelinated axons in the mouse nervous system. L1 and 440-kD ankyrin B are colocalized in pre-myelinated axon tracts in the developing nervous system and are both down-regulated after myelination. Ankyrin B (Ϫ / Ϫ) mice exhibit a phenotype similar to, but more severe, than L1 (Ϫ / Ϫ) mice and share features of human patients with L1 mutations. Ankyrin B (Ϫ / Ϫ) mice exhibit hypoplasia of the corpus callosum and pyramidal tracts, dilated ventricles, and extensive degeneration of the optic nerve, and they die by postna-tal day 21. Ankyrin B (Ϫ / Ϫ) mice have reduced L1 in premyelinated axons of long fiber tracts, including the corpus callosum, fimbria, and internal capsule in the brain, and pyramidal tracts and lateral columns of the spinal cord. L1 was evident in the optic nerve at postna-tal day 1 but disappeared by postnatal day 7 in mutant mice while NCAM was unchanged. Optic nerve axons of ankyrin B (Ϫ / Ϫ) mice become dilated with diameters up to eightfold greater than normal, and they degenerated by day 20. These findings provide the first evidence for a role of ankyrin B in the nervous system and support an interaction between 440-kD ankyrin B and L1 that is essential for maintenance of premyelinated axons in vivo. T he L1 CAM 1 family of cell adhesion molecules (comprised of L1, NgCAM, NrCAM, CHL1, and neurofascin) is a major contributor to intercellular interactions in the vertebrate nervous system (Hortsch, 1996; Brummendorf et al., 1998). L1 CAM molecules, which are represented in Drosophila by neuroglian (Bie-ber et al., 1989), possess variable extracellular domains composed of six Ig domains, three to five fibronectin type III domains, and a relatively conserved cytoplasmic domain (Sonderegger and Rathjen, 1992; Hortsch, 1996). Ex-tracellular domains of L1 CAMs participate in homophilic interactions as well as a variety of interactions with soluble proteins and other cell adhesion molecules (Hortsch, 1996; Brummendorf et al., 1998). Extensive diversity in extracel-lular interactions of L1 CAM family members is provided by divergence between extracellular domains encoded by different genes as well as multiple alternatively spliced variants of each gene (as many …
Assessing Vulnerability and Adaptation to Climate Change by Farming Communities in Southwestern Coastal Bangladesh

Southwestern coastal Bangladesh is characterized by low-lying topography, high productive mangrove ecosystem and unique biodiversity. At the same time, the region is highly prone to cyclones, coasting flooding, and salinity, which causes huge losses to agriculture production and rural livelihoods. Marginal and small farmers are affected more. The objective of this paper is to examine the extent of climatic variations and to analyze farming communities’ vulnerabilities and adaptations to climate change in the saline prone southwestern coastal Bangladesh. We used both primary and secondary data for this study. We collected primary data from Atulia and Padmapukur unions of Shyamnagar upazila under Satkhira district of Bangladesh in April 2013. We collected secondary data from published statistics. We did not find significant changes in temperature and rainfall over time but salinity level has increased over time. Major vulnerability faced by farming communities due to climate change were saline water intrusion, scarcity of safe drinking and irrigation water, and problems on crop production, livestock rearing, fresh water fish culture, and sanitary latrines. Major adaptations practiced by farmers were culturing saline water shrimp in farms, harvesting rain water, drinking pond’s water, catching fish from the sea and river, and desalinization of river water by constructing embankments. Agricultural adaptation practices such as saline tolerant rice varieties cultivation, crabs fattening, sowing and planting date shifting, mulching, soil flashing, fertilizers management, seeds sowing using dibbling method, raise or slopping bed method crop cultivation in embankments, pit method crop cultivation, changing cropping patterns, zero tillage, and sorjan method crop cultivation can helps minimize the impacts of climate change, particularly to vulnerable smallholder farmers. Policies and programs are needed to develop and disseminate these adaptation practices complemented by farmers’ training on these practices. DOI: http://dx.doi. org/10.3329/jesnr.v7i2. 22200 J. Environ. Sci. & Natural Resources, 7(2): 31-35 2014
Borehole coupling at sonic frequencies

An elastic plane wave incident on a borehole couples through the borehole wall to produce a compressional wave inside the borehole, and the effect of this coupling varies with incident angle. Imaging experiments that include a downhole source and/or hydrophones must account for this effect to achieve optimal results. In configurations pertinent to VSP surveys and cross‐well surveys at seismic frequencies, a low‐frequency source can be assumed. Recently, however, both cross‐well and single‐well imaging experiments have been undertaken at sonic frequencies (above 2000 Hz) where low‐frequency approximations are no longer valid. We have developed new formulas which are valid over all frequencies and incident angles. For both shear and compressional incident waves, we present explicit formulas to describe this dependence. Contrary to what might be expected from low‐frequency approximations, we find that at certain angles and for high enough frequencies, marked resonances in the coupling terms for both shear an.
Possible Joint Pathways of Early Pre-eclampsia and Congenital Heart Defects via Angiogenic Imbalance and Potential Evidence for Cardio-placental Syndrome This Editorial Refers to 'maternal and Foetal Angiogenic Imbalance in Congenital Heart Defects'

Foetal vasculogenesis and angiogenesis and maternal angiogenesis are essential requirements for a pregnancy. Decidua-associated vascular changes arise in the inner junctional zone myometrium in early pregnancy, followed by trophoblast invasion with associated remodelling. 1 Decidual natural killer and dendritic cells regulate key developmental processes at the human foetal – maternal interface via human leucocyte antigen (HLA)-C, HLA-E, and HLA-G. 2 Intervillous flow starts at 7 – 8 weeks gestation, via connecting channels between maternal myometrial spiral arteries and lacunae in the wall of the implanted cytoblast. Early tropho-blast plugging might protect the embryo against high oxygen concentrations , and it has to be postulated that premature loss of those plugs could lead to early miscarriage or early-onset pre-eclampsia. 3 In the past decade, extensive research has investigated the abnormalities that can occur in the first trimester of pregnancy that could lead to chorionic regression or small placenta, contributing to intra-uterine growth restriction and early-onset pre-eclampsia. 4 Placental flow defects can occur as early as 12 weeks in women who subsequently develop pre-eclampsia. Hypoxia and reoxygenation episodes can generate reactive oxygen species, leading to placental oxidative stress and placental dysfunction. Although the causes of pre-eclampsia, defined as new hypertension (diastolic blood pressure .90 mmHg) and substantial proteinuria (.300 mg in 24 h) after 20 weeks gestation, 4 remains largely unknown, the leading hypothesis strongly suggests disturbed placental function in early pregnancy, possibly due to failed interaction between two genetically different organisms. 4 As a second stage of the foetal – maternal interphase, research by Levine and Karumanchi has shown an increased production of bioactive trophoblast debris, including an excess of syncytiotrophoblast-derived antiangiogenic factors, such as soluble forms of vascular endothelial growth factor (VEGF) receptors, including the VEGF receptor-1, also called fms-like tyrosine kinase 1 (Flt-1). 5 This excessive systemic inflammatory response results in endothe-lial dysfunction and an associated increase in vascular reactivity, preceding onset of the clinical condition pre-eclampsia, which affects 2–8 % of all pregnancies. 4 Flt-1 is expressed on endothelial cells and macrophages, and binds to VEGF and a platelet-derived protein called placental growth factor (PlGF), with a wide range of functions which are not completely understood. 6 A potential endogenous opponent of PlGF in the plasma is soluble fms-like tyrosine kinase (sFlt-1), which represents a type of Flt-1, without the transmembrane and intracellular tyrosine kinase domain. sFlt-1 and PlGF have comprehensive involvement not only in the development of …
Exploiting CPU Bit Parallel Operations to Improve Efficiency in Search

It is the authors' belief that the ability of processors to compute bit parallel operations should have a right to exist as an optimization discipline, rather than a state-of- the-art technique. This paper is a step forward in this direction analysing a number of key issues related to bit model design and implementation of search problems. Building efficient search algorithms optimized at bit level is a difficult task It requires not only a good implementation but also an adequate model so as to make bitwise operations meaningful, and only by addressing design and implementation globally an improvement in efficiency can be obtained. On the other hand, we have proved in this paper that the improvement can conceivably be exponential on the size of the CPU register for problems in NP. This global approach has been used to implement the fastest complete algorithm, to the best of our knowledge, for the maximum clique problem, an important NP-hard combinatorial problem from the graph domain. Our solver clearly outperforms other existing algorithms for hard instances, in some cases by nearly an order of magnitude.
Additional cause for reduced JA-Ile in the root of a Lotus japonicus phyB mutant

Light is critical for supplying carbon for use in the energetically expensive process of nitrogen-fixing symbiosis between legumes and rhizobia. We recently showed that root nodule formation in phyB mutants [which have a constitutive shade avoidance syndrome (SAS) phenotype] was suppressed in white light, and that nodulation in wild-type is controlled by sensing the R/FR ratio through jasmonic acid (JA) signaling. We concluded that the cause of reduced root nodule formation in phyB mutants was the inhibition of JA-Ile production in root. Here we show that the shoot JA-Ile level of phyB mutants is higher than that of the wild-type strain MG20, suggesting that translocation of JA-Ile from shoot to root is impeded in the mutant. These results indicate that root nodule formation in phyB mutants is suppressed both by decreased JA-Ile production, caused by reduced JAR1 activity in root, and by reduced JA-Ile translocation from shoot to root.
Tethyan collision forces and the stress field of the Eurasian plate

Resistive forces along convergent plate boundaries have a major impact on surface deformation, most visibly at collisional plate boundaries. Although quantification of these forces is key to understanding the evolution and present state of mountain belts, they remain highly uncertain due to the complexity of plate boundary structures and rheologies. In previous studies of the Eurasian Plate, we have analysed the balance of plate boundary forces, tractions resulting from lithosphere–mantle coupling, and intraplate variations in topography and density structure. This yielded a range of acceptable force distributions. In this study, we investigate to which extent the observed present-day stress field provides further constraints on the distribution of forces. We address the dynamics of the Eurasian Plate as a whole. This enables us to base our analysis on mechanical equilibrium of a tectonic plate and to evaluate all forces as part of an internally consistent set of forces driving and deforming Eurasia. We incorporate tractions from convective mantle flow modelling in a lithospheric model in which edge and lithospheric body forces are modelled explicitly and compute resulting stresses in a homogeneous elastic thin shell. Intraplate stress observations used are from the World Stress Map project. Eurasia's stress field turns out to be particularly sensitive to the distribution of collision forces on the plate's southern margin and, to a much lesser extent, to lithospheric density structure and tractions from mantle flow. Stress observations require collision forces on the India–Eurasia boundary of 7.0–10.5 TN m−1 and on the Arabia–Eurasia boundary of 1.3–2.7 TN m−1. Implication of mechanical equilibrium of the plate is that forces on the contacts with the African and Australian plates amount to 1.0–2.5 and 0–1.3 TN m−1, respectively. We use our results to assess the validity of the classical view that the mean elevation of an orogenic plateau can be taken as a measure of the magnitude of the compressive (in this case: collision-related) forces involved. For both the Tibetan and the Iranian plateaus, two plateaus with significantly different average elevations, we find that the horizontal force derived from the excess gravitational potential energy (collapse force) is in balance with the collision force.
-.-Comparison of the Toxic Effects of Hydrogen Peroxide and Ozone on Cultured Human Bronchial Epithelial Cells

In this study, we compad the ytotoric and genotoxic effects of hydrogen perozade and ozone on culuw hu aiy lial cels in pr_imayuue Both agnscue a d*e-dt . ass.in the repl.cat:v ab.il. ity Of epteilclsada ihrlvl fPO- sure caused amte d by release of lactte dehog Difeence were seen, however, between the agents' effects with regard to induction:ofeDNA sin- gle-stran br* a measured. by alkline . :. ;t:. :. ilkalin elation: e slstd br`aks were dfetected in siwdfs aotmwa conentra dons of hdgpide tt c Iaute cytotoxicity, nsonte were detcted :at any of the level of ozone euoure eaid.A dif- ference was alose in the abiltyofte iron chelator daemab to protccel from -. th fet. th two.re incubations o fiunres thadefe tine appreciably atene the not of T data suggest efet eptedaaclsnt ated
Uncertainties in passive seismic monitoring

The use of passive seismic techniques to monitor oil- field completion and production processes is on the rise. Stress changes induced by such reservoir activities as hydraulic fracturing, water injection, or fluid extraction will often result in failure of the rocks with a concurrent release of seismic energy in the form of compressional (P) and shear (S) waves. Passive seismic monitoring is based on recording these emitted waves and then using their arrival times to estimate the location of the failure events.
Interferon--y Depresses Binding of Ligand by C3b and C3bi Receptors on Cultured Human Monocytes, an Effect Reversed by Fibronectin

Receptors for C3 bind ligand and generate intracellular signals that lead to the engulfment of C3-coated particles. Recent experiments suggest that both the binding and the subsequent signal transduction activities of C3 receptors can be regulated. Cultured human monocytes (MO) 1 express receptors for C3b (CR1) and C3bi (CR3) that bind ligand-coated particles but do not signal the cell to initiate phagocytosis. After stimulation of the MO with PMA (1), or after interaction of the MO with surfaces coated with fibronectin (Fn, reference 2), CR1 and CR3 readily generate signals leading to phagocytosis. Thus PMA and Fn regulate the signaling capacity of CR1 and CR3 in these cells. In polymor-phonuclear leukocytes, both the binding and the signaling activities are coordi-nately regulated. Brief (15 min) stimulation with PMA increases binding and signaling activities of CR 1 and CR3, but prolonged (60 min) incubation with PMA eliminates both binding and signaling (3). Since the PMA-mediated decline in the binding capacity of CR1 and CR3 is not accompanied by a loss of cell surface receptors, it appears that PMA regulates the binding and signaling activities of existing cell surface receptors. In this report, we show that treatment of human monocytes and MO with recombinant IFN-~, causes CR1 and CR3 to lose the ability to bind ligand. IFN-"),-treated cells express normal levels of cell surface CRI and CR3 as measured with anti-receptor antibodies, and the inhibition of ligand binding by CR 1 and CR3 is reversed in minutes by interaction of the phagocytes with Fn-coated surfaces. Therefore, cultivation with IFN-~, causes a reversible change in the nature of these receptors, which prevents them from interacting with ligand. Although Fn enables CR1 and CR3 on IFN-~'-treated MO to bind ligand, these receptors fail to promote phagocytosis (signaling). For signaling to occur, IFN-y-treated cells require exposure to both Fn and PMA. PMA enables only signaling
Comparative Assembly Hubs: Web Accessible Browsers for Comparative Genomics

We introduce a pipeline to easily generate collections of web accessible UCSC genome browsers interrelated by an alignment. Using the alignment, all annotations and the alignment itself can be efficiently viewed with reference to any genome in the collection, symmetrically. A new, intelligently scaled alignment display makes it simple to view all changes between the genomes at all levels of resolution, from substitutions to complex structural rearrangements, including duplications.
Extension of the Method of Characteristics for Simulation of Solute Transport in Three Dimensions

The method of characteristics (e.g., Garder et al., 1964; Konikow and Bredehoeft, 1978) has been widely used in the simulation of solute transport in ground-water systems because of its effectiveness for handling advection-dominated problems. However, the method requires a large amount of computer memory and execution time when it is necessary to track a large number of moving particles, especially in three dimensions. The method can also lead to large mass balance discrepancies under certain circumstances. This paper describes a number of changes which may be made in the traditional method of characteristics approach to mitigate these difficulties. These changes include a dynamic particle allocation procedure, which often reduces dramatically the total number of moving particles needed in a simulation; and a consistent velocity interpolation scheme and higher-order particle tracking techniques, which, coupled with effective handling of particle insertion and deletion at sources and sinks, can provide improved mass balance results. The accuracy of a method-of-characteristics model incorporating these changes is evaluated by comparison with analytical solutions for (1) three-dimensional advection and dispersion in a spherical flow field, and (2) concentration change in a well during an injection/pumping cycle.
Is there a component of Pleistocene CO2 change associated with carbonate dissolution cycles

The only processes which could have decreased atmospheric CO2 during glacial climates without appreciably changing the carbon isotope distribution in the sea appear to be (1) dissolved calcium carbonate input to the ocean, e.g., coral reef buildup and erosion, (2) the ocean solubility pump, due to changes in surface temperature or air-sea exchange, or (3) decreased biological production of calcium carbonate. It is assumed here that one of these mechanisms caused part of the atmospheric CO2 changes recorded in the 200-kyr-long Vostok ice core. Two residual CO2 records are generated by scaling the δ13C difference between planktonic and benthic foraminifera in marine sediment cores to −82 ppm CO2 per 1‰ increase in Δδ13C and subtracting from this the measured CO2 concentration in the ice core. Both residual CO2 records exhibit two broad maximums between about 20–50 ka and 140–200 ka, indicating that during these times, about 40 ppm of the CO2 decrease from interglacial levels cannot be explained by the interaction of the ocean's biological and vertical mixing cycles. The shape of the residual CO2 curve is similar qualitatively to the variation of calcium carbonate in central equatorial Pacific sediments during this time period, which would imply that changes in dissolved carbonate input to the ocean contributed the added component of CO2 change. However, recent models of atmospheric CO2 change in response to changing alkaline input to the ocean exhibit about a 25 to 35 ppm decrease per 1013 mol yr−1 increase in dissolved CaCO3 input. If compensation for the changing input is occurring mostly within an area of about 40 × 106 km² below the lysocline in the Indo-Pacific, the change in carbonate accumulation rate corresponding to a −40 ppm CO2 change would be a minimum of 3 mg cm−2 yr−1. This can be compared to glacial increases of 0.5 to 1.0 mg cm−2 yr−1 during the last 200 kyr in central equatorial Pacific sediments. Thus, the added glacial accumulation of carbonate does not seem to match quantitatively with the 40 ppm amplitude of the residual CO2 signal, leading one to suspect that solubility plays a greater role than expected on the basis of a 2°C cooler surface ocean.