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1.
A two-temperature magnetohydrodynamic model of an ideal, fully ionized magnetized plasma consisting of electrons and several types of ions is developed for the case in which the mass of ions of the first type is much lower than that of jth-type ions, where j = 2,3,…, m 1 ? m j, while the densities of heavy ions are so low that collisions between them can be neglected. The ion component is assigned a common velocity, common temperature, and common density, while its composition can vary in time and space. 相似文献
2.
Voltage Gating of Gap Junctions in Cochlear Supporting Cells: Evidence for Nonhomotypic Channels 总被引:4,自引:0,他引:4
The organ of Corti has been found to have multiple gap junction subunits, connexins, which are localized solely in nonsensory
supporting cells. Connexin mutations can induce sensorineural deafness. However, the characteristics and functions of inner
ear gap junctions are not well known. In the present study, the voltage-dependence of gap junctional conductance (G
j
) in cochlear supporting cells was examined by the double voltage clamp technique. Multiple types of asymmetric voltage dependencies
were found for both nonjunctional membrane voltage (V
m
) and transjunctional (V
j
) voltage. Responses for each type of voltage dependence were categorized into four groups. The first two groups showed rectification
that was polarity dependent. The third group exhibited rectification with either voltage polarity, i.e., these cells possessed
a bell-shaped G
j
-V
j
or G
j
-V
m
function. The rectification due to V
j
had fast and slow components. On the other hand, V
m
-dependent gating was fast (<5 msec), but stable. Finally, a group was found that evidenced no voltage dependence, although
the absence of V
j
dependence did not preclude V
m
dependence and vice versa. In fact, for all groups V
j
sensitivity could be independent of V
m
sensitivity. The data show that most gap junctional channels in the inner ear have asymmetric voltage gating, which is indicative
of heterogeneous coupling and may result from heterotypic channels or possibly heteromeric configurations. This heterogeneous
coupling implies that single connexin gene mutations may affect the normal physiological function of gap junctions that are
not limited to homotypic configurations.
Received: 17 September 1999/Revised: 12 January 2000 相似文献
3.
Nagarajan Muthukaman Sanjay Deshmukh Macchindra Tambe Dnyandeo Pisal Shital Tondlekar Mahamadhanif Shaikh Neelam Sarode Vidya G. Kattige Pooja Sawant Monali Pisat Vikas Karande Srinivasa Honnegowda Abhay Kulkarni Dayanidhi Behera Satyawan B. Jadhav Ramchandra R. Sangana Girish S. Gudi Neelima Khairatkar-Joshi Laxmikant A. Gharat 《Bioorganic & medicinal chemistry letters》2018,28(7):1211-1218
In an effort to identify CYP and hERG clean mPGES-1 inhibitors from the dihydrofuran-fused tricyclic benzo[d]imidazole series lead 7, an extensive structure-activity relationship (SAR) studies were performed. Optimization of A, D and E-rings in 7 afforded many potent compounds with human whole blood potency in the range of 160–950?nM. Selected inhibitors 21d, 21j, 21m, 21n, 21p and 22b provided selectivity against COX-enzymes and mPGES-1 isoforms (mPGES-2 and cPGES) along with sufficient selectivity against prostanoid synthases. Most of the tested analogs demonstrated required metabolic stability in liver microsomes, low hERG and CYP liability. Oral pharmacokinetics and bioavailability of lead compounds 21j, 21m and 21p are discussed in multiple species like rat, guinea pig, dog, and cynomolgus monkey. Besides, these compounds revealed low to moderate activity against human pregnane X receptor (hPXR). The selected lead 21j further demonstrated in vivo efficacy in acute hyperalgesia (ED50: 39.6?mg/kg) and MIA-induced osteoarthritic pain models (ED50: 106?mg/kg). 相似文献
4.
2 k contingency tables in ecology 总被引:1,自引:0,他引:1
E C Pielou 《Journal of theoretical biology》1972,34(2):337-352
Suppose observations are made on the presence or absence of k different species in N sampling units. Denote by s the number of species per sampling unit and let m2 and Var(s) respectively be the observed variance of s and its expectation under the null hypothesis that all k species are independent. It is shown that the difference m2—Var(s) is directly interpretable as a measure of the overall association among the species. Examples using field data are given and it is shown how the proposed measure of association may be used to judge: (i) whether some chosen group of species contributes markedly to the total amount of interdependence within a community; and (ii) whether some chosen group of species may be disregarded without affecting the result when ecological data are to be classified or ordinated. 相似文献
5.
《Bioorganic & medicinal chemistry》2020,28(10):115470
Acylhydrazones 1a-o, derived from isoniazid, were synthesized and evaluated for Myeloperoxidase (MPO) and Acetylcholinesterase (AChE) inhibition, as well as their antioxidant and metal chelating activities, with the purpose of investigating potential multi-target profiles for the treatment of Alzheimer’s disease. Synthesized compounds were tested using the 2,2-diphenyl-2-picrylhydrazyl (DPPH) method and 1i, 1j and 1 m showed radical scavenging ability. Compounds 1b, 1 h, 1i, 1 m and 1o inhibited MPO activity (10 μM) at 96.1 ± 5.5%, 90 ± 2.1%, 100.3 ± 1.7%, 80.1 ± 9.4% and 82.2 ± 10.6%, respectively, and only compound 1 m was able to inhibit 54.2 ± 1.7% of AChE activity (100 μM). Docking studies of the most potent compound 1 m were carried out, and the computational results provided the theoretical basis of enzyme inhibition. Furthermore, compound 1 m was able to form complexes with Fe2+ and Zn2+ ions in a 2:1 ligand:metal ratio according to the Job Plot method. 相似文献
6.
Tatiana Dimitriu Dusan Misevic Ariel B. Lindner Francois Taddei Sam P. Brown 《PLoS biology》2021,19(12)
A recent commentary raised concerns about aspects of the model and assumptions used in a previous study which demonstrated that selection can favor chromosomal alleles that confer higher plasmid donation rates. Here, the authors of that previous study respond to the concerns raised.In our original work [1], we demonstrated experimentally that selection can favor chromosomal alleles that confer higher plasmid donation rates, given the plasmid is beneficial and the recipient has an elevated chance of carrying the donor allele (i.e., preferential donation to kin). Our experiments demonstrated this effect via 2 mechanisms of preferential donation: biased conjugation rates and structured populations. We interpreted these results through the lens of kin selection theory (benefits via horizontal gene transfer to kin), supported by simulations and an analytical fitness function model. These results hold importance by outlining that the evolution of plasmid transfer rates (a key aspect of the antibiotic resistance crisis) is not necessarily the sole product of selection on the plasmid itself and forms part of a broader series of papers from our labs investigating the sociomicrobiology of plasmids [2–4].A new commentary raises concerns over our fitness function model, flagging issues with both the structure of the model and assumptions made in our analysis [5]. We stand by the general conclusions of our work but accept that our fitness function and stated analysis assumptions could be better formulated. Our initial fitness function is heuristic in the sense it was designed to capture general processes acting on the fitness of individuals, dependent on the plasmid and donor allele status—without explicitly modeling the myriad demographic events of dispersal, reproduction, conjugation, and death that result in selective shifts across a metapopulation of cells. Specifically, we captured the “force of infection” faced by an uninfected cell as the product of average plasmid prevalence and average donor allele prevalence in the local patch (pjqj; see commentary for notation details). We agree with the authors that this force of infection is better phrased as the average of the product ((1/N)∑pij qij), in part because this avoids the potential pathology under limit conditions described by the authors, but also because this approach better highlights that the particular social trait in question is an “other only” cooperative trait [6], illustrated by commentary equation [2], where transmission to self and transmission to others are separated. This separation has the important consequence of highlighting that unlike many microbial social traits where benefits accrue to a group (including self), a cooperative plasmid donor trait can only benefit other cells that lack the plasmid. Given established costs of donation (e.g., see figure S2 in our original article), this defines our “donor” behavior as an altruistic trait, which can, therefore, only be favored by selection given nonrandom interactions among individuals (e.g., [7]).Our experimental results outline 2 mechanisms of nonrandom interactions: preferential donation to kin and population structure. Each of these mechanisms will generate positive covariances between focal individual qij and non-self-recipient qj donor allele states (cov(qj, qij) > 0). The pathway via preferential donation to kin (order-of-magnitude differences according to our analyses and more recent measurements among lineages coexisting within natural populations [8]) will also likely generate positive covariances between donor and recipient abilities (cov(sij, qij) > 0). In contrast, to arrive at the result that selection always works against plasmid donor alleles (equation [4]), the commentary makes the assumption that both of the above covariances are zero. We suggest that the additional analyses begun by the authors are an exciting starting point to better map selection on donor alleles, under a broader array of defined assumptions on cell–cell and gene–gene structure, ideally informed by data on structures found in natural bacterial populations. 相似文献
7.
A novel series of benzoic acid N′-[2-(4-benzothiazol-2-yl-piperazin-1-yl)-acetyl]-hydrazides 6a–j were synthesized and characterized by IR, 1H, 13C NMR, elemental and mass spectral analyses. The in-vitro cytotoxicity and cell viability assay of the synthesized compounds 6a–j were evaluated against Dalton’s lymphoma ascites (DLA) cells. Our results showed that compound 6c with a bromo group on phenyl ring has showed promising antiproliferative efficacy. Further investigation of compound 6c on in-vivo treatment model depicts the increased tumor suppression through inhibition of angiogenesis. 相似文献
8.
During running, muscles of the lower limb act like a linear spring bouncing on the ground. When approaching an obstacle, the overall stiffness of this leg-spring system (kleg) is modified during the two steps preceding the jump to enhance the movement of the center of mass of the body while leaping the obstacle. The aim of the present study is to understand how kleg is modified during the running steps preceding the jump. Since kleg depends on the joint torsional stiffness and on the leg geometry, we analyzed the changes in these two parameters in eight subjects approaching and leaping a 0.65 m-high barrier at 15 km h−1. Ground reaction force (F) was measured during 5–6 steps preceding the obstacle using force platform and the lower limb movements were recorded by camera. From these data, the net muscular moment (Mj), the angular displacement (θj) and the lever arm of F were evaluated at the hip, knee and ankle. At the level of the hip, the Mj–θj relation shows that muscles are not acting like torsional springs. At the level of the knee and ankle, the Mj–θj relation shows that muscles are acting like torsional springs: as compared to steady-state running, the torsional stiffness kj decreases from ~1/3 two contacts before the obstacle, and increases from ~2/3 during the last contact. These modifications in kj reflect in changes in the magnitude of F but also to changes in the leg geometry, i.e. in the lever arms of F. 相似文献
9.
Binding equations for interacting systems comprising multivalent acceptor and bivalent ligand: application to antigen-antibody systems 总被引:1,自引:0,他引:1
Consideration is given to the reversible interaction of a bivalent ligand, B, with a multivalent acceptor, A (possessing f reactive sites) which leads to the formation of a series of complexes, AiBj, comprising networks of alternating acceptor and ligand molecules. A binding equation is derived on the basis of a site association constant, k, defined in terms of reacted site probability functions. This equation, which relates the binding function, r (the moles of ligand bound per mole of acceptor) to the concentration of unbound ligand, mb, is used to show that plots of r vs. 2kmB constructed with fixed but different values of intersect at the point () where the extent of reaction and the concentrations of those complexes for which attain maximal values. Corresponding Scatchard plots are shown by numerical example to be non-linear, their second derivative being positive for all r. It follows that such deviations from linearity cannot be taken alone as evidence for site heterogeneity in cross-linking systems. The binding equation obtained directly is shown to be identical with that obtained with f = 2 by summation procedures involving the general expression for concentrations of complexes, mAiBj, formulated in terms of appropriate statistical factors. In this way, previous findings on precipitation and gel formation in cross-linking systems are correlated with the present development of binding theory. 相似文献
10.
A finite diploid population, observed at times t = 0, 1, 2,…, is studied. An individual is said to be in age group i at time t if its age is between i and i + 1 units at that time, where i ? 1. It is assumed that the number of individuals in a particular age-sex class is the same for every t and that the probability that a male offspring was produced by a mating of a male in age group i and a female in age group j is pijm (with a corresponding probability pfij for a female offspring), regardless of when the individual is born. The probability of ultimate fixation of an allele A1 and the inbreeding effective number, for large populations, is calculated under the further assumptions that A1 is neutral and that mating is random, given the ages of the mates. 相似文献
11.
《Bioorganic & medicinal chemistry》2016,24(10):2330-2341
Two series of novel 4-chlorophenyl N-alkyl phosphoramidates of 3′-O-(t-butoxycarbonyl)-5-fluoro-2′-deoxyuridine (3′-BOC-FdU) (9a–9j) and 5-fluoro-2′-deoxyuridine (FdU) (10a–10j) were synthesized by means of phosphorylation of 3′-BOC-FdU (4) with 4-chlorophenyl phosphoroditriazolide (7), followed by a reaction with the appropriate amine. Phosphoramidates 9a–9j were converted to the corresponding 10a–10j by removal of the 3′-t-butoxycarbonyl protecting group (BOC) under acidic conditions. The synthesized phosphoramidates 9a–9j and 10a–10j were evaluated for their cytotoxic activity in five human cancer cell lines: cervical (HeLa), nasopharyngeal (KB), breast (MCF-7), liver (HepG2), osteosarcoma (143B) and normal human dermal fibroblast cell line (HDF) using the sulforhodamine B (SRB) assay. Two phosphoramidates 9b and 9j with the N-ethyl and N-(methoxy-(S)-alaninyl) substituents, respectively, displayed remarkable activity in all the investigated cancer cells, and the activity was considerably higher than that of the parent nucleoside 4 and FdU. Among phosphoramidates 10a–10j compound 10c with the N-(2,2,2-trifluoroethyl) substituent showed the highest activity. Phosphoramidate 10c was more active than the FdU in all the cancer cell lines tested. 相似文献
12.
Amino-terminus and carboxyl-terminus of connexins have been proposed to be responsible for the transjunctional voltage-dependent gating (Vj-gating) and the unitary gap junction channel conductance (γj). To better understand the molecular structure(s) determining the Vj-gating properties and the γj of Cx50, we have replaced part of the amino-terminus of mCx50 by the corresponding domain of mCx36 to engineer a chimera Cx50-Cx36N, and attached GFP at the carboxyl-terminus of mCx50 to construct Cx50-GFP. The dual whole-cell patch-clamp technique was used to test the resulting gap junction channel properties in N2A cells. The Cx50-Cx36N gap junction channel lowered the sensitivity of steady-state junctional conductance to Vj (Gj/Vj relationship), slowed Vj-gating kinetics, and reduced γj as compared to Cx50 channel. Cx50-GFP gap junction channel showed similar Vj-gating properties and γj to Cx50 channel. We further characterized a mutation, Cx50N9R, where the Asn (N) at the ninth position of Cx50 was replaced by the corresponding Arg (R) at Cx36. The Gj/Vj relationship of Cx50N9R channel was significantly changed; most strikingly, the macroscopic residual conductance (Gmin) was near zero. Moreover, the single Cx50N9R channel only displayed one open state (γj = 132 ± 4 pS), and no substate could be detected. Our data suggest that the NT of Cx50 is critical for both the Vj-gating and the γj, and the introduction of a positively charged Arg at the ninth position reduced the Gmin with a correlated disappearance of the substate at the single channel level. 相似文献
13.
《Bioorganic & medicinal chemistry》2019,27(17):3929-3937
Targeting of tyrosinase has proven to be the best means of identifying safe, efficacious, and potent tyrosinase inhibitors for whitening skin. We designed and synthesized ten NAB (N-(acryloyl)benzamide) derivatives (1a–1j) using the Horner-Wadsworth-Emmons olefination of diethyl (2-benzamido-2-oxoethyl)phosphonate and appropriate benzaldehydes. A mushroom tyrosinase inhibitory assay showed compounds 1a (36.71 ± 2.14% inhibition) and 1j (25.99 ± 2.77% inhibition) inhibited tyrosinase more than the other eight NAB derivatives and kojic acid (21.56 ± 2.93% inhibition), and docking studies indicated 1a (−6.9 kcal/mole) and 1j (−7.5 kcal/mole) had stronger binding affinities for tyrosinase than kojic acid (−5.7 kcal/mole). At a concentration of 25 μM, 1a and 1j were nontoxic in B16F10 melanoma cells and exhibited stronger tyrosinase inhibition (59.70% and 76.77%, respectively) than kojic acid (50.30% inhibition) or arbutin (41.78% inhibition at 400 μM). Similarly, in B16F10 melanoma cells, compounds 1a and 1j at 25 μM decreased total melanin content by 47.97% and 61.77%, respectively (kojic acid; 38.98%). Similarities between inhibitions of tyrosinase activity and melanin contents suggested the anti-melanogenic effects of 1a and 1j were due to tyrosinase inhibition. The excellent DPPH scavenging activity of 1j suggests it might enhance in vivo effect on melanin contents. The study suggests compound 1j offers a potential starting point for the development of safe, potent tyrosinase inhibitors. 相似文献
14.
Gap junction channels are gated by a chemical gate and two transjunctional voltage (V
j)-sensitive gates: fast and slow. Slow V
j gate and chemical gate are believed to be the same. The slow gate closes at the negative side of V
j and is mostly inactive without uncouplers or connexin (Cx) mutations. In contrast, our present data indicate otherwise. Oocytes
expressing Cx32 were subjected to series of −100 mV
V
j pulses (12-s duration, 30-s intervals). Both peak (PK) and steady-state (SS) junctional conductances (G
j), measured at each pulse, decreased exponentially by 50−60% (tau = ∼1.2 min). G
jPK dropped more dramatically, such that G
jSS/G
jPK increased from 0.4 to 0.6, indicating a drop in V
j sensitivity. Less striking effects were obtained with –60 mV pulses. During recovery, G
j, measured by applying 20 mV pulses (2-s duration, 30-s intervals), slowly returned to initial values (tau = ∼7 min). With reversal of V
j polarity, G
jPK briefly increased and G
jSS/G
jPK decreased, suggesting that V
j-dependent hemichannel reopening is faster than hemichannel closing. Similar yet more dramatic results were obtained with
COOH-terminus truncated Cx32 (Cx32-D225), a mutant believed to lack fast V
j gating. The data indicate that the slow gate of Cx32 is active in the absence of uncouplers or mutations and displays unusual
V
j behavior. Based on previous evidence for direct calmodulin (CaM) involvement in chemical/slow gating, this may also be CaM-mediated. 相似文献
15.
Keisuke Kitamura Shigehiko Takegami Takumi Kobayashi Kumi Makihara Chie Kotani Tatsuya Kitade Maki Moriguchi Yuki Inoue Tomoko Hashimoto Midori Takeuchi 《生物化学与生物物理学报:生物膜》2004,1661(1):61-67
The dissociation constants (pKms) of the phenothiazine drugs promazine, chlorpromazine, and triflupromazine, incorporated in the phosphatidylcholine (PC) bilayer of small unilamellar vesicles (SUV), were investigated by a 13C nuclear magnetic resonance (NMR) titration method employing their N-13CH3 (ionizable group) labelled derivatives. Use of the labelled drugs enabled direct observations of the ionization equilibrium of the N-dimethyl group. A second derivative spectrophotometric study proved that 95-98% of the phenothiazine species in the sample solutions (200 μM phenothiazine in the presence of 27 mM PC SUV) were incorporated into the PC bilayer, which simplified the calculation of pKm values by allowing that the phenothiazines in the aqueous phase could be neglected. The pKm values were calculated from the chemical shift dependence of the N-dimethyl 13C NMR signal on the pH value of sample solutions. The pKm values obtained were smaller than those measured in aqueous solutions by about one unit. The existence of cholesterol (30 mol%) in the PC bilayer showed little effect on the pKm values, suggesting that cholesterol in the bilayer does not largely affect the interfacial region where the N-dimethyl group of the incorporated phenothiazines is located. The results offered clear evidence for the pKm decrease and provided their precise values. 相似文献
16.
17.
A group of N-benzylpiperidine-3/4-carbohydrazide-hydrazones were designed, synthesized and evaluated for acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) activities, Aβ42 self-aggregation inhibitory potentials, and antioxidant capacities, in vitro. All of the compounds displayed eeAChE and huAChE inhibitory activity in a range of IC50 = 5.68–11.35 µM and IC50 = 8.80–74.40 µM, respectively and most of the compounds exhibited good to moderate inhibitory activity on BuChE enzyme. Kinetic analysis and molecular modeling studies were also performed for the most potent compounds (1g and 1j). Not only the molecular modeling studies but also the kinetic analysis suggested that these compounds might be able to interact with the catalytic active site (CAS) and the peripheral anionic site (PAS) of the enzymes. In the light of the results, compound 1g and compound 1j may be suggested as lead compounds for multifunctional therapy of AD. 相似文献
18.
The effects of m-octopamine on salivary flow rates and protein secretion by rat submandibular glands
《Comparative biochemistry and physiology. C: Comparative pharmacology》1992,101(3):469-476
1. m-Octopamine given i.v. or i.p. was a potent sialogogue for rat salivary glands.2. Salivation in response to i.v. m-octopamine was completely abolished by prazosin and phenoxybenzamine.3. The α-type of proteins were secreted in response to all doses of i.v. and i.p. m-octopamine and these were converted into the β-type with prazosin, but not with yohimbine.4. m-Octopamine stimulated both α- and β-adrenoceptors and was a much more selective α1-agonist than was the p-isomer. 相似文献
19.
A flexible approach to previously unknown spirofused and linked 1,3,4-thiadiazine derivatives of steroids with selective control of heterocyclization patterns is disclosed. (N-Arylcarbamoyl)spiroandrostene-17,6′ [1,3,4]thiadiazines and (N-arylcarbamoyl)17-[1′,3′,4′]thiadiazine-substituted androstenes, novel types of heterosteroids, were prepared from 16β,17β-epoxypregnenolone and 21-bromopregna-5,16-dien-20-one in good to high yields by the treatment with oxamic acid thiohydrazides. The synthesized compounds were screened for antiproliferative activity against the human androgen receptor-positive prostate cancer cell line 22Rv1. Most of (N-arylcarbamoyl)17-[1′,3′,4′]thiadiazine-substituted androstenes exhibit better antiproliferative potency (IC50 = 2.1–6.6 µM) than the antiandrogen bicalutamide. Compounds 7d with IC50 = 3.0 μM and 7j with IC50 = 2.1 μM proved to be the most active in the series under study. Lead synthesized compound 7j downregulates AR expression and activity in 22Rv1 cells. NF-κB activity is also blocked in 7j-treated 22Rv1 cells. Apoptosis is considered as a possible mechanism of 7j-induced cell death. 相似文献
20.