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121.
122.
Zn(2+) modulation of neuronal transient K(+) current: fast and selective binding to the deactivated channels 总被引:1,自引:0,他引:1
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Modulation of voltage-dependent transient K(+) currents (A type K(+) or K(A) current) by Zn(2+) was studied in rat hippocampal neurons by the whole-cell patch-clamp technique. It is found that Zn(2+) selectively binds to the resting (deactivated or closed) K(A) channels with a dissociation constant (K(d)) of approximately 3 &mgr;M, whereas the affinity between Zn(2+) and the inactivated K(A) channels is 1000-fold lower. Zn(2+) therefore produces a concentration-dependent shift of the K(A) channel inactivation curve and enhances the K(A) current elicited from relatively positive holding potentials. It is also found that the kinetics of Zn(2+) action are fast enough to compete with the transition rates between different gating states of the channel. The rapid and selective binding of Zn(2+) to the closed K(A) channels keeps the channel in the closed state and explains the ion's concentration-dependent slowing effect on the activation of K(A) current. This in turn accounts for the inhibitory effect of Zn(2+) on the K(A) current elicited from hyperpolarized holding potentials. Because the molecular mechanisms underlying these gating changes are kinetic interactions between the binding-unbinding of Zn(2+) and the intrinsic gating processes of the channel, the shift of the inactivation curve and slowing of K(A) channel activation are quantitatively correlated with ambient Zn(2+) over a wide concentration range without "saturation"; i.e., The effects are already manifest in micromolar Zn(2+), yet are not saturated even in millimolar Zn(2+). Because the physiological concentration of Zn(2+) could vary over a similarly wide range according to neural activities, Zn(2+) may be a faithful physiological "fine tuner," controlling and controlled by neural activities through its effect on the K(A) current. 相似文献
123.
Sarah E. Westrick E. Dale Broder David N. Reznick Cameron K. Ghalambor Lisa Angeloni 《Ethology : formerly Zeitschrift fur Tierpsychologie》2019,125(4):232-240
Adaptive behavioral plasticity can play a beneficial role when a population becomes established in a novel environment if environmental cues allow the expression of appropriate behavior. Further, plasticity itself can evolve over time in a new environment causing changes in the way or degree to which animals respond to environmental cues. Colonization events provide an opportunity to investigate such relationships between behavioral plasticity and adaptation to new environments. Here, we investigated the evolution of behavior and behavioral plasticity during colonization of a new environment, by testing if female mate‐choice behavior diverged in Trinidadian guppies 2–3 years (~6–9 generations) after being introduced to four locations with reduced predation risk. We collected wild‐caught fish from the source and introduced populations, and we reared out second‐generation females in the laboratory with and without predator cues to examine their plastic responses to a bright and dull male. We found introduced females were less responsive to males when reared without predator cues, but both introduced and source females were similarly responsive when reared with predator cues. Thus, the parallel evolution of behavior across multiple populations in the low‐predation environment was only observed in the treatment mimicking the introduction environment. Such results are consistent with theory predicting that the evolution of plasticity is a by‐product of differential selection across environments. 相似文献
124.
125.
Introduction
We compared the odds of vitamin D deficiency in three chronic diseases: systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 2 diabetes (T2DM), adjusting for medications, demographics, and laboratory parameters, common to all three diseases. We also designed multivariate models to determine whether different factors are associated with vitamin D deficiency in different racial/ethnic groups. 相似文献126.
CC van Diemen DS Postma M Siedlinski A Blokstra HA Smit HM Boezen 《Respiratory research》2011,12(1):57
Background
An imbalance in Matrix MetalloProteases (MMPs) and Tissue Inhibitors of MMPs (TIMPs) contributes to Chronic Obstructive Pulmonary Disease (COPD) development. Longitudinal studies investigating Single Nucleotide Polymorphisms (SNPs) in MMPs and TIMPs with respect to COPD development and lung function decline in the general population are lacking.Methods
We genotyped SNPs in MMP1 (G-1607GG), MMP2 (-1306 C/T), MMP9 (3 tagging SNPs), MMP12 (A-82G and Asn357Ser) and TIMP1 (Phe124Phe and Ile158Ile) in 1390 Caucasians with multiple FEV1 measurements from a prospective cohort study in the general population. FEV1 decline was analyzed using linear mixed effect models adjusted for confounders. Analyses of the X-chromosomal TIMP1 gene were stratified according to sex. All significant associations were repeated in an independent general population cohort (n = 1152).Results
MMP2 -1306 TT genotype carriers had excess FEV1 decline (-4.0 ml/yr, p = 0.03) compared to wild type carriers. TIMP1 Ile158Ile predicted significant excess FEV1 decline in both males and females. TIMP1 Phe124Phe predicted significant excess FEV1 decline in males only, which was replicated (p = 0.10) in the second cohort. The MMP2 and TIMP1 Ile158Ile associations were not replicated. Although power was limited, we did not find associations with COPD development.Conclusions
We for the first time show that TIMP1 Phe124Phe contributes to excess FEV1 decline in two independent prospective cohorts, albeit not quite reaching conventional statistical significance in the replication cohort. SNPs in MMPs evidently do not contribute to FEV1 decline in the general population. 相似文献127.
128.
Jennifer Fredlund Dan Broder Tinya Fleming Clémence Claussin Kit Pogliano 《Molecular microbiology》2013,89(6):1053-1068
Bacillus subtilis sporulation depends on the forespore membrane protein SpoIIQ, which interacts with the mother cell protein SpoIIIAH at the septum to localize other sporulation proteins. It has remained unclear how SpoIIQ localizes. We demonstrate that localization of SpoIIQ is achieved by two pathways: SpoIIIAH and the SpoIID, SpoIIM, SpoIIP engulfment proteins. SpoIIQ shows diffuse localization only in a mutant lacking both pathways. Super‐resolution imaging shows that in the absence of SpoIIIAH, SpoIIQ forms fewer, slightly larger foci than in wild type. Surprisingly, photobleaching experiments demonstrate that, although SpoIIQ localizes without SpoIIIAH, it is no longer immobilized, and is therefore able to exchange subunits within a localized pool. SpoIIQ mobility is further increased by the additional absence of the engulfment proteins. However an enzymatically inactive SpoIID protein immobilizes SpoIIQ even in the absence of SpoIIIAH, indicating that complete septal thinning is not required for SpoIIQ localization. This suggests that SpoIIQ interacts with both SpoIIIAH and the engulfment proteins or their peptidoglycan cleavage products. They further demonstrate that apparently normal localization of a protein without a binding partner can mask dramatic alterations in protein mobility. We speculate that SpoIIQ assembles foci along the path defined by engulfment proteins degrading peptidoglycan. 相似文献
129.
Humoral response to oligomeric human immunodeficiency virus type 1 envelope protein. 总被引:10,自引:9,他引:1
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T M Richardson Jr B L Stryjewski C C Broder J A Hoxie J R Mascola P L Earl R W Doms 《Journal of virology》1996,70(2):753-762
The humoral immune response to human immunodeficiency virus type 1 (HIV-1) is often studied by using monomeric or denatured envelope proteins (Env). However, native HIV-1 Env complexes that maintain quaternary structure elicit immune responses that are qualitatively distinct from those seen with monomeric or denatured Env. To more accurately assess the levels and types of antibodies elicited by HIV-1 infection, we developed an antigen capture enzyme-linked immunosorbent assay using a soluble, oligomeric form of HIV-1IIIB Env (gp140) that contains gp120 and the gp41 ectodomain. The gp140, captured by various monoclonal antibodies (MAbs), retained its native oligomeric structure: it bound CD4 and was recognized by MAbs to conformational epitopes in gp120 and gp41, including oligomer-specific epitopes in gp41. We compared the reactivities of clade B and clade E serum samples to captured Env preparations and found that while both reacted equally well with oligomeric gp140, clade B seras reacted more strongly with monomeric gp120 than did clade E samples. However, these differences were minimized when gp120 was captured by a V3 loop MAb, which may lead to increased exposure of the CD4 binding site. We also measured the ability of serum samples to block binding of MAbs to epitopes in gp120 and gp41. Clade B serum samples consistently blocked binding of oligomer-dependent MAbs to gp41 and, to a slightly lesser extent, MAbs to the CD4 binding site in gp120. Clade E serum samples showed equivalent or greater blocking of oligomer-dependent gp41 antibodies and considerably less blocking of CD4-binding-site MAbs. Finally, we found that < 5% of the antibodies in clade B sera bound to epitopes present only in monomeric gp120, 30% bound to epitopes present in both monomeric gp120 and oligomeric gp140, and 70% bound to epitopes present in oligomeric gp140, which includes gp41. Thus, captured oligomeric Env closely reflects the antigenic characteristics of Env protein on the surface of virions and infected cells, retains highly conserved epitopes that are recognized by antibodies raised against different clades, and makes it possible to detect a much greater fraction of total anti-HIV-1 Env activity in sera than does native monomeric gp120. 相似文献
130.
Identification of Hendra virus G glycoprotein residues that are critical for receptor binding 总被引:1,自引:1,他引:0
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Bishop KA Stantchev TS Hickey AC Khetawat D Bossart KN Krasnoperov V Gill P Feng YR Wang L Eaton BT Wang LF Broder CC 《Journal of virology》2007,81(11):5893-5901
Hendra virus (HeV) is an emerging paramyxovirus capable of infecting and causing disease in a variety of mammalian species, including humans. The virus infects its host cells through the coordinated functions of its fusion (F) and attachment (G) glycoproteins, the latter of which is responsible for binding the virus receptors ephrinB2 and ephrinB3. In order to identify the receptor binding site, a panel of G glycoprotein constructs containing mutations was generated using an alanine-scanning mutagenesis strategy. Based on a predicted G structure, charged amino acids residing in regions that could be homologous to those in the measles virus H attachment glycoprotein known to be involved in its protein receptor interaction were targeted. Using a coprecipitation-based assay, seven single-amino-acid substitutions in HeV G were identified as having significantly impaired binding to both the ephrinB2 and ephrinB3 viral receptors: D257A, D260A, G439A, K443A, G449A, K465A, and D468A. The impairment of receptor interaction conferred a concomitant diminution in their abilities to promote membrane fusion when coexpressed with F. The G glycoprotein mutants were also recognized by three or more conformation-dependent monoclonal antibodies of a panel of five, were expressed on the cell surface, and retained their abilities to bind and coprecipitate F. Interestingly, some of these mutant G glycoproteins coprecipitated with F more efficiently than wild-type G. Taken together, these data provide strong biochemical and functional evidence that some of these residues could be part of a conformation-dependent, discontinuous, and overlapping ephrinB2 and -B3 binding domain within the HeV G glycoprotein. 相似文献