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81.
Delays in the development of exploratory and locomotor behavior in neonatal male rats (up to 21 days of age) are shown to accrue as a consequence of low level lead exposure. Cross fostering experiments indicate that these delays are primarily due to prenatal exposure. These Pb induced behavioral modifications appear to be associated with the delays in synaptogenesis and biochemical development of the cerebral cortex reported previously (4, 18). A new behavioral bioassay for detecting delays in brain development is described. 相似文献
82.
《Journal of molecular biology》2021,433(5):166809
Macroautophagy is a bulk degradation mechanism in eukaryotic cells. Efficiency of an essential step of this process in yeast, Atg8 lipidation, relies on the presence of Atg16, a subunit of the Atg12–Atg5-Atg16 complex acting as the E3-like enzyme in the ubiquitination-like reaction. A current view on the functional structure of Atg16 in the yeast S. cerevisiae comes from the two crystal structures that reveal the Atg5-interacting α-helix linked via a flexible linker to another α-helix of Atg16, which then assembles into a homodimer. This view does not explain the results of previous in vitro studies revealing Atg16-dependent deformations of membranes and liposome-binding of the Atg12–Atg5 conjugate upon addition of Atg16. Here we show that Atg16 acts as both a homodimerizing and peripheral membrane-binding polypeptide. These two characteristics are imposed by the two distinct regions that are disordered in the nascent protein. Atg16 binds to membranes in vivo via the amphipathic α-helix (amino acid residues 113–131) that has a coiled-coil-like propensity and a strong hydrophobic face for insertion into the membrane. The other protein region (residues 64–99) possesses a coiled-coil propensity, but not amphipathicity, and is dispensable for membrane anchoring of Atg16. This region acts as a Leu-zipper essential for formation of the Atg16 homodimer. Mutagenic disruption in either of these two distinct domains renders Atg16 proteins that, in contrast to wild type, completely fail to rescue the autophagy-defective phenotype of atg16Δ cells. Together, the results of this study yield a model for the molecular mechanism of Atg16 function in macroautophagy. 相似文献
83.
Jin Wei Mia Madel Alfajaro Peter C. DeWeirdt Ruth E. Hanna William J. Lu-Culligan Wesley L. Cai Madison S. Strine Shang-Min Zhang Vincent R. Graziano Cameron O. Schmitz Jennifer S. Chen Madeleine C. Mankowski Renata B. Filler Neal G. Ravindra Victor Gasque Fernando J. de Miguel Ajinkya Patil Huacui Chen Craig B. Wilen 《Cell》2021,184(1):76-91.e13
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84.
Roger Cardinal 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2009,364(1522):1459-1466
Outsider Art (art brut) is defined as a mode of original artistic expression which thrives on its independence, shunning the public sphere and the art market. Such art can be highly idiosyncratic and secretive, and reflects the individual creator''s attempt to construct a coherent, albeit strange, private world. Certain practitioners of what may be termed autistic art are examined in the light of this definition; their work is considered as evidence not of a medical condition but of an expressive intentionality entirely worthy of the interest of those drawn to the aesthetic experience. 相似文献
85.
86.
Inflammatory responses mediated by activated microglia play a pivotal role in the pathogenesis of human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorders. Studies on identification of specific targets to control microglia activation and resultant neurotoxic activity are imperative. Increasing evidence indicate that voltage-gated K+ (Kv) channels are involved in the regulation of microglia functionality. In this study, we investigated Kv1.3 channels in the regulation of neurotoxic activity mediated by HIV-1 glycoprotein 120 (gp120)-stimulated rat microglia. Our results showed treatment of microglia with gp120 increased the expression levels of Kv1.3 mRNA and protein. In parallel, whole-cell patch-clamp studies revealed that gp120 enhanced microglia Kv1.3 current, which was blocked by margatoxin, a Kv1.3 blocker. The association of gp120 enhancement of Kv1.3 current with microglia neurotoxicity was demonstrated by experimental results that blocking microglia Kv1.3 attenuated gp120-associated microglia production of neurotoxins and neurotoxicity. Knockdown of Kv1.3 gene by transfection of microglia with Kv1.3-siRNA abrogated gp120-associated microglia neurotoxic activity. Further investigation unraveled an involvement of p38 MAPK in gp120 enhancement of microglia Kv1.3 expression and resultant neurotoxic activity. These results suggest not only a role Kv1.3 may have in gp120-associated microglia neurotoxic activity, but also a potential target for the development of therapeutic strategies. 相似文献
87.
Herbert L. Needleman 《人类与生态风险评估》2005,11(1):153-157
In the environmental health literature, errors in interpreting studies or data are not infrequent. Many are of the Type II variety. Common solecisms of this type are: treating the criterion of p < 0.05 as a sacrament; demanding complete confounder control; arguing for the existence of phantom confounders; arguing that the effect size is trivial; building nonveridical models; arguing for no effect from inadequate sample size; demanding causal proof; arguing that causality is reversed; conducting a ballot of published studies. These are examined in this paper. 相似文献
88.
《Journal of molecular biology》2021,433(22):167254
Tau is an intrinsically disordered protein implicated in many neurodegenerative diseases. The repeat domain fragment of tau, tau-K18, is known to undergo a disorder to order transition in the presence of lipid micelles and vesicles, in which helices form in each of the repeat domains. Here, the mechanism of helical structure formation, induced by a phospholipid mimetic, sodium dodecyl sulfate (SDS) at sub-micellar concentrations, has been studied using multiple biophysical probes. A study of the conformational dynamics of the disordered state, using photoinduced electron transfer coupled to fluorescence correlation spectroscopy (PET-FCS) has indicated the presence of an intermediate state, I, in equilibrium with the unfolded state, U. The cooperative binding of the ligand (L), SDS, to I has been shown to induce the formation of a compact, helical intermediate (IL5) within the dead time (∼37 µs) of a continuous flow mixer. Quantitative analysis of the PET-FCS data and the ensemble microsecond kinetic data, suggests that the mechanism of induction of helical structure can be described by a U ↔ I ↔ IL5 ↔ FL5 mechanism, in which the final helical state, FL5, forms from IL5 with a time constant of 50–200 µs. Finally, it has been shown that the helical conformation is an aggregation-competent state that can directly form amyloid fibrils. 相似文献
89.
《Journal of molecular biology》2021,433(4):166812
Spindly is a dynein adaptor involved in chromosomal segregation during cell division. While Spindly's N-terminal domain binds to the microtubule motor dynein and its activator dynactin, the C-terminal domain (Spindly-C) binds its cargo, the ROD/ZW10/ZWILCH (RZZ) complex in the outermost layer of the kinetochore. In humans, Spindly-C binds to ROD, while in C. elegans Spindly-C binds to both Zwilch (ZWL-1) and ROD-1. Here, we employed various biophysical techniques to characterize the structure, dynamics and interaction sites of C. elegans Spindly-C. We found that despite the overall disorder, there are two regions with variable α-helical propensity. One of these regions is located in the C-terminal half and is compact; the second is sparsely populated in the N-terminal half. The interactions with both ROD-1 and ZWL-1 are mostly mediated by the same two sequentially remote disordered segments of Spindly-C, which are C-terminally adjacent to the helical regions. The findings suggest that the Spindly-C binding sites on ROD-1 in the ROD-1/ZWL-1 complex context are either shielded or conformationally weakened by the presence of ZWL-1 such that only ZWL-1 directly interacts with Spindly-C in C. elegans 相似文献
90.
Masayo Suzuki Hiroyuki Ishida Yukimasa Shiotsu Taisuke Nakata Shiro Akinaga Shigemitsu Takashima Toshiaki Utsumi Toshiaki Saeki Nobuhiro Harada 《The Journal of steroid biochemistry and molecular biology》2009,113(3-5):195-201
In order to evaluate the importance of estrogen production in tumor and surrounding tissues, we measured mRNA expression levels of 5 enzymes participating to estrogen synthesis in situ and 4 breast cancer-related proteins in 27 pairs of tumor and non-malignant tissues. Steroid sulfatase (STS) mRNA was more frequently detected in tumor tissues rather than in their non-malignant counterparts. Estrogen sulfotransferase (EST) was constantly expressed with high level not only in tumor tissues but also in their surrounding non-malignant counterparts. In contrast, mRNA expression levels of aromatase, and 17β-hydroxysteroid dehydrogenase type I and II were relatively low and detected only in small proportion of the patients. We also measured the mRNA expression levels of the same nine genes in tumor tissues of 197 breast cancer patients, and analyzed relationship between the mRNA expression level and the clinicopathological parameters. The mRNA expression levels of STS, aromatase and erbB2 in tumor tissues increased as breast cancer progressed. The tumoral mRNA expression levels of STS, estrogen receptor β, and erbB2 in patients with recurrence were higher than those in patients without recurrence. Upregulation of STS expression plays an important role in tumor progression of human breast cancer and is considered to be responsible for estrogen production in tumor and surrounding tissues. 相似文献