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Cloud-point temperatures for lysozyme in electrolyte solutions: effect of salt type, salt concentration and pH 总被引:1,自引:0,他引:1
Liquid-liquid phase-separation data were obtained for aqueous saline solutions of hen egg-white lysozyme at a fixed protein concentration (87 g/l). The cloud-point temperature (CPT) was measured as a function of salt type and salt concentration to 3 M, at pH 4.0 and 7.0. Salts used included those from mono and divalent cations and anions. For the monovalent cations studied, as salt concentration increases, the CPT increases. For divalent cations, as salt concentration rises, a maximum in the CPT is observed and attributed to ion binding to the protein surface and subsequent water structuring. Trends for sulfate salts were dramatically different from those for other salts because sulfate ion is strongly hydrated and excluded from the lysozyme surface. For anions at fixed salt concentration, the CPT decreases with rising anion kosmotropic character. Comparison of CPTs for pH 4.0 and 7.0 revealed two trends. At low ionic strength for a given salt, differences in CPT can be explained in terms of repulsive electrostatic interactions between protein molecules, while at higher ionic strength, differences can be attributed to hydration forces. A model is proposed for the correlation and prediction of the CPT as a function of salt type and salt concentration. NaCl was chosen as a reference salt, and CPT deviations from that of NaCl were attributed to hydration forces. The Random Phase Approximation, in conjunction with a square-well potential, was used to calculate the strength of protein-protein interactions as a function of solution conditions for all salts studied. 相似文献
3.
Iwen F Grigsby Wei Zhang Jolene L Johnson Keir H Fogarty Yan Chen Jonathan M Rawson Aaron J Crosby Joachim D Mueller Louis M Mansky 《Retrovirology》2010,7(1):1-13
Background
The human immunodeficiency virus type 1 (HIV-1) Vpu protein degrades CD4 and counteracts a restriction factor termed tetherin (CD317; Bst-2) to enhance virion release. It has been suggested that both functions can be genetically separated by mutation of a serine residue at position 52. However, recent data suggest that the S52 phosphorylation site is also important for the ability of Vpu to counteract tetherin. To clarify this issue, we performed a comprehensive analysis of HIV-1 with a mutated casein kinase-II phosphorylation site in Vpu in various cell lines, primary blood lymphocytes (PBL), monocyte-derived macrophages (MDM) and ex vivo human lymphoid tissue (HLT).Results
We show that mutation of serine 52 to alanine (S52A) entirely disrupts Vpu-mediated degradation of CD4 and strongly impairs its ability to antagonize tetherin. Furthermore, casein-kinase II inhibitors blocked the ability of Vpu to degrade tetherin. Overall, Vpu S52A could only overcome low levels of tetherin, and its activity decreased in a manner dependent on the amount of transiently or endogenously expressed tetherin. As a consequence, the S52A Vpu mutant virus was unable to replicate in macrophages, which express high levels of this restriction factor. In contrast, HIV-1 Vpu S52A caused CD4+ T-cell depletion and spread efficiently in ex vivo human lymphoid tissue and PBL, most likely because these cells express comparably low levels of tetherin.Conclusion
Our data explain why the effect of the S52A mutation in Vpu on virus release is cell-type dependent and suggest that a reduced ability of Vpu to counteract tetherin impairs HIV-1 replication in macrophages, but not in tissue CD4+ T cells. 相似文献4.
Notch-deficient skin induces a lethal systemic B-lymphoproliferative disorder by secreting TSLP, a sentinel for epidermal integrity 总被引:1,自引:1,他引:0
Demehri S Liu Z Lee J Lin MH Crosby SD Roberts CJ Grigsby PW Miner JH Farr AG Kopan R 《PLoS biology》2008,6(5):e123
Epidermal keratinocytes form a highly organized stratified epithelium and sustain a competent barrier function together with dermal and hematopoietic cells. The Notch signaling pathway is a critical regulator of epidermal integrity. Here, we show that keratinocyte-specific deletion of total Notch signaling triggered a severe systemic B-lymphoproliferative disorder, causing death. RBP-j is the DNA binding partner of Notch, but both RBP-j–dependent and independent Notch signaling were necessary for proper epidermal differentiation and lipid deposition. Loss of both pathways caused a persistent defect in skin differentiation/barrier formation. In response, high levels of thymic stromal lymphopoietin (TSLP) were released into systemic circulation by Notch-deficient keratinocytes that failed to differentiate, starting in utero. Exposure to high TSLP levels during neonatal hematopoiesis resulted in drastic expansion of peripheral pre- and immature B-lymphocytes, causing B-lymphoproliferative disorder associated with major organ infiltration and subsequent death, a previously unappreciated systemic effect of TSLP. These observations demonstrate that local skin perturbations can drive a lethal systemic disease and have important implications for a wide range of humoral and autoimmune diseases with skin manifestations. 相似文献
5.
Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation 总被引:3,自引:0,他引:3
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Hagerman RJ Leavitt BR Farzin F Jacquemont S Greco CM Brunberg JA Tassone F Hessl D Harris SW Zhang L Jardini T Gane LW Ferranti J Ruiz L Leehey MA Grigsby J Hagerman PJ 《American journal of human genetics》2004,74(5):1051-1056
We describe five female carriers of the FMR1 premutation who presented with symptoms of tremor and ataxia and who received a diagnosis of definite or probable fragile-X-associated tremor/ataxia syndrome (FXTAS). Unlike their male counterparts with FXTAS, none of the women had dementia. Females had not been reported in previous studies of FXTAS, suggesting that they may be relatively protected from this disorder. Brain tissue was available from one of the five subjects, a women who died at age 85 years; microscopic examination revealed intranuclear neuronal and astrocytic inclusions, in accord with the findings previously reported in males with FXTAS. The work-up of families with the FMR1 mutation should include questions regarding neurological symptoms in both older male and female carriers, with the expectation that females may also manifest the symptoms of FXTAS, although more subtly and less often than their male counterparts. 相似文献
6.
Ramachandran Rashmi Carl DeSelm Cynthia Helms Anne Bowcock Buck E. Rogers Janet Rader Perry W. Grigsby Julie K. Schwarz 《PloS one》2014,9(4)
Background
PI3K/AKT pathway alterations are associated with incomplete response to chemoradiation in human cervical cancer. This study was performed to test for mutations in the PI3K pathway and to evaluate the effects of AKT inhibitors on glucose uptake and cell viability.Experimental Design
Mutational analysis of DNA from 140 pretreatment tumor biopsies and 8 human cervical cancer cell lines was performed. C33A cells (PIK3CAR88Q and PTENR233*) were treated with increasing concentrations of two allosteric AKT inhibitors (SC-66 and MK-2206) with or without the glucose analogue 2-deoxyglucose (2-DG). Cell viability and activation status of the AKT/mTOR pathway were determined in response to the treatment. Glucose uptake was evaluated by incubation with 18F-fluorodeoxyglucose (FDG). Cell migration was assessed by scratch assay.Results
Activating PIK3CA (E545K, E542K) and inactivating PTEN (R233*) mutations were identified in human cervical cancer. SC-66 effectively inhibited AKT, mTOR and mTOR substrates in C33A cells. SC-66 inhibited glucose uptake via reduced delivery of Glut1 and Glut4 to the cell membrane. SC-66 (1 µg/ml-56%) and MK-2206 (30 µM-49%) treatment decreased cell viability through a non-apoptotic mechanism. Decreases in cell viability were enhanced when AKT inhibitors were combined with 2-DG. The scratch assay showed a substantial reduction in cell migration upon SC-66 treatment.Conclusions
The mutational spectrum of the PI3K/AKT pathway in cervical cancer is complex. AKT inhibitors effectively block mTORC1/2, decrease glucose uptake, glycolysis, and decrease cell viability in vitro. These results suggest that AKT inhibitors may improve response to chemoradiation in cervical cancer. 相似文献7.
Keir H. Fogarty Serkan Berk Iwen F. Grigsby Yan Chen Louis M. Mansky Joachim D. Mueller 《Journal of molecular biology》2014
The early events in the retrovirus assembly pathway, particularly the timing and nature of Gag translocation from the site of protein translation to the inner leaflet of the plasma membrane, are poorly understood. We have investigated the interrelationship between cytoplasmic Gag concentration and plasma membrane association using complementary live-cell biophysical fluorescence techniques in real time with both human T-cell leukemia virus type 1 (HTLV-1) and human immunodeficiency virus type 1 (HIV-1) Gag proteins. In particular, dual-color, z-scan fluorescence fluctuation spectroscopy in conjunction with total internal reflection fluorescence and conventional, epi-illumination imaging were utilized. Our results demonstrate that HTLV-1 Gag is capable of membrane targeting and particle assembly at low (i.e., nanomolar) cytoplasmic concentrations and that there is a critical threshold concentration (approaching micromolar) prior to the observation of HIV-1 Gag associated with the plasma membrane. These observations imply fundamental differences between HIV-1 and HTLV-1 Gag trafficking and membrane association. 相似文献
8.
Cleaning symbioses on coral reefs involve small cleaner fish or shrimps picking ectoparasites from the exterior surfaces of
larger client organisms. These mutualisms are thought to evolve in part because the cleaner receives a reliable source of
profitable prey items and immunity from predation. However, the benefits of cleaning behavior have never been measured relative
to those of alternative, non-cleaning strategies. This study examined these costs and benefits in the sharknose goby, Elacatinus evelynae, a facultative cleaner fish, at the Caribbean island of St. Croix. Sharknose gobies are found on coral heads, where they
maintain cleaning stations, and on basket sponges, where they spend little time cleaning and feed predominantly on nonparasitic
copepods. For immature gobies that are not allocating energy to reproduction, hindcast otolith growth rates (a reliable proxy
for somatic growth) were significantly higher for non-cleaning sponge-dwellers than for coral-dwellers. Furthermore, tagging
large, competitively dominant gobies on sponges and corals revealed that mortality rates were higher for coral-dwelling gobies.
These unexpected results provide further evidence that cleaning mutualisms are context dependent: far from being a uniformly
profitable life history strategy, cleaning may be a suboptimal choice at some times and places. 相似文献
9.
Preventing out-of-home placement for high-risk children 总被引:1,自引:0,他引:1
L A Vitulano S Nagler J Adnopoz R K Grigsby 《The Yale journal of biology and medicine》1990,63(4):285-291
Preventing the removal of high-risk children from their families is investigated through two community-based programs. One program followed a day treatment model; the other used a home-based approach. These programs treated populations that shared common features but also had important differences. In both programs, a high percentage of children were maintained in the home and were still at home one year after discharge. It is suggested that such community-based intervention programs enhance the likelihood that high-risk children can remain with their families. 相似文献
10.
Randi T Garmo Steinar Waage Ståle Sviland Britt IF Henriksen Olav Østerås Olav Reksen 《Acta veterinaria Scandinavica》2010,52(1):11