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101.
102.
Sisir Bhattacharya Sunny P. Bhardwaj Raj Suryanarayanan 《Pharmaceutical research》2014,31(10):2822-2828
Purpose
To determine the effect of annealing on the two secondary relaxations in amorphous sucrose and in sucrose solid dispersions.Methods
Sucrose was co-lyophilized with either PVP or sorbitol, annealed for different time periods and analyzed by dielectric spectroscopy.Results
In an earlier investigation, we had documented the effect of PVP and sorbitol on the primary and the two secondary relaxations in amorphous sucrose solid dispersions (1). Here we investigated the effect of annealing on local motions, both in amorphous sucrose and in the dispersions. The average relaxation time of the local motion (irrespective of origin) in sucrose, decreased upon annealing. However, the heterogeneity in relaxation time distribution as well as the dielectric strength decreased only for β1- (the slower relaxation) but not for β2-relaxations. The effect of annealing on β2-relaxation times was neutralized by sorbitol while PVP negated the effect of annealing on both β1- and β2-relaxations.Conclusions
An increase in local mobility of sucrose brought about by annealing could be negated with an additive. 相似文献103.
Diana Leticia Coronel-MartÍnez Juliana Park Eduardo López-Medina María Rosario Capeding Andrés Angelo Cadena Bonfanti María Cecilia Montalbán Isabel Ramírez María Liza Antoinette Gonzales Carlos A DiazGranados Betzana Zambrano Gustavo Dayan Stephen Savarino Zhenghong Chen Hao Wang Sunny Sun Matthew Bonaparte Andrey Rojas Jenny Carolina Ramírez Fernando Noriega 《The Lancet infectious diseases》2021,21(4):517-528
104.
Olivier Deltombe Wim Van Biesen Griet Glorieux Ziad Massy Annemieke Dhondt Sunny Eloot 《Toxins》2015,7(10):3933-3946
As protein binding of uremic toxins is not well understood, neither in chronic kidney disease (CKD) progression, nor during a hemodialysis (HD) session, we studied protein binding in two cross-sectional studies. Ninety-five CKD 2 to 5 patients and ten stable hemodialysis patients were included. Blood samples were taken either during the routine ambulatory visit (CKD patients) or from blood inlet and outlet line during dialysis (HD patients). Total (CT) and free concentrations were determined of p-cresylglucuronide (pCG), hippuric acid (HA), indole-3-acetic acid (IAA), indoxyl sulfate (IS) and p-cresylsulfate (pCS), and their percentage protein binding (%PB) was calculated. In CKD patients, %PB/CT resulted in a positive correlation (all p < 0.001) with renal function for all five uremic toxins. In HD patients, %PB was increased after 120 min of dialysis for HA and at the dialysis end for the stronger (IAA) and the highly-bound (IS and pCS) solutes. During one passage through the dialyzer at 120 min, %PB was increased for HA (borderline), IAA, IS and pCS. These findings explain why protein-bound solutes are difficult to remove by dialysis: a combination of the fact that (i) only the free fraction can pass the filter and (ii) the equilibrium, as it was pre-dialysis, cannot be restored during the dialysis session, as it is continuously disturbed. 相似文献
105.
106.
The immune regulatory protein B7-H3 promotes osteoblast differentiation and bone mineralization 总被引:1,自引:0,他引:1 下载免费PDF全文
Suh WK Wang SX Jheon AH Moreno L Yoshinaga SK Ganss B Sodek J Grynpas MD Mak TW 《Proceedings of the National Academy of Sciences of the United States of America》2004,101(35):12969-12973
B7-H3, a member of the B7 family of the Ig superfamily proteins, is expressed on the surface of the antigen-presenting cells and down-regulates T cell functions by engaging an unknown counterreceptor on T cells. Although B7-H3 is ubiquitously expressed, its potential nonimmune functions have not been addressed. We found that B7-H3 is highly expressed in developing bones during embryogenesis and that its expression increases as osteoblast precursor cells differentiate into mature osteoblasts. In vitro bone formation by osteoblastic cells was inhibited when B7-H3 function was interrupted by the soluble recombinant protein B7-H3-Fc. Analysis of calvarial cells derived from neonatal B7-H3 knockout (KO) mice revealed normal numbers of osteoblast precursor cells possessing a normal proliferative capacity. However, the B7-H3-deficient calvarial cells exhibited impaired osteogenic differentiation, resulting in decreased mineralized bone formation in vitro. These results suggest that B7-H3 is required for the later phase of osteoblast differentiation. Although B7-H3 KO mice had no gross skeletal abnormalities, they displayed a lower bone mineral density in cortical (but not trabecular) bones compared with WT controls. Consistent with the reduced bone mineral density, the femurs of B7-H3 KO mice were more susceptible to bone fracture compared with those of WT mice. Taken together, these results indicate that B7-H3 and its unknown counterreceptor play a positive regulatory role in bone formation. In addition, our findings identified B7-H3 as another molecule that has a dual role in the bone-immune interface. 相似文献
107.
Zhenyue Hao Rob A. Cairns Satoshi Inoue Wanda Y. Li Yi Sheng Fran?ois Lemonnier Andrew Wakeham Bryan E. Snow Carmen Dominguez-Brauer Jing Ye Dana M. Larsen Kimberly S. Straley Erica R. Tobin Rohini Narayanaswamy Philippe Gaulard Tak W. Mak 《Proceedings of the National Academy of Sciences of the United States of America》2016,113(5):1387-1392
Gain-of-function mutations in isocitrate dehydrogenase 1 (IDH1) are key drivers of hematopoietic malignancies. Although these mutations are most commonly associated with myeloid diseases, they also occur in malignancies of the T-cell lineage. To investigate their role in these diseases and provide tractable disease models for further investigation, we analyzed the T-cell compartment in a conditional knock-in (KI) mouse model of mutant Idh1. We observed the development of a spontaneous T-cell acute lymphoblastic leukemia (T-ALL) in these animals. The disease was transplantable and maintained expression of mutant IDH1. Whole-exome sequencing revealed the presence of a spontaneous activating mutation in Notch1, one of the most common mutations in human T-ALL, suggesting Idh1 mutations may have the capacity to cooperate with Notch1 to drive T-ALL. To further investigate the Idh1 mutation as an oncogenic driver in the T-cell lineage, we crossed Idh1-KI mice with conditional Trp53 null mice, a well-characterized model of T-cell malignancy, and found that T-cell lymphomagenesis was accelerated in mice bearing both mutations. Because both IDH1 and p53 are known to affect cellular metabolism, we compared the requirements for glucose and glutamine in cells derived from these tumors and found that cells bearing the Idh1 mutation have an increased dependence on both glucose and glutamine. These data suggest that mutant IDH1 contributes to malignancy in the T-cell lineage and may alter the metabolic profile of malignant T cells.Somatic mutations in isocitrate dehydrogenase 1 (IDH1) are frequently observed in a number of malignancies, including glioma, cholangiocarcinoma, chondrosarcoma, and several hematological malignancies (1). IDH1 is a cytoplasmic enzyme that catalyzes the NADP-dependent conversion of isocitrate to α-ketoglutarate (αKG). Mutations in IDH1 at arginine 132 (R132) cause an enzymatic gain of function that results in the NADPH-dependent conversion of αKG to d-2-hydroxyglutarate (2HG) (2). This metabolite is normally maintained at very low levels in cells and tissues and is not part of any known productive metabolic pathway. However, in cells and tissues of patients with IDH1 mutant tumors, 2HG builds up to high levels and is thought to contribute to tumorigenesis by inhibiting a class of αKG-dependent enzymes (1). The precise effects important for driving tumorigenesis downstream of IDH1 mutations are not fully understood and may differ between disease states.In the hematopoietic system, IDH1 mutations are most often associated with myeloid diseases, where they are commonly found in myelodysplastic syndrome and acute myeloid leukemia (3). However, IDH1 mutations are also found in a small proportion of adult T-cell acute lymphoblastic leukemia (T-ALL) (4, 5). T-ALL is an aggressive malignancy of developing T cells and is responsible for ∼25% of adult ALL (6, 7). T-ALL is thought to arise via a multistep process of oncogenic mutation that leads to the transformation of immature T cells. The genetic landscape of the disease has been characterized, and a large number of driver mutations have been identified (6). The most common genetic feature of T-ALL is the presence of activating mutations in Notch1, which are present in more than 50% of patients (8). Interestingly, IDH1 mutations seem to be confined to a subset of adult patients with T-ALL bearing an immature T-cell gene expression signature and harboring other oncogenic mutations in genes more commonly associated with myeloid malignancy, including Flt3 and DNMT3A (4, 9). This subset of T-ALL has recently been recognized as a distinct disease entity called early T-cell precursor T-ALL and is associated with therapy resistance and a particularly poor outcome (10). The role of IDH1 mutations in this subset of T-ALL is not understood.Using a myeloid lineage-specific conditional Idh1-R132-KI mouse model, we previously showed that mutant IDH1 partially blocks differentiation and produces a hematopoietic phenotype similar to human myelodysplastic syndrome (11). In this study, we crossed the Idh1-R132-KI mouse with Vav-cre animals to introduce the IDH1 R132 mutation into the entire hematopoietic system to investigate the role of Idh1 mutations in T-cell malignancy. 相似文献
108.
目前对心房颤动(简称房颤)机制的基本认识有①局灶起源机制;②多子波折返机制;③主导折返环机制。以这些机制为指导的消融治疗房颤,存在消融时间长、并发症多,且成功率不高的缺点。因此,人们在不断地探索新的标测方法。由于各个研究中心所采取的标测方法和技术不同,出现以复杂碎裂心房电图区、房颤巢、主频点以及心脏神经丛为消融靶点的治疗方法。这些方法均取得了较好的疗效,又对房颤的机制有了更深入的认识。从所有方法标测的部位上看,似乎这些方法均有联系,均与心脏神经丛关联。如果能透过这些现象认识到房颤的本质,那么就有可能找到消融治疗房颤的简单方法。 相似文献
109.
Xue L Nolla H Suzuki A Mak TW Winoto A 《Proceedings of the National Academy of Sciences of the United States of America》2008,105(6):2022-2027
PTEN is a tumor suppressor gene but whether cancer can develop in all PTEN-deficient cells is not known. In T cell-specific PTEN-deficient (tPTEN−/−) mice, which suffer from mature T cell lymphomas, we found that premalignancy, as defined by elevated AKT and senescence pathways, starts in immature T cell precursors and surprisingly not in mature T cells. Premalignancy only starts in 6-week-old mice and becomes much stronger in 9-week-old mice although PTEN is lost since birth. tPTEN−/− immature T cells do not become tumors, and senescence has no role in this model because these cells exist in a novel cell cycle state, expressing proliferating proteins but not proliferating to any significant degree. Instead, the levels of p27kip1, which is lower in tPTEN−/− immature T cells and almost nonexistent in tPTEN−/− mature T cells, correlate with the proliferation capability of these cells. Interestingly, transient reduction of these cancer precursor cells in adult tPTEN−/− mice within a crucial time window significantly delayed lymphomas and mouse lethality. Thus, loss of PTEN alone is not sufficient for cells to become cancerous, therefore other developmental events are necessary for tumor formation. 相似文献
110.
A high frequency of nonhemolytic hereditary ovalocytosis in Malayan aborigines is thought to result from reduced susceptibility of affected individuals to malaria. Indeed, Kidson et al. recently showed that ovalocytes from Melanesians in Papua New Guinea are resistant to infection in culture by the malarial parasite Plasmodium falciparum. In order to determine if protection against parasitic invasion in these ovalocytes might be the result of some altered membrane material property in these unusual cells, we measured their membrane and cellular deformability characteristics using an ektacytometer . Ovalocytic red cells were found to be much less deformable in comparison to normal discoid red cells. Similar measurements on isolated membrane preparations revealed a marked reduction in ovalocytic membrane deformability. To produce equal deformation of ovalocytic and normal membranes, ovalocytes required an 8-10-fold increase in applied shear stress, indicating that their membrane was capable of deforming under sufficient stress. To test the possibility that this increased membrane rigidity might confer resistance to parasitic invasion, we performed an in vitro invasion assay using Plasmodium falciparum merozoites and Malayan ovalocytes of varying deformability from seven different donors. The level of infection of the ovalocytes ranged from 1% to 35% of that in control cells, and the extent of inhibition appeared to be closely related to the reduction in membrane deformability. Moreover, we were able to induce similar resistance to parasitic invasion in nonovalocytic normal red cells by increasing their membrane rigidity with graded exposure to a protein crosslinking agent. Our findings suggest that resistance to parasite invasion of Malayan ovalocytes is the result of a genetic mutation that causes increased membrane rigidity. 相似文献