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971.
Uterine receptivity is prerequisite for the attachment of the embryo to the uterine epithelium and involves a specialized polarity-dependent property of uterine epithelial (UE) cells. These UE cells, when polarized in culture, behave like cells in utero by exhibiting apico-basal polarity. In order to develop an implantation model in vitro, UE cells were polarized on extracellular matrix (ECM), and polarity was validated by response to estradiol-17β administered exogenously. UE cells of pregnant rats at day-3 and day-4 post-coitum (p.c.) and of non-pregnant rats were cultured on bare and extracellular-matrix-coated petri dishes until confluency. Hatched blastocysts were transferred to the cultures, and adhesion was monitored every 24 h. Although blastocysts attached to UE cells that were taken from non-pregnant rats and from rats of day-3 p.c. and cultured on bare plastic, they failed to attach to these cells polarized on ECM. However, blastocysts attached firmly to UE cells that had been taken from rats of day-4 p.c. and polarized on ECM. Receptivity of UE cells taken from non-pregnant and pregnant (day-4 p.c.) rats was quantitated by flow cytometric estimation of cellular levels of β3 integrin. The expression of β3 integrin in UE cells from rats of day-4 p.c. was highly significant (P<0.01) when compared with its expression in UE cells from non-pregnant rats. The expression of β3 integrin in UE cells of day-4 p.c. confirmed the receptivity of these cells to blastocyst implantation. Uterine receptivity was also validated in vivo by inducing the decidual cell reaction in rats ovariectomized on day-3 and day-4 p.c. Whereas remarkable deciduoma was noticed in the animals of day-4 p.c., it was absent in the animals of day-3 p.c., thereby indicating that the uterus was receptive on day-4 p.c. only. Thus, blastocysts do not attach to polarized UE cells that have been obtained from a non-receptive uterus. Attachment will occur only if the cells are obtained from a receptive uterus. UE cell receptivity is therefore essential for mimicking the process of implantation in vitro.The authors are grateful to the Ministry of Health and Family welfare, Government of India, for financial support 相似文献
972.
Effects of glucose and its modulation by insulin and estradiol on BMSC differentiation into osteoblastic lineages. 总被引:12,自引:0,他引:12
V Gopalakrishnan R C Vignesh J Arunakaran M M Aruldhas N Srinivasan 《Biochimie et biologie cellulaire》2006,84(1):93-101
It is well known that diabetes affects bone in human and animal models, and leads to osteopenia and osteoporosis. Bone-mineral density and other biochemical markers of bone turnover are very much affected in people with diabetes. Reduced bone mass, occurring with increased frequency in diabetes mellitus, has been attributed to poor glycemic control, but the pathogenic mechanisms remain unknown. High concentrations of glucose (hyperglycemia) in diabetics leads to this complication. Very few in vitro studies using bone-cell lines have been carried out to address this problem. In this study, we examined the effects of different doses of glucose concentration (5.5, 16.5, and 49.4 mmol/L), alone, with insulin (0.6 microg/mL), or with 17beta-estradiol (E2) (10 nmol/L), on rat bone-marrow stromal cells (BMSCs) in the presence of an osteogenic medium. BMSC proliferation and alkaline phosphatase (ALP) were studied after 3 and 7 d of culture, respectively; the area stained for collagen and mineralized nodules was studied after 28 d of culture. With high concentrations of glucose, BMSC proliferation, ALP activity, the number of nodules formed, and the area stained for collagen were greatly reduced. Insulin treatment alone was able to increase [3H]-thymidine uptake or ALP activity, whereas both insulin and estradiol were able to increase the number of mineralized nodules and the area stained for collagen and mineralization. In conclusion, this study suggests that insulin and estradiol are able to contain the deleterious effect of high concentrations of glucose on BMSC-derived osteoblast proliferation and function. 相似文献
973.
Lateralization of function is a well-known phenomenon in humans. The two hemispheres of the human brain are functionally specialized such that certain cognitive skills, such as language or musical ability, conspecific recognition, and even emotional responses, are mediated by one hemisphere more than the other [1, 2]. Studies over the past 30 years suggest that lateralization occurs in other vertebrate species as well [3-11]. In general, lateralization is observed in different sensory modalities in humans as well as vertebrates, and there are interesting parallels (reviewed in [12]). However, little is known about functional asymmetry in invertebrates [13, 14] and there is only one investigation in insects [15]. Here we show, for the first time, that the honeybee Apis mellifera displays a clear laterality in responding to learned odors. By training honeybees on two different versions of the well-known proboscis extension reflex (PER) paradigm [16, 17], we demonstrate that bees respond to odors better when they are trained through their right antenna. To our knowledge, this is the first demonstration of asymmetrical learning performance in an insect. 相似文献
974.
Walking insects probably monitor leg movements to estimate how far they travel, whereas flying insects monitor optic flow. 相似文献
975.
Arasappan A Njoroge FG Chen KX Venkatraman S Parekh TN Gu H Pichardo J Butkiewicz N Prongay A Madison V Girijavallabhan V 《Bioorganic & medicinal chemistry letters》2006,16(15):3960-3965
Synthesis and HCV NS3 serine protease inhibitory activity of 4-hydroxyproline derived macrocyclic inhibitors and SAR around this macrocyclic core is described in this communication. X-ray structure of inhibitor 38 bound to the protease is discussed. 相似文献
976.
977.
Hyunbum Jang Fernando Teran Arce Srinivasan Ramachandran Ruth Nussinov 《Biophysical journal》2009,97(11):3029-3037
In Alzheimer's disease, calcium permeability through cellular membranes appears to underlie neuronal cell death. It is increasingly accepted that calcium permeability involves toxic ion channels. We modeled Alzheimer's disease ion channels of different sizes (12-mer to 36-mer) in the lipid bilayer using molecular dynamics simulations. Our Aβ channels consist of the solid-state NMR-based U-shaped β-strand-turn-β-strand motif. In the simulations we obtain ion-permeable channels whose subunit morphologies and shapes are consistent with electron microscopy/atomic force microscopy. In agreement with imaged channels, the simulations indicate that β-sheet channels break into loosely associated mobile β-sheet subunits. The preferred channel sizes (16- to 24-mer) are compatible with electron microscopy/atomic force microscopy-derived dimensions. Mobile subunits were also observed for β-sheet channels formed by cytolytic PG-1 β-hairpins. The emerging picture from our large-scale simulations is that toxic ion channels formed by β-sheets spontaneously break into loosely interacting dynamic units that associate and dissociate leading to toxic ionic flux. This sharply contrasts intact conventional gated ion channels that consist of tightly interacting α-helices that robustly prevent ion leakage, rather than hydrogen-bonded β-strands. The simulations suggest why conventional gated channels evolved to consist of interacting α-helices rather than hydrogen-bonded β-strands that tend to break in fluidic bilayers. Nature designs folded channels but not misfolded toxic channels. 相似文献
978.
Ishfaq Ahmed Sheikh Amit Kumar Singh Nagendra Singh Mau Sinha S. Baskar Singh Asha Bhushan Punit Kaur Alagiri Srinivasan Sujata Sharma Tej P. Singh 《The Journal of biological chemistry》2009,284(22):14849-14856
The crystal structure of the complex of lactoperoxidase (LPO) with its
physiological substrate thiocyanate (SCN–) has been
determined at 2.4Å resolution. It revealed that the
SCN– ion is bound to LPO in the distal heme cavity. The
observed orientation of the SCN– ion shows that the sulfur
atom is closer to the heme iron than the nitrogen atom. The nitrogen atom of
SCN– forms a hydrogen bond with a water (Wat) molecule at
position 6′. This water molecule is stabilized by two hydrogen bonds
with Gln423 Nε2 and Phe422 oxygen. In
contrast, the placement of the SCN– ion in the structure of
myeloperoxidase (MPO) occurs with an opposite orientation, in which the
nitrogen atom is closer to the heme iron than the sulfur atom. The site
corresponding to the positions of Gln423, Phe422 oxygen,
and Wat6′ in LPO is occupied primarily by the side chain of
Phe407 in MPO due to an entirely different conformation of the loop
corresponding to the segment Arg418–Phe431 of LPO.
This arrangement in MPO does not favor a similar orientation of the
SCN– ion. The orientation of the catalytic product
OSCN– as reported in the structure of
LPO·OSCN– is similar to the orientation of
SCN– in the structure of LPO·SCN–.
Similarly, in the structure of
LPO·SCN–·CN–, in which
CN– binds at Wat1, the position and orientation of
the SCN– ion are also identical to that observed in the
structure of LPO·SCN.Lactoperoxidase
(LPO4; EC 1.11.1.7) is
a Fe3+ heme enzyme that belongs to the mammalian peroxidase family
(1). The family of mammalian
peroxidases comprises lactoperoxidase
(2), eosinophil peroxidase
(3), thyroid peroxidase
(4), and myeloperoxidase (MPO)
(5). LPO, eosinophil
peroxidase, and MPO are responsible for antimicrobial function and innate
immune responses
(6–8),
whereas thyroid peroxidase plays a key role in thyroid hormone biosynthesis
(9). These peroxidases are
different from plant and fungal peroxidases because unlike plant and fungal
enzymes, the prosthetic heme group in mammalian peroxidases is covalently
linked to the protein (10).
There are also several striking structural and functional differences among
the mammalian peroxidases
(11). The heme group in MPO is
attached to the protein via three covalent linkages
(12), whereas LPO
(12,
13), eosinophil peroxidase
(12), and thyroid peroxidase
(12) contain only two ester
linkages. These covalent and various non-covalent linkages contribute
differentially to the high stability of the heme core as well as for the
peculiar values of their redox potentials
(2,
14). Furthermore, MPO consists
of two disulfide-linked protein chains, whereas LPO, eosinophil peroxidase,
and thyroid peroxidase are single chain proteins, although their chain lengths
differ greatly. In addition, their sequences contain several critical amino
acid differences that may also contribute to the variations in the
stereochemical environments of the substrate-binding sites. As a consequence
of these differences, the mammalian enzymes oxidize various inorganic ions
such as SCN–, Br–, Cl–, and
I– with differing specificities and potencies. Biochemical
studies have shown that LPO catalyzes preferentially the conversion of
SCN– to OSCN–
(15,
16), whereas MPO uses halides
(17,
18) with a preference for
chloride ion as the substrate. The preferences of eosinophil peroxidase and
thyroid peroxidase are bromide and iodide, respectively. However, the
stereochemical basis of the reported preferences for the substrates by
mammalian heme peroxidases is still unclear. So far, the structures of only
two mammalian enzymes, MPO and LPO, have been determined
(12,
13). It is of considerable
importance to identify the structural parameters that are responsible for the
subtle specificities. In the present work, we have attempted to address this
question through the new crystal structures of LPO complexes with
SCN– ions using goat, bovine, and buffalo lactoperoxidases.
Because the overall structures of complexes of SCN– with LPO
from all three species were found to be identical, the structure of the
complex of buffalo LPO with SCN– and the ternary complex with
SCN– and CN– will be discussed here, and
buffalo LPO will be termed hereafter as LPO. To highlight the factors
pertaining to binding specificity of SCN–, a comparison of
the structures of LPO·SCN– and
MPO·SCN– has also been made, revealing many valuable
differences pertaining to the observed orientations of the common substrate,
SCN– ion, when bound at the substrate-binding site in the
distal heme cavity of the two structures. The structures of
LPO·SCN– and MPO·SCN– clearly
show that the bound SCN– ions are present in the distal heme
cavity of two enzymes with opposite orientations. In the structure of
LPO·SCN–, the sulfur atom is closer to the heme iron
than the nitrogen atom, whereas in that of MPO·SCN–,
the nitrogen atom is closer to the heme iron than the sulfur atom. As a result
of this, the interactions of the SCN– ion in the distal site
of two proteins differ drastically. Gln423, a conserved water (Wat)
molecule at position 6′, and a well aligned carbonyl oxygen of
Phe422 in the proximity of the substrate-binding site in LPO
against a protruding Phe407 in MPO seem to play the key roles in
inducing the observed orientations of SCN– ions in LPO and
MPO. The structure of LPO·SCN– has also been compared
with the structure of its ternary complex with SCN– and
CN– ions. 相似文献
979.
Nazish Abdullah Bharani Srinivasan Nir Modiano Apurba Kumar Sau 《Journal of molecular biology》2009,386(3):690-298
Unlike other GTPases, interferon-gamma-induced human guanylate binding protein-1 has the ability to hydrolyze GTP to both GDP and GMP, with GMP being the major product of the reaction. This protein has two domains, an N-terminal globular domain and a C-terminal helical domain. These two domains are connected by a short intermediate region consisting of a two-stranded β-sheet and a helix. As human guanylate binding protein-1 has been shown to undergo stimulated GTPase activity without external GTPase-activating protein, we sought to understand the roles of each of the two individual domains, the intermediate region, a conserved motif (103DXEKGD108), and the mechanism of the stimulation of GTPase activity. The steady-state assays using radiolabeled [α-32P]GTP on the wild-type protein suggest that the stimulation of activity primarily occurs during the cleavage of the second phosphate of GTP rather than the first, through allosteric interaction. Using several truncated and mutant proteins, we demonstrate for the first time that both the α-helix of the intermediate region and the 103DXEKGD108 motif play critical roles for the hydrolysis to GMP, but they appear to act in different ways: α-helix acts through structural stabilization by allosteric interaction and, thus, acts as an internal GTPase-activating protein, whereas the motif might act by providing necessary catalytic residues. Our data also show that the N-terminal globular domain is able to perform only the first catalysis (GTP to GDP, an activity associated with basal level), but the helical domain in the full-length protein stimulates the hydrolysis of GTP to GMP with higher GMP formation by preventing the dissociation of GDP-bound enzyme dimer. 相似文献
980.
Patke S Maheshwari R Litt J Srinivasan S Aguilera JJ Colón W Kane RS 《Biochemistry》2012,51(14):3092-3099
The fibrillar deposition of serum amyloid A (SAA) has been linked to the disease amyloid A (AA) amyloidosis. We have used the SAA isoform, SAA2.2, from the CE/J mouse strain, as a model system to explore the inherent structural and biophysical properties of SAA. Despite its nonpathogenic nature in vivo, SAA2.2 spontaneously forms fibrils in vitro, suggesting that SAA proteins are inherently amyloidogenic. However, whereas the importance of the amino terminus of SAA for fibril formation has been well documented, the influence of the proline-rich and presumably disordered carboxy terminus remains poorly understood. To clarify the inherent role of the carboxy terminus in the oligomerization and fibrillation of SAA, we truncated the proline-rich final 13 residues of SAA2.2. We found that unlike full-length SAA2.2, the carboxy-terminal truncated SAA2.2 (SAA2.2ΔC) did not oligomerize to a hexamer or octamer, but formed a high molecular weight soluble aggregate. Moreover, SAA2.2ΔC also exhibited a pronounced decrease in the rate of fibril formation. Intriguingly, when equimolar amounts of denatured SAA2.2 and SAA2.2ΔC were mixed and allowed to refold together, the mixture formed an octamer and exhibited rapid fibrillation kinetics, similar to those for full-length SAA2.2. These results suggest that the carboxy terminus of SAA, which is highly conserved among SAA sequences in all vertebrates, might play important structural roles, including modulating the folding, oligomerization, misfolding, and fibrillation of SAA. 相似文献