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31.
Identification of a Polar Region in Transmembrane Domain 6 That Regulates the Function of the G Protein-Coupled α-Factor Receptor 下载免费PDF全文
The α-factor pheromone receptor (Ste2p) of the yeast Saccharomyces cerevisiae belongs to the family of G protein-coupled receptors that contain seven transmembrane domains (TMDs). Because polar residues can influence receptor structure by forming intramolecular contacts between TMDs, we tested the role of the five polar amino acids in TMD6 of the α-factor receptor by mutating these residues to nonpolar leucine. Interestingly, a subset of these mutants showed increased affinity for ligand and constitutive receptor activity. The mutation of the most polar residue, Q253L, resulted in 25-fold increased affinity and a 5-fold-higher basal level of signaling that was equal to about 19% of the α-factor induced maximum signal. Mutation of the adjacent residue, S254L, caused weaker constitutive activity and a 5-fold increase in affinity. Comparison of nine different mutations affecting Ser254 showed that an S254F mutation caused higher constitutive activity, suggesting that a large hydrophobic amino acid residue at position 254 alters transmembrane helix packing. Thus, these studies indicate that Gln253 and Ser254 are likely to be involved in intramolecular interactions with other TMDs. Furthermore, Gln253 and Ser254 fall on one side of the transmembrane helix that is on the opposite side from residues that do not cause constitutive activity when mutated. These results suggest that Gln253 and Ser254 face inward toward the other TMDs and thus provide the first experimental evidence to suggest the orientation of a TMD in this receptor. Consistent with this, we identified two residues in TMD7 (Ser288 and Ser292) that are potential contact residues for Gln253 because mutations affecting these residues also cause constitutive activity. Altogether, these results identify a new domain of the α-factor receptor that regulates its ability to enter the activated conformation. 相似文献
32.
Michael Liebrenz Marcel Schneider Anna Buadze Marie-Therese Gehring Anish Dube Carlo Caflisch 《PloS one》2015,10(11)
Background
High-dose benzodiazepine (BZD) dependence is associated with a wide variety of negative health consequences. Affected individuals are reported to suffer from severe mental disorders and are often unable to achieve long-term abstinence via recommended discontinuation strategies. Although it is increasingly understood that treatment interventions should take subjective experiences and beliefs into account, the perceptions of this group of individuals remain under-investigated.Methods
We conducted an exploratory qualitative study with 41 adult subjects meeting criteria for (high-dose) BZD-dependence, as defined by ICD-10. One-on-one in-depth interviews allowed for an exploration of this group’s views on the reasons behind their initial and then continued use of BZDs, as well as their procurement strategies. Mayring’s qualitative content analysis was used to evaluate our data.Results
In this sample, all participants had developed explanatory models for why they began using BZDs. We identified a multitude of reasons that we grouped into four broad categories, as explaining continued BZD use: (1) to cope with symptoms of psychological distress or mental disorder other than substance use, (2) to manage symptoms of physical or psychological discomfort associated with somatic disorder, (3) to alleviate symptoms of substance-related disorders, and (4) for recreational purposes, that is, sensation-seeking and other social reasons. Subjects often considered BZDs less dangerous than other substances and associated their use more often with harm reduction than as recreational. Specific obtainment strategies varied widely: the majority of participants oscillated between legal and illegal methods, often relying on the black market when faced with treatment termination.Conclusions
Irrespective of comorbidity, participants expressed a clear preference for medically related explanatory models for their BZD use. We therefore suggest that clinicians consider patients’ motives for long-term, high-dose BZD use when formulating treatment plans for this patient group, especially since it is known that individuals are more compliant with approaches they perceive to be manageable, tolerable, and effective. 相似文献33.
V. R. Sundareswaran Ashish Kumar Singh Smita Dube S. Shivaji 《Archives of microbiology》2010,192(8):663-672
CSM2, a cold-sensitive mutant of psychrophilic Pseudomonas syringae, grows like wild-type cells when cultured at 22 and 28°C; but at 4°C, the growth is retarded. In CSM2, AAT (coding for aspartate aminotransferase) is identified as the mutated gene. The expression of AAT in Pseudomonas syringae was transiently enhanced when cells were shifted from 22 to 4°C indicating that AAT is cold-inducible. Complementation of the mutated AAT transformed CSM2 from a cold-sensitive phenotype to a cold-resistant phenotype like the wild-type cells, thus providing evidence
for the first time that AAT is required for low-temperature growth. 相似文献
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35.
The succulent thicket of the Eastern Cape, South Africa, is characterized by densely wooded vegetation that is dominated by succulents with little understory of ephemeral and weakly perennial grasses and forbs. Studies have developed around the question: how do bulk grazers such as the African buffalo (Syncerus caffer) survive in the succulent thicket? In this study, the diet of the African buffalo at the Great Fish River Reserve (GFRR) was studied in two seasons (wet and dry). The diet profile was assessed from faecal matter, using the micro‐histological analysis method. During the wet season, grass species contributed 72% to the diet while 28% was contributed by browse species. In the dry season there was a significant increase in the intake of browse by 5% (χ2 = 19.94, df = 11, P < 0.05). There were species that were neglected in the wet season but became principal dietary items in the dry season, these included Setaria neglecta, Cymbopogon plurinodis, Capparis sepiaria and Portulacaria afra. Diet quality, as estimated from faecal samples, suggested that the buffalo were nutritionally stable; however, the presence of sarcoptic mange in the buffalo suggests nutritional stress. 相似文献
36.
Jose MG Vilar 《BMC systems biology》2010,4(1):152
Background
Cellular responses to death-promoting stimuli typically proceed through a differentiated multistage process, involving a lag phase, extensive death, and potential adaptation. Deregulation of this chain of events is at the root of many diseases. Improper adaptation is particularly important because it allows cell sub-populations to survive even in the continuous presence of death conditions, which results, among others, in the eventual failure of many targeted anticancer therapies. 相似文献37.
Dose response of physostigmine (Phy) was studied in rat using various doses (25-500 micrograms/kg i.m.). Rats were sacrificed 15 min after Phy administration. Blood and tissues were analyzed for ChE activity by radiometric method and Phy concentration by HPLC method. A comparison of ChE values in different tissues of rats indicated that ChE activity was highest in brain (7.11 mumol/min/g) and least in diaphragm (0.67 mumol/min/g). The enzyme activity was eleven times more in brain as compared to diaphragm. Phy produced a dose-dependent inhibition of ChE in RBC (18-42%), brain (23-35%) and diaphragm (25-35%) from 50 to 200 micrograms/kg, then ChE inhibition was plateaued from 200 to 500 micrograms/kg in these tissues. A dose related ChE inhibition was seen in heart (16-50%) and thigh muscle (8-53%) from 50 to 500 micrograms/kg. Phy concentration increased linearly from 50 to 400 micrograms/kg in plasma, brain, heart and thigh muscle. These results indicate that ChE inhibition is linear up to 200 micrograms/kg in RBC, 150 micrograms/kg in brain and 300 micrograms/kg in heart. This linearity is not consistent in other tissues. 相似文献
38.
Joseph Zahn Mark H Kaplan Sabrina Fischer Manhong Dai Fan Meng Anjan Kumar Saha Patrick Cervantes Susana M Chan Derek Dube Gilbert S Omenn David M Markovitz Rafael Contreras-Galindo 《Genome biology》2015,16(1)
BackgroundApproximately 8% of the human genome consists of sequences of retroviral origin, a result of ancestral infections of the germ line over millions of years of evolution. The most recent of these infections is attributed to members of the human endogenous retrovirus type-K (HERV-K) (HML-2) family. We recently reported that a previously undetected, large group of HERV-K (HML-2) proviruses, which are descendants of the ancestral K111 infection, are spread throughout human centromeres.ResultsStudying the genomes of certain cell lines and the DNA of healthy individuals that seemingly lack K111, we discover new HERV-K (HML-2) members hidden in pericentromeres of several human chromosomes. All are related through a common ancestor, termed K222, which is a virus that infected the germ line approximately 25 million years ago. K222 exists as a single copy in the genomes of baboons and high order primates, but not New World monkeys, suggesting that progenitor K222 infected the primate germ line after the split between New and Old World monkeys. K222 exists in modern humans at multiple loci spread across the pericentromeres of nine chromosomes, indicating it was amplified during the evolution of modern humans.ConclusionsCopying of K222 may have occurred through recombination of the pericentromeres of different chromosomes during human evolution. Evidence of recombination between K111 and K222 suggests that these retroviral sequences have been templates for frequent cross-over events during the process of centromere recombination in humans. 相似文献
39.
40.
Alessandro S Guimarães Filipe B Carmo Marcos B Heinemann Ricardo WD Portela Roberto Meyer Andrey P Lage Núbia Seyffert Anderson Miyoshi Vasco Azevedo Aurora MG Gouveia 《BMC veterinary research》2011,7(1):1-5