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At least 613 records · Page 34Linked to original sources
PubMed1992

Histone H1 subtype synthesis in neurons and neuroblasts.

Rat cerebral cortex neurons contain the five histone H1 subtypes H1a-e and the subtype H1 zero present in other mammalian somatic tissues. The four subtypes H1a-d decay exponentially during postnatal development and are partially or totally replaced by H1e that becomes the major H1 subtype in adults. H1 zero accumulates in a period restricted to neuronal terminal differentiation. Here we study the synthesis of the H1 subtypes in cortical neurons and their neuroblasts by in vivo labeling with [14C]lysine. The subtype synthesis pattern of neuroblasts has been determined by labeling gravid rats during the period of proliferation of cortical neurons and synthesis in neurons has been studied by postnatal labeling. The subtype H1a is synthesized in neuroblasts but not in neurons and is therefore rapidly removed from neuronal chromatin. The synthesis of H1b and H1d is much lower in neurons than in neuroblasts so that these subtypes are replaced to a large extent during postnatal development. H1c is synthesized at levels much higher than the other subtypes both in neurons and neuroblasts, but its very high turnover, about one order of magnitude faster than that of H1e in neurons, favors its partial replacement during postnatal development. Comparison of the synthesis rates of H1 zero in newborn and 30-day-old rats shows that the accumulation of H1 zero in differentiating neurons is due to an increased level of synthesis.

Animals↗
PubMed2001

Affinity of serotonin receptor antagonists and agonists to recombinant and native alpha1-adrenoceptor subtypes.

Binding affinities of serotonin (5-HT)-receptor antagonists and agonists at human recombinant alpha1-adrenoceptor subtypes (alpha1a-, alpha1b- and alpha1d-subtypes) were examined and compared with the functional affinities obtained in rat caudal artery (alpha1A-subtype), dog carotid artery (alpha1B-subtype) and rat thoracic aorta (alpha1D-subtype). Most of the 5-HT-receptor antagonists and agonists tested showed relatively high affinity to three alpha1-adrenoceptor subtypes. The highest affinity close to 1 nM was seen for NAN-190 (5-HT1A antagonist) in binding and functional studies. 5-Methylurapidil (5-HT1A agonist) and BMY7378 (5-HT1A agonist) showed, respectively, alpha1a(alpha1A)- or alpha1d(alpha1D)-subtype selectivity in both binding and functional affinities, but spiperone (5-HT2A antagonist) showed alpha1b-selectivity only in binding affinity. Functional affinity of ritanserin (5-HT2A antagonist) to the alpha1B-subtype was approximately 500-fold lower than that of affinity to the alpha1b-subtype. The present results show that many 5-HT-receptor antagonists and agonists have high affinity to alpha1-adrenoceptors, but suggest that there is deviation between their functional affinities and binding affinities for some drugs.

Animals↗
PubMed2006

Clinical disease in children associated with newly described coronavirus subtypes.

OBJECTIVES: Coronaviruses cause upper respiratory illness and occasionally lower tract disease in susceptible populations. In this study we examined the prevalence of 4 human coronaviruses, including subtypes OC43, 229E, and the recently described NL63 and HKU1 in a pediatric population presenting to a children's hospital. PATIENTS AND METHODS: Specimens collected over a 1-year period from pediatric patients presenting with acute respiratory illness were analyzed for the presence of 4 coronavirus subtypes using consensus and subtype-specific real-time reverse-transcription polymerase chain reaction assays. The demographic and clinical characteristics associated with coronavirus infection were examined retrospectively. RESULTS: Coronaviruses were detected in 66 of 1043 children. Eight, 11, 19, and 28 specimens were positive for subtypes 229E, NL63, OC43, and HKU1, respectively. Coronaviruses were detected throughout the study period; all 4 of the subtypes were present simultaneously in December. The acute clinical features were similar across subtypes. Of 32 children infected with a coronavirus as the sole respiratory pathogen, 13 had lower respiratory tract disease. Children whose only detectable respiratory virus was a coronavirus were more likely to have underlying chronic disease than were children coinfected with another respiratory virus. CONCLUSIONS: Although 4 subtypes of coronavirus were detected, the recently discovered coronavirus subtypes NL63 and HKU1 accounted for the majority of coronaviruses detected in our cohort of mostly hospitalized children with respiratory symptoms. New subtypes likely represent a substantial portion of previously unexplained respiratory illnesses.

Adolescent↗
PubMed2005

Human immunodeficiency virus type 1 (HIV-1) genotyping in Rio de Janeiro, Brazil: assessing subtype and drug-resistance associated mutations in HIV-1 infected individuals failing highly active antiretroviral therapy.

In order to assess the human immunodeficiency virus type 1 (HIV-1) drug resistance mutation profiles and evaluate the distribution of the genetic subtypes in the state of Rio de Janeiro, Brazil, blood samples from 547 HIV-1 infected patients failing antiretroviral (ARV) therapy, were collected during the years 2002 and 2003 to perform the viral resistance genotyping at the Renageno Laboratory from Rio de Janeiro (Oswaldo Cruz Foundation). Viral resistance genotyping was performed using ViroSeq Genotyping System (Celera Diagnostic-Abbott, US). The HIV-1 subtyping based on polymerase (pol) gene sequences (protease and reverse transcriptase-RT regions) was as follows: subtype B (91.2%), subtype F (4.9%), and B/F viral recombinant forms (3.3%). The subtype C was identified in two patients (0.4%) and the recombinant CRF_02/AG virus was found infecting one patient (0.2%). The HIV-1 genotyping profile associated to the reverse transcriptase inhibitors has shown a high frequency of the M184V mutation followed by the timidine-associated mutations. The K103N mutation was the most prevalent to the non-nucleoside RT inhibitor and the resistance associated to protease inhibitor showed the minor mutations L63P, L10F/R, and A71V as the more prevalent. A large proportion of subtype B was observed in HIV-1 treated patients from Rio de Janeiro. In addition, we have identified the circulation of drug-resistant HIV-1 subtype C and are presenting the first report of the occurrence of an African recombinant CRF_02/AG virus in Rio de Janeiro, Brazil. A clear association between HIV-1 subtypes and protease resistance mutations was observed in this study. The maintenance of resistance genotyping programs for HIV-1 failing patients is important to the management of ARV therapies and to attempt and monitor the HIV-1 subtype prevalence in Brazil.

Anti-HIV Agents↗
PubMed2005

Predicting the potential public health impact of disease-modifying HIV vaccines in South Africa: the problem of subtypes.

Current HIV vaccines in development appear unlikely to prevent infection, but could provide benefits by increasing survival; such vaccines are described as disease-modifying vaccines. We review the current status of vaccines and modeling vaccines. We also predict the impact that disease-modifying vaccines could have in South Africa, where multiple subtypes are co-circulating. We model transmissibility/fitness differences among subtypes. We used uncertainty analyses to model vaccines with four characteristics: (i) take, (ii) duration of immunity, (iii) reduction in transmissibility/fitness, and (iv) increase in survival. We reconstructed, and forecasted, the South African epidemic from 1940 to 2140 (assuming no vaccination). We predict that: (i) incidence will peak in 2014, decline, and stabilize, (ii) prevalence will continue to rise, and (iii) the AIDS death rate curve will peak in 2022. Our predictions show that (over the next 135 years) the epidemic in South Africa will switch from a predominantly Subtype C epidemic to an epidemic driven by other subtypes. We predict that the epidemic could remain unchanged, even with mass vaccination with a vaccine that is equally effective against all co-circulating subtypes. However, if the non-C subtypes are less (or equally) transmissible as Subtype C then disease-modifying vaccines could result in eradication. Thus, in countries where multiple-subtypes are co-circulating it is critical to realize that small biological differences among subtypes will have dramatic consequences for the effectiveness of HIV vaccination campaigns. A slight difference in fitness will determine whether a disease-modifying vaccine has almost no impact on the epidemic or can achieve eradication.

AIDS Vaccines↗
PubMed2006

Role of p53 in the inhibitory effects of interferon-alpha subtypes on proliferation of hepatocellular carcinoma cells.

While interferon-alpha (IFN-alpha) subtypes share a common specific receptor composed of two subunits, interferon-alpha receptor (IFNAR)-1 and IFNAR-2, their subtype activities are exhibited via several intracellular signaling pathways and thus subsequently show different biological effects. Anti-proliferative effects of single treatment with IFN-alpha subtypes or 5-fluorouracil (FU), and of combined treatment with each IFN-alpha subtype and 5-FU were examined on three hepatocellular carcinoma cell lines, HepG2, HLE and PLC/PRF/5. HepG2 and PLC/PRF/5 cells were susceptible to the combination treatment, but HLE cells were not. Proliferation of PLC/PRF/5 cells was also inhibited by the IFN-alpha subtypes singly. In addition, apoptosis was observed in HepG2 cells upon treatment with 5-FU alone and with the combination treatment, and in PLC/PRF/5 cells after single treatment with the IFN-alpha subtypes and after the combination treatment. IFN-alpha subtypes induced cell cycle arrest in the G2/M phase in HepG2 and PLC/PRF/5. Analyses by Western blotting and immunoprecipitation revealed increased p53 phosphorylation in HepG2 and PLC/PRF/5 cells but not in HLE cells after combined treatment. Single treatment with IFN-alpha subtypes promoted p53 activation only in PLC/PRF/5 cells. These results propose that IFN-alpha subtypes induce cells to undergo apoptosis through p53 activation directly and indirectly, in collaboration with 5-FU, further suggesting the presence of distinct signal pathways for IFN-alpha-induced apoptosis.

Antineoplastic Combined Chemotherapy Protocols↗
PubMedDate not supplied

Characterization of muscarinic cholinergic receptor subtypes in rat prostate.

The purpose of this study was to characterize the muscarinic receptor subtypes in the individual lobes of the rat prostate. Immunoprecipitation was performed on homogenates of these 3 lobes using antibodies to the m1-m4 muscarinic receptor subtypes. Reverse transcriptase polymerase chain reaction assays (RT-PCR) were also performed using primers specific for each of the five muscarinic receptor subtypes (m1-m5). The susceptibility of the receptors to degradation by endogenous prostate proteases was assessed by mixing rat ventral prostate with rat heart (m2) and rat parotid (m3) prior to immunoprecipitation. In the ventral lobe, transcripts for the m1-m4 subtypes were amplified whereas in the dorsal and lateral lobes only the m2 and m3 sets of primers amplified PCR products of the predicted size. Immunoprecipitation of the ventral lobe resulted in predominantly m3 receptors, while the majority of receptors immunoprecipitated from lateral and dorsal lobes were the m2 subtype. The m3 muscarinic subtype was apparently susceptible to degradation by prostate proteases whereas the m2 subtype was not. These results demonstrate a regional distribution in the subtypes of muscarinic receptors in the rat prostate, and a greater susceptibility of the m3 receptor to degradation during immunoprecipitation than the m2 subtype.

Animals↗
PubMed2006

Relationship between somatostatin receptor subtype expression and clinicopathology, Ki-67, Bcl-2 and p53 in colorectal cancer.

AIM: To study the SSTR1, 2, 3, 4, 5 expression and their relationships with clinico-pathological factors, cell proliferation, Bcl-2 and p53 expression in colorectal cancer cells. METHODS: Immunohistochemical staining of five SSTR subtypes, Ki-67, Bcl-2 and p53 was performed by the standard streptavidin-peroxidase (SP) technique for the paraffin sections of 127 colorectal cancers. and expression of five SSTR subtypes in 40 specimens of normal colorectal mucosae was detected with the same method. RESULTS: Positive staining for five SSTR subtypes was observed in colorectal cancer cells and normal colorectal mucosae. SSTR1 was the most predominant subtype in both colorectal cancer and normal colorectal mucosa, and the second was SSTR5 or SSTR2. As compared with normal colorectal mucosa, SSTR4 was more frequently expressed in colorectal cancer cells (2.5% vs 18.9%, P<0.05); the expression of SSTR2, 4, 5 in moderately to well differentiated colorectal adenocarcinoma was significantly higher than that in poorly differentiated ones (P<0.05), the SSTR1 expression in colorectal cancer with positive lymph node metastasis was significantly higher than that with negative lymph node metastasis (72.2% and 54.5%,P<0.05). In addition, in the ulcerative type of colorectal cancer, SSTR2 expression was obviously decreased (P<0.05); the correlation did not reach a statistical significance between the five SSTR subtypes expression and Dukes'stages (P>0.05), but the frequency of SSTR1 expression increased with Dukes'stage, while SSTR3 and SSTR5 expression decreased with Dukes' stage. Moreover, there was no correlation between expression of the five SSTR subtypes and other clinicopathological factors such as age, sex, tumor site, tumor depth, distant metastasis. The proliferative indexes in colorectal cancer cells with negative expression of SSTR2 and SSTR3 were significantly higher than that with positive expression (P<0.05). The Bcl-2 expression in colorectal cancer cells with positive expression of SSTR1, 2, 3, 5 was significantly lower than that with negative expression (P<0.05). There was no correlation between five SSTR subtypes and p53 expression. CONCLUSION: The most predominant SSTR subtype is SSTR1, and the second is SSTR2 or SSTR5. Five SSTR subtypes play different roles in the development of colorectal cancer. SSTR2 and SSTR3 can inhibit the proliferation and promote apoptosis of tumor cells.

Adult↗
PubMed2000

In vivo gene modification elucidates subtype-specific functions of alpha(2)-adrenergic receptors.

Mice with altered alpha(2)-adrenergic receptor genes have become important tools in elucidating the subtype-specific functions of the three alpha(2)-adrenergic receptor subtypes because of the lack of sufficiently subtype-selective pharmacological agents. Mice with a deletion (knockout) of the alpha(2A)-, alpha(2B)-, or alpha(2C)-gene as well as a point mutation of the alpha(2A)-gene (alpha(2A)-D79N) and a 3-fold overexpression of the alpha(2C)-gene have been generated. Studies with these mice indicate that most of the classical functions mediated by the alpha(2)-adrenergic receptor, such as hypotension, sedation, analgesia, hypothermia, and anesthetic-sparing effect, are mediated primarily by the alpha(2A)-subtype. The alpha(2B)-subtype is the principal mediator of the hypertensive response to alpha(2)-agonists, appears to play a role in salt-induced hypertension, and may be important in developmental processes. The alpha(2C)-subtype appears to be involved in many central nervous system processes such as the startle reflex, stress response, and locomotion. Both the alpha(2A)- and alpha(2C)-subtypes are important in the presynaptic inhibition of norepinephrine release and appear to have distinct regulatory roles. The ability to study subtype-specific functions in different mouse strains by altering the same alpha(2)-adrenergic receptor in different ways strengthens the conclusions drawn from these studies. Although these genetic approaches have limitations, they have significantly increased our understanding of the functions of alpha(2)-adrenergic receptor subtypes.

Adrenergic alpha-Agonists↗
PubMed2000

HIV-1 subtypes in injecting drug users & their non-injecting wives in Manipur, India.

The presence of HIV-1 antibodies was determined among the injecting drug users (IDUs) and their non-injecting wives. A total of 233 (72%) were found to be HIV-1 seropositive among the 322 subjects recruited in this study between August, 1996 and September, 1997. The distribution of HIV-1 subtypes among the injecting drug users (IDUs) and their wives was determined using peptide enzyme immunoassay (EIA). Sexual transmission of HIV-1 occurred frequently (45%) from HIV-1 infected IDUs to their spouses. The majority of the subjects (167/233) were infected with subtype C followed by subtype Thai B (29/233). Subtype C was the most common among both IDUs (78%) and their wives (57%), followed by subtype Thai B (12% and 13% respectively). The distribution of subtypes was significantly different between IDUs and their wives with a lower percentage of subtype C and higher percentage of subtype D in the infected wives (P < 0.03). Discordance for subtypes transmitted from IDUs to their wives suggests the occurrence of dual and/or recombinant infection in the IDUs.

Female↗
PubMed1975

Change in prevalent subtypes of HBsAg in acute hepatitis B infections and its implications.

Subtyping of hepatitis B antigen in patients with acute hepatitis B revealed subtype ay in 75% while subtype ad was much more common in chronic asymptomatic carriers of the antigen (in 81% of blood donors). In contrast to blood donors, a change of the prevalent subtype was noted in acute hepatitis patients between 1970 and 1974. Before May 1972, subtype ad was found in 67% of patients, whereas later subtype ay dominated in 93%. An unequal distribution of subtypes between acute and chronic forms of hepatitis B infections has been explained by differences in the virulence of virus strains. Our results suggest that the higher prevalence of subtype ad was also common in acute infections. The change of the prevalent subtype in acute infections may be attributed to differences in contagion rather than differences in virulence of virus strains.

Acute Disease↗
PubMed2000

Distribution of HIV-1 subtypes in female sex workers of Calcutta, India.

BACKGROUND & OBJECTIVES: Different routes for the transmission of HIV-1 in India have been reported and the majority of infections occurred through heterosexual route of transmission. In order to understand the dynamics of HIV-1 transmission, a systematic study was undertaken to determine the viral subtypes circulating among the female sex workers in Calcutta, India. METHODS: Peptide enzyme immunoassay (PEIA), heteroduplex mobility assay (HMA) and DNA sequence analysis were used to ascertain the HIV-1 subtypes. RESULTS: V3 serotyping of 52 HIV-1 seropositive samples identified 33 (60%) to be subtype C. A DNA fragment within C2-V3/C2-V5 regions of HIV-1 gp120 was amplified directly from the lymphocyte DNA to avoid any bias in selecting viral variants and used in HMA. Of the 40 samples analyzed, 38 (95%) belonged to subtype C and 2 were found to be non-typable. Further analysis of these 38 samples revealed that 26 (68%) had maximum homology to the C3-Indian reference strain (IND868), 11 (29%) were most homologous to C2-Zambian strain (ZM18) and 1 (3%) showed close resemblance to C1-Malawi strain (MA959). Nucleotide sequence of 11 subsamples encompassing about 325 base pairs was aligned for the Indian and other geographically distinct isolates. On distance and parsimony trees, most of the samples (8/11) clustered together as subtype C. INTERPRETATION & CONCLUSIONS: Subtype C was the major circulating HIV-1 strain in this geographical region, although variation within this subtype was also noticed. DNA sequence analysis was found to be the best method in determining the nature of the HIV-1 subtype followed by HMA and peptide enzyme immunoassay. These findings may have important implications for the design of effective vaccines in India and emphasizes the need for constant monitoring of the HIV-1 subtypes in different parts of India.

Amino Acid Sequence↗
PubMed1992

Subtype-selective desensitization of alpha 2-adrenergic receptors. Different mechanisms control short and long term agonist-promoted desensitization of alpha 2C10, alpha 2C4, and alpha 2C2.

We have recently shown that the alpha 2C10 adrenergic receptor (AR) undergoes short term agonist-promoted desensitization, mediated by phosphorylation of sites in the third intracellular loop. There is significant divergence in the third loop amino acid sequences between alpha 2C10 and the other subtypes, alpha 2C4 and alpha 2C2. We therefore explored the mechanisms of alpha 2AR subtype desensitization by expressing each human subtype in Chinese hamster ovary cells and subjecting them to short and long term epinephrine exposures. After 30 min of agonist exposure, alpha 2C10 and alpha 2C2 displayed desensitization characterized by rightward shifts in the curves for epinephrine-mediated inhibition of adenylyl cyclase (EC50 = alpha 2C10, 0.24 +/- 0.02 microM increasing to 1.1 +/- 0.1 microM; alpha 2C2, 1.3 +/- 0.3 increasing to 2.6 +/- 0.3 microM). Coincident with alpha 2C10 and alpha 2C2 desensitizations were decreases in agonist high affinity binding. In contrast, alpha 2C4 underwent no functional desensitization after short term agonist exposure, nor were there any changes in agonist high affinity binding. Agonist-promoted receptor sequestration was clearly greater with alpha 2C10 (approximately 26%) and alpha 2C2 (approximately 35%) as compared to alpha 2C4 (approximately 12%), but such sequestration did not play a significant role in short term desensitization, as blockade with concanavalin A had no effect on desensitization patterns. In contrast to these findings, all alpha 2AR subtypes underwent desensitization after prolonged (24 h) agonist exposure. However, alpha 2C10 and alpha 2C2 displayed substantially more desensitization (approximately 20-fold increase in EC50) as compared to alpha 2C4 (approximately 5-fold increase). The primary mechanism of desensitization during long term agonist exposure was found to be a decrease in the amount of cellular Gi, which was equivalent in magnitude in cells expressing all three subtypes. However, in addition to a decrease in Gi, alpha 2C10 and alpha 2C2 underwent down-regulation of receptor levels during long term agonist exposure, while alpha 2C4 did not. Given that all three subtypes bind endogenous catecholamines with high affinity and inhibit adenylyl cyclase efficiently, the significance of multiple subtypes has heretofore been obscure. Our results show that alpha 2AR undergo subtype-selective desensitization to agonists and suggest that alpha 2AR subtypes may have evolved to meet differing needs for adaptive regulation.

Adenylyl Cyclase Inhibitors↗
PubMed1992

Subtypes of acute postinfectious glomerulonephritis: a clinico-pathological correlation.

The case records and histopathology of 42 adults with the characteristic light and electron microscopic features of Acute Postinfectious Glomerulonephritis (APGN) were studied. The biopsies were divided into three subtypes depending on the form and distribution of subepithelial "humps" and other immune-complex deposits on electron microscopy (EM): the "starry sky", "garland" and "mesangial" patterns. There was no significant difference between the three subtypes with regard to age, hypertension, creatinine, anti-streptolysin 0 titer and low serum complement levels on presentation. The "garland" subtype had significantly more proteinuria than both the "starry sky" (p = 0.04) and "mesangial" (p = 0.003) subtypes. The "mesangial" pattern had a lesser degree of cellular proliferation and leukocytosis in the glomeruli than the other subtypes. The "starry sky" subtype was present in 4 of the 5 cases of crescentic nephritis and in 6 of the 7 patients with a chronic course. Our study suggests that the higher degree of proteinuria in the "garland" subtype and the chronic course of the "starry sky" subtype are the main clinical features that distinguish the three histological subtypes. Our patients, from a developing community with poor socio-economic conditions, had a poor prognosis.

Acute Disease↗
PubMed2004

The epidemiology of HIV-1 subtypes in infected patients from northeastern Thailand.

In total, 117 HIV-1 infected patients from several provinces in Northeastern Thailand were analysed. All blood samples collected from individuals were confirmed by EIA and Western blot and partially by HIV-1 gag-, pol- and env-PCR. By serotyping with a V3-peptide ELISA, 108 (92.3%) of the sera samples belonged to subtype E, 9 (7.7%) were serotype B. For 10 Thai HIV-1 infections, the serotype and genotype were determined. The genotype was determined by phylogenetic analysis of directly sequenced PCR amplicons, 8 were subtype E, 2 subtype B. For these patients the serotype did correlate with the genotype. Tracing back the origin of Thai patients, it seems that most were infected within early years of the epidemic and the Thai subtype B infected patients have been imported directly from foreign countries via sexual contact. The findings suggest there are two district subtypes in Thailand with the majority being subtype E. The relatively high prevalence of subtype B in Northeastern Thailand may be due to the increasing intermix of the two strains (subtypes E and B) and the migration for employment from foreign countries. This may lead to public health concerns regarding surveillance of HIV-1 subtypes and the regulation of potentially infected workers returning from abroad to the country.

Blotting, Western↗
PubMed1991

Interaction of subtype-selective antagonists with alpha 1-adrenergic receptor-mediated second messenger responses in rat brain.

The selective antagonists (+)-niguldipine and 5-methylurapidil (5-MU) were used to more clearly identify the alpha 1-adrenergic receptor subtypes involved in second messenger responses in slice and culture preparations of rat brain. The alpha 1-adrenergic receptor activating [3H]inositol phosphate (InsP) formation in neocortical and hippocampal slices appeared to have mixed characteristics. Although the low potency of (+)-niguldipine indicated involvement of the alpha 1B subtype, 5-MU had an alpha 1A-like potency at this subtype. (+)-Niguldipine did not inhibit the alpha 1 receptor-mediated potentiation of the cAMP response to either isoproterenol or adenosine in cortical slices, even at high concentrations. 5-MU inhibited both cAMP responses, although this inhibition appeared non-competitive. Thus, these receptors are clearly different from those mediating InsP formation. In primary glial cultures, (+)-niguldipine also had a low potency in blocking norepinephrine-stimulated [3H]InsP formation, consistent with involvement of the alpha 1B subtype. However, both 5-MU and WB 4101 had high potencies in blocking this response, suggesting involvement of the alpha 1A subtype. Inactivation of the alpha 1B subtype by pretreatment of cultures with chloroethylclonidine did not increase the potencies of any of these antagonists. The inhibition by 5-MU and WB 4101 was competitive in both control and chloroethylclonidine-pretreated cultures, whereas the inhibition by (+)-niguldipine was primarily noncompetitive. The use of these more selective antagonists shows that the current alpha 1A/alpha 1B subclassification scheme is inadequate to identify the receptors mediating these responses. None of the responses were blocked by (+)-niguldipine with the high potency expected at the alpha 1A subtype, although all InsP responses were blocked by 5-MU with a relatively high (alpha 1A-like) potency. In addition, very low affinity and noncompetitive effects of (+)-niguldipine were observed. These data raise the possibility of additional subtypes of alpha 1-adrenergic receptors or as yet unidentified functional interactions between known subtypes.

Adrenergic alpha-Antagonists↗
PubMed1990

Importance of subtype in the immune response to the pre-S(2) region of the hepatitis B surface antigen. II. Synthetic Pre-S(2) immunogen.

One purpose of this study was to examine the influence of viral subtype on in vivo antibody production to the pre-S(2) region of the hepatitis B surface Ag. Immunization with hepatitis B surface Ag particles containing the pre-S(2) region of the d or y subtypes identified the B10.M (H-2f) strain as an antibody nonresponder to the pre-S(2) and S regions after immunization with the y subtype, but as an antibody responder to the pre-S(2) and S regions after immunization with the d subtype. Both the S region and pre-S(2) region-specific antibody responses emanated from pre-S(2)/d-specific Th cell function because B10.M mice are T cell nonresponsive to the S region of both subtypes. Although responder/nonresponder status of the B10.M strain was dependent on the pre-S(2) subtype used for immunization, the anti-pre-S(2) antibody produced was totally cross-reactive on both subtypes. This is consistent with the conserved nature of the dominant pre-S(2) antibody-binding site and the highly polymorphic nature of the pre-S(2) sequence that represents the focus of T cell recognition. These data suggest that, to fully benefit from the inclusion of pre-S(2) region sequences, third generation hepatitis B virus vaccines should contain both the d and y subtype sequences of the pre-S(2) region to increase the frequency of pre-S(2) and S-specific antibody responses and to insure Th cell memory relevant to both viral subtypes. A second purpose of this study was to "design" a synthetic pre-S(2) immunogen based on combining the dominant B and T cell recognition sites into a single peptide. A composite peptide consisting of the dominant T cell recognition sequence p151-174 positioned N-terminal to the dominant B cell site p133-143 (i.e., p151-174(133-143] yielded an effective pre-S(2) synthetic immunogen. Interestingly, the orientation of the T and B cell determinants and the context of the T cell site within the larger composite peptide influenced both antibody fine specificity and T cell fine specificity.

Amino Acid Sequence↗
PubMed2006

Investigation of baseline susceptibility to protease inhibitors in HIV-1 subtypes C, F, G and CRF02_AG.

OBJECTIVE: To compare baseline susceptibility to protease inhibitors among HIV-1 isolates of subtypes C, F, G and CRF02_AG, and to identify polymorphisms that determine the differences in susceptibility. METHODS: A total of 42 samples of drug-naive patients infected with subtypes G (n=19), CRF02_AG (n = 10), F (n = 6) and C (n = 7) were phenotyped and genotyped with the Antivirogram and the ViroSeq 2.0 genotyping system, respectively. A Bayesian network approach was used for a preliminary analysis of the collected data and the dependencies indicated by the network were statistically confirmed. RESULTS: CRF02_AG samples were found to be more susceptible to nelfinavir and ritonavir than other subtypes. Hypersusceptibility to these drugs was associated with the 70R polymorphism. 37D/S/T was associated with reduced susceptibility to indinavir and 89M with reduced susceptibility to lopinavir. Susceptibility to tipranavir was the lowest among the subtype F samples and the highest for subtype G samples, with samples carrying 57R being more susceptible than samples carrying 57K. CONCLUSIONS: Our study suggests that there are baseline susceptibility differences between subtypes and these differences are due to naturally occurring polymorphisms in these subtypes. The predictive value for phenotype of these polymorphisms was even valid in subtypes where these polymorphisms are less prevalent. Taking into account such polymorphisms should improve current algorithms for interpretation of genotyping results in a subtype-independent way.

Algorithms↗