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PubMedDate not supplied

Systemic administration of human leukocyte interferon to melanoma patients. III. Increased helper:suppressor cell ratios in melanoma patients during interferon treatment.

Malignant melanoma patients treated with human leukocyte interferon (IFN-alpha) displayed increased natural killer (NK) cytotoxicity to K562 targets within the first 2 weeks of therapy. This study explored the possibility of T-cell regulation of this NK response, as evidenced by a variation in T-cell subpopulations. T-cell subset levels were studied in 9 patients who received daily doses of IFN-alpha over a period of 42 days. Five monoclonal antibodies to T-cell surface markers were used: Leu 1 (pan-T), Leu 2a (T suppressor/cytotoxic), Leu 3a (T helper/inducer), HNK-1 (Leu 7, a marker for NK cells), and B73.1 (an antibody against the Fc receptor on NK/K cells). Percentages of these markers were measured on days 0, 3, 7, and 21 of treatment. Percentages of Leu 1-positive cells and Fc-receptor-positive cells remained relatively constant throughout treatment in all patients. A trend toward a decrease in suppressor cells and an increase in helper cells peaking on day 7 and returning to earlier values by day 21 was found in 5 patients. The increase in NK cytotoxicity was not reflected consistently in proportions of HNK-1-positive cells or Fc receptor-bearing cells within the first week of therapy. The most significant finding was an increase in the helper:suppressor cell ratio peaking on day 7 and returning to pretreatment values by day 21. This increase was seen in every patient studied. The average pretreatment Leu 3a:Leu 2a ratio was 0.67 increasing to an average value of 1.47 on day 7 (p less than 0.005). Leu 3a:Leu 2a ratios returned to pretreatment values, in parallel to NK activity, despite continuation of interferon therapy.

Cytotoxicity, Immunologic↗
PubMed1992

Stable expression of a cDNA encoding a human beta 1 --> 3galactosyltransferase responsible for lacto-series type 1 core chain synthesis in non-expressing cells: variation in the nature of cell surface antigens expressed.

Transient expression of a human colonic adenocarcinoma Colo 205 cell derived cDNA in cell lines which ordinarily express only neolacto-series glycolipids has resulted in the expression of a beta 1 --> 3galactosyltransferase gene responsible for synthesis of glycolipids based upon the lacto-series type 1 core chain. Calcium phosphate transfected cells were panned on anti-IgM coated plates after initial treatment with a combination of monoclonal antibodies specific for type 1 chain terminal structures (TE-3) and a very broadly specific antibody reactive with multiple type 1 chain derivatives (TE-2). Adherent cells after panning were capable of efficiently transferring Gal in beta 1 --> 3-linkage to the acceptor glycolipid Lc3. Using these reagents, clones of stably transfected human colonic adenocarcinoma HCT-15 cells were produced and isolated. Parental HCT-15 cells do not express type 1 chain based antigens. The nature of the type 1 chain based antigens produced in each of these clones was analyzed by solid phase antibody binding assays. Three types of behavior were observed. Formation of type 1 terminal structures that were either exclusively sialylated or fucosylated, or a mixture of sialylated and fucosylated determinants occurred. In contrast, no difference in type 2 antigen expression between any clone and the parental cells was observed. These data suggest that coordination of subsequent reactions capable of modifying type 1 chain structures is not the same in all clones. The relationship of these results to aspects of cellular regulation of carbohydrate biosynthesis is discussed.

Adenocarcinoma↗
PubMed1998

A major histocompatibility complex class I allele shared by two species of chimpanzee.

Little is known regarding the rates at which natural selection can modify or retain antigen presenting alleles at the major histocompatibility complex (MHC). Discovery of identical [1101 base pairs (bp)] coding regions at the MHC class I C locus in Pan troglodytes and Pan paniscus, chimpanzee species that diverged approximately 2.3 million years ago, now indicates that a class I allotype can survive for at least this period. Remarkable conservation was also reflected in the (1799 bp) introns where a maximum of only six substitutions distinguished five alleles (three from P. troglodytes and two from P. paniscus) that encoded the identical heavy chain allotype. Analysis of a more distantly related human allele, HLA-Cw*0702, corroborated that intron variation was non-uniform along the gene. Thus we provide a clear reference frame for the lifetime of an MHC class I allotype, a direct estimate of allelic substitution rates, and evidence for an unusual evolution of MHC class I introns.

Alleles↗
PubMed1997

Mhc-E polymorphism in Pongidae primates: the same allele is found in two different species.

Mhc-E intron 1, exon 2, intron 2, and exon 3 from pygmy chimpanzee (Pan paniscus), chimpanzee (Pan troglodytes), gorilla (Gorilla gorilla) and orangutan (Pongo pygmaeus) have been sequenced; six new Mhc-E alleles have been obtained but sequence changes are only placed either in introns or in synonymous exonic bases. One pygmy chimpanzee Mhc-E DNA sequence is identical to another sequence from chimpanzee; the fact that no variation is found also at the intronic level suggests that these two species of chimpanzee may have recently separated and/or that both of them might only represent subspecies. Mhc-E phylogenetic trees separate two evolutionary groups: Pongidae, including humans, and Cercopithecinae; this is also found by studying another non-classical class I gene, Mhc-G. The Mhc-E alleles' invariance at the protein level supports that strong selective forces are operating at the Mhc-E locus, as has also been found in both Cercopithecinae and humans. These allelic and evolutionary data suggest an altogether different functionality for HLA-E (and also HLA-G) compared with classical class I proteins: i.e., sending negative (tolerogenic) signals to NK and T cells.

Alleles↗
PubMed2006

Systematical evaluation of the effects of sample collection procedures on low-molecular-weight serum/plasma proteome profiling.

Blood is an ideal source for biomarker discovery. However, little has been done to address the effects of sampling, handling and storage procedures on serum/plasma proteomes. We used magnetic bead-based MALDI-TOF MS to systematically evaluate the influence of each procedure on low-molecular-weight serum/plasma proteome profiling on the basis of the whole spectra. We found that sampling procedures, including the selection of blood collection tubes and anticoagulants, variations in clotting time or time lag before centrifugation, and hemolysis, displayed significant effects on the proteomes. Moreover, serum and plasma were mutually incompatible for proteome comparison. By contrast, overnight fasting, handling procedures, including centrifugation speeds (1500 x g vs. 3000 x g) or time (15 min vs. 30 min), and storage conditions, such as at 4 degrees C or 25 degrees C for up to 24 h or at -80 degrees C for up to 3 months, and repeated freeze/thaw of up to ten cycles, had relatively minor effects on the proteomes based upon our analysis of about 100 peaks. We concluded that low-molecular-weight serum/plasma proteomes were diversely affected by sampling, handling and storage with most change from variations of sampling procedures. We therefore suggest the necessity of standardizing sampling procedure for proteome comparison and biomarker discovery.

Adult↗
PubMed2005

Counting primates for conservation: primate surveys in Uganda.

Primate census techniques have been developed over the past 35-40 years yet there is still some confusion and great variation in the methods used. This precludes comparisons between sites where different techniques have been used. This paper discusses the variations between the methods that seem to be practiced currently and then describes a census of primates in the forests of western Uganda. Primate density and biomass varied greatly between forests as well as within forests and this is probably related to food availability. Chimpanzee (Pan troglodytes) density was strongly correlated with nest encounter rates from reconnaissance walks in the forest. This result can be used to estimate chimpanzee density in forests where it is difficult to survey this species (e.g., due to security reasons). A total of 4,980 chimpanzee was estimated for Uganda which is higher than previously guessed, but still of conservation concern. Only four forests had more than 500 individuals which gives concern for long-term population viability.

Animals↗
PubMed2001

Distribution of streptococcal inhibitor of complement variants in pharyngitis and invasive isolates in an epidemic of serotype M1 group A Streptococcus infection.

Streptococcal inhibitor of complement (Sic) is a highly polymorphic extracellular protein made predominantly by serotype M1 group A Streptococcus (GAS). New variants of the Sic protein frequently appear in M1 epidemics as a result of positive natural selection. To gain further understanding of the molecular basis of M1 epidemics, the sic gene was sequenced from 471 pharyngitis and 127 pyogenic and blood isolates recovered from 598 patients living in metropolitan Helsinki, Finland, during a 37-month population-based surveillance study. Most M1 GAS subclones recovered from pyogenic infections and blood were abundantly represented in the pool of subclones causing pharyngitis. Alleles shared among the pharyngitis, pyogenic, and blood samples were identified in throat isolates a mean of 9.8 months before their recovery from pyogenic infections and blood, which indicates that selection of most sic variants occurs on mucosal surfaces. In contrast, no variation was identified in the emm and covR/covS genes.

Alleles↗
PubMed1993

Relaxed natural selection in human populations during the Pleistocene.

Available genetic data reveals that the human population is more variable than the chimpanzee population at the protein level, whereas the opposite is the case at the DNA level. The lower level of silent polymorphism in the human population suggests that its long-term breeding size is smaller than the chimpanzee's. The neutral theory suggests that natural selection has been relaxed in the human population under the improved environment. The possibility that the relaxation began with the emergence of Homo sapiens is examined, because it is known that H. habilis underwent for the first time dramatic changes in brain size, way of life, and culture, and that the childhood of H. erectus was already twice as long as that of chimpanzee. The relaxation hypothesis predicts that, relative to chimpanzee, some 20% of deleterious mutations became harmless under the changed environment throughout the Pleistocene. More extensive study of genetic variation in non-human primates is necessary not only to confirm the hypothesis, but also to better understand the human genome itself.

Alleles↗
PubMed1983

Size and diet in the evolution of African ape craniodental form.

Interspecific differences in craniodental morphology among Pan paniscus, Pan troglodytes, and Gorilla gorilla are analyzed. These apes differ in both diet and body size, and thus present an excellent example in which to apply an allometric criterion of subtraction in order to determine morphological differences which might be related to divergent dietary specialization. The use of ontogenetic allometry in particular as a criterion of subtraction is discussed. Bivariate and multivariate results indicate that most of the variation in skull form among the species relates to the extension of a common growth trend to different sizes. Comparative analysis of growth trajectories reveals a number of differences, but none that appear to relate to a reorganization of skull proportions which might correspond to a dietary shift towards increased folivory. The dentition clearly exhibits non-allometric shape changes corresponding to the dietary differences, however. The meaning of these differences between cranial and dental patterns is discussed.

Africa↗
PubMed2005

Identification and characterization of six new alternatively spliced variants of the human mu opioid receptor gene, Oprm.

The mu opioid receptor plays an important role in mediating the actions of morphine and morphine-like drugs. Receptor binding and a wide range of pharmacological studies have proposed several mu receptor subtypes, but only one mu opioid receptor (Oprm) gene has been isolated. Like the mouse and rat, the human Oprm gene undergoes alternative splicing. In the present studies, we have identified and characterized six new splice variants from the human Oprm gene using a reverse transcription-polymerase chain reaction strategy, yielding a total of 10 human splice variants of the mu opioid receptor MOR-1. All the variants identified contained exons 1, 2 and 3, but differed from MOR-1 itself and each other by splicing downstream from exon 3, resulting in different amino acid sequences. Northern blot analysis demonstrated expression of the variant mRNAs. Receptor binding assays established that these variants belonged to the mu opioid receptor family with limited differences in mu opioid ligand affinities and selectivity. However, adenylyl cyclase and [35S]GTPgammaS binding assays revealed major differences in both potency and efficacy among these variants. The dissociation between binding affinity, potency and efficacy for the opioids among these variants may provide insights into the wide range of opioid responses among these agents observed clinically and opens new avenues in designing selective drugs based upon their efficacy and potency rather simple binding affinity.

Adenylyl Cyclases↗
PubMed1997

Evaluation of haemodialysis membrane biocompatibility by parallel assessment in an ex vivo model in healthy volunteers.

BACKGROUND: Precise evaluation of the haemocompatibility of prototype membranes, flow configurations and anticoagulant regimens is an essential step in the development of dialysis systems minimizing blood activation. An ex vivo model in humans currently employed in our laboratory has recently been adapted to allow the parallel evaluation of two minimodule dialysers with blood from a single donor, thus eliminating differences due to donor variability in the comparison of test and control dialysis modules. METHODS: The ex vivo flow system is designed to reproduce the haemodynamic conditions of clinical dialysis on a 1/50 scale. A blood line from the forearm vein of the volunteer donor is divided at a Y-shaped junction, two roller pumps assure equivalent blood flow (5 ml/min) in the branches leading to two minimodule dialysers and heparin (0.1 IU/ml final concentration) is injected into each branch immediately after the Y junction. Samples for analysis of blood activation markers are collected at the exits of the two minimodules over a test period of 27 min. In the present series of tests, a new polyacrylonitrile membrane (PAN) was evaluated relative to standard commercial polysulphone (PS), acrylonitrile copolymer (AN 69) and cuprophan (CUP) membranes. RESULTS: A steady minimal level of anticoagulation corresponding to a slightly less than two-fold prolongation of APTT (activated partial thromboplastin time) was maintained throughout testing in both branches of the ex vivo flow system. Time curves for the accumulation of activation markers (thrombin-antithrombin III complexes, prothrombin fragment 1 + 2, platelet beta-thromboglobulin, and complement fragment C3a) showed all four types of minimodule dialyser to induce comparable low levels of activation of coagulation parameters and platelets, together with similar mild activation of complement for AN 69, PAN, and PS dialysers as compared to stronger activation for CUP modules. Overall results thus confirmed the acceptable haemocompatibility of the prototype polyacrylonitrile (PAN) membrane. CONCLUSIONS: Among current methods for evaluation of the biocompatibility of haemodialysis systems, ex vivo flow models in humans avoid problems arising from species differences and may be designed to closely reproduce the conditions of clinical dialysis. A parallel configuration eliminates artefacts due to individual variations in donor response. This not only facilitates the direct comparison of test and control membranes under close to identical experimental conditions, but also provides a model particularly well adapted to studies of the effects of different anticoagulation regimens, flow configurations, and dialysates, or alternative methods of sterilization, rinsing, and priming of the dialysers.

Adolescent↗
PubMed1997

Leaf nutrient variation in mature carob (Ceratonia siliqua) trees in response to irrigation and fertilization.

Seasonal variations in leaf nitrogen, phosphorus and potassium concentrations were studied in a mature carob (Ceratonia siliqua L. cv "Mulata") orchard subjected to a 4-year irrigation and fertilization experiment. Three irrigation regimes (0, 50 and 100%), based on the evaporation values obtained from a class A pan, were tested in combination with two nitrogen (N) supply regimes in which 21 kg ha(-1) year(-1) (low-N) and 63 kg ha(-1) year(-1) (high-N) were supplied as ammonium nitrate. Leaf nitrogen concentration increased throughout the experiment, independently of treatments. There were no significant differences in leaf N concentration between trees in the high-N and low-N treatments. Irrigation regimes had no effect on leaf mineral concentration but influenced the amount of leaves shed and slightly modified the pattern of leaf shedding that occurred during the summer drought period. Nutritional balances between N and P and N and K were both closely and significantly correlated. Potassium was translocated from leaves to fruits during spring, independently of treatments. Severe water stress periods occurring during spring or autumn induced shedding of leaves leading to nutrient mobilization. Nutrient retranslocation during these drought periods may represent an adaptive mechanism. Nitrogen retranslocation was higher for trees in the high-N treatments than for trees in the low-N treatments, whereas phosphorus retranslocation was independent of the irrigation and fertilization treatments.

Journal Article↗
PubMed1989

Serological evidence for variation in the incidence of herpesvirus infections in different species of apes.

Sera from captive lowland gorillas, chimpanzees, orangutans, and gibbons were screened by enzyme-linked immunosorbent assay (ELISA) for antibody to herpesviruses serologically related to human herpes simplex virus types 1 and 2 (HSV-1, HSV-2), a baboon virus (SA8), and a macaque herpesvirus (B virus). The incidence of herpesvirus antibodies varied considerably among the different species, gorillas having the highest incidence of seropositivity (65.4%) and orangutans the lowest. The virus specificity of positive sera was further analyzed by examining the kinetics of virus neutralization, competition of reactivity in ELISAs, and immunoblotting against HSV-1, HSV-2, SA8, and B virus antigens. Using these assays, the majority of positive gorilla sera (49 of 53, 92%) were determined to react in a manner identical to human HSV-1 immune sera. The remaining four positive gorilla sera reacted as HSV-2-positive sera. In contrast, the majority of positive chimpanzee sera (5 of 7, 71%) reacted as HSV-2 immune rather than HSV-1 immune. All positive sera from gibbon apes reacted as HSV-1 positive. No orangutan sera were identified which gave positive reactions by ELISAs to any of the four primate herpesviruses tested. Although four orangutan sera gave equivocal results against HSV-1 antigen, further analysis by immunoblotting could not confirm any specific reactivity with any of the primate herpesvirus antigens. Varied reactivity among individual animals with both SA8 and B virus proteins was observed, but none of the seropositive primates detected appeared to be infected with either of these simian viruses. Three gorilla sera had antigen recognition patterns slightly different from those of HSV-2-positive human and chimpanzee sera and another HSV-2-positive gorilla serum, raising the possibility that these animals harbor an indigenous virus related to HSV-2.

Animals↗
PubMed2004

Lineage-specific gene duplication and loss in human and great ape evolution.

Given that gene duplication is a major driving force of evolutionary change and the key mechanism underlying the emergence of new genes and biological processes, this study sought to use a novel genome-wide approach to identify genes that have undergone lineage-specific duplications or contractions among several hominoid lineages. Interspecies cDNA array-based comparative genomic hybridization was used to individually compare copy number variation for 39,711 cDNAs, representing 29,619 human genes, across five hominoid species, including human. We identified 1,005 genes, either as isolated genes or in clusters positionally biased toward rearrangement-prone genomic regions, that produced relative hybridization signals unique to one or more of the hominoid lineages. Measured as a function of the evolutionary age of each lineage, genes showing copy number expansions were most pronounced in human (134) and include a number of genes thought to be involved in the structure and function of the brain. This work represents, to our knowledge, the first genome-wide gene-based survey of gene duplication across hominoid species. The genes identified here likely represent a significant majority of the major gene copy number changes that have occurred over the past 15 million years of human and great ape evolution and are likely to underlie some of the key phenotypic characteristics that distinguish these species.

Animals↗
PubMed2003

[Origin of Hakka and Hakkanese: a genetics analysis].

Hakka is a distinctive Han Chinese population in Southern China speaking Hakkanese. The origin of Hakka has been controversial. In this report, we analyzed Y chromosomal markers in 148 Hakka males. Principle component analysis of Y-SNP haplotype distribution shows Hakka is clusteed strongly with the Han in Northern China, and is also close to She, a Hmong-Mien-speaking population, while the general Southern Han is fairly close to Daic populations. Admixture analysis revealed that the relative genetic contribution 80.2% (Han), 13% (She) and 6.8% (Kam) in Hakka. The network of Y-STR haplotype of M7 individuals in all concerned populations suggested two possible origins of Hmong-Mien contribution in Hakka: One is from Hubei and the other is from Canton. The Kam contribution in Hakka is likely from Kan-Yue, the ancient aborigine of Kiangsi (Jiangxi). The frequency of 9bp-deletion in Region V of mitochondrial DNA of Hakka is 19.7%, which is quite close to She but far from Han. We therefore concluded that genetically the majority of Hakka gene pool shall come from North Han with She contributing the most among all non-Han groups. Regarding the Hmong-Mien character of Hakkanese, the genetic structure of Hakka shows their core may be Kim-man, the ancient Hmong-Mien. We hypothesized that a great number of Han people from North China join this population in succession. Southern Chinese dialects, such as Hakkanese may also be those languages of Southern aborigines at first, and turn to extant appearance under the continuance effect of Northern Chinese.

China↗
PubMed1999

Methylation of inorganic arsenic in different mammalian species and population groups.

Thousands of people in different parts of the world are exposed to arsenic via drinking water or contaminated soil or food. The high general toxic of arsenic has been known for centuries, and research during the last decades has shown that arsenic is a potent human carcinogen. However, most experimental cancer studies have failed to demonstrate carcinogenicity in experimental animals, indicating marked variation in sensitivity towards arsenic toxicity between species. It has also been suggested that there is a variation in susceptibility among human individuals. One reason for such variability in toxic response may be variation in metabolism. Inorganic arsenic is methylated in humans as well as animals and micro-organisms, but there are considerable differences between species and individuals. In many, but not all, mammalian species, inorganic arsenic is methylated to methylarsonic acid (MMA) and dimethylarsinic acid (DMA), which are more rapidly excreted in urine than is the inorganic arsenic, especially the trivalent form (AsIII, arsenite) which is highly reactive with tissue components. Absorbed arsenate (AsV) is reduced to trivalent arsenic (AsIII) before the methyl groups are attached. It has been estimated that as much as 50-70% of absorbed AsV is rapidly reduced to AsIII, a reaction which seems to be common for most species. In most experimental animal species, DMA is the main metabolite excreted in urine. Compared to human subjects, very little MMA is produced. However, the rate of methylation varies considerably between species, and several species, e.g. the marmoset monkey and the chimpanzee have been shown not to methylate inorganic arsenic at all. In addition, the marmoset monkey accumulates arsenic in the liver. The rat, on the other hand, has an efficient methylation of arsenic but the formed DMA is to a large extent accumulated in the red blood cells. As a result, the rat shows a low rate of excretion of arsenic. In both human subjects and rodents exposed to DMA, about 5% of the dose is excreted in the urine as trimethylarsine oxide. It is obvious from studies on human volunteers exposed to specified doses of inorganic arsenic that the rate of excretion increases with the methylation efficiency, and there are large inter-individual variations in the methylation of arsenic. Recent studies on people exposed to arsenic via drinking water in northern Argentina have shown unusually low urinary excretion of MMA. Furthermore, children had a lower degree of methylation of arsenic than adults. Some studies indicate a lower degree of arsenic methylation in men than in women, especially during pregnancy. Whether the observed differences in methylation of arsenic are associated with variations in the susceptibility of arsenic remains to be investigated.

Adult↗
PubMed2006

Identification, characterization and comparative genomics of chimpanzee endogenous retroviruses.

BACKGROUND: Retrotransposons, the most abundant and widespread class of eukaryotic transposable elements, are believed to play a significant role in mutation and disease and to have contributed significantly to the evolution of genome structure and function. The recent sequencing of the chimpanzee genome is providing an unprecedented opportunity to study the functional significance of these elements in two closely related primate species and to better evaluate their role in primate evolution. RESULTS: We report here that the chimpanzee genome contains at least 42 separate families of endogenous retroviruses, nine of which were not previously identified. All but two (CERV 1/PTERV1 and CERV 2) of the 42 families of chimpanzee endogenous retroviruses were found to have orthologs in humans. Molecular analysis (PCR and Southern hybridization) of CERV 2 elements demonstrates that this family is present in chimpanzee, bonobo, gorilla and old-world monkeys but absent in human, orangutan and new-world monkeys. A survey of endogenous retroviral positional variation between chimpanzees and humans determined that approximately 7% of all chimpanzee-human INDEL variation is associated with endogenous retroviral sequences. CONCLUSION: Nine families of chimpanzee endogenous retroviruses have been transpositionally active since chimpanzees and humans diverged from a common ancestor. Seven of these transpositionally active families have orthologs in humans, one of which has also been transpositionally active in humans since the human-chimpanzee divergence about six million years ago. Comparative analyses of orthologous regions of the human and chimpanzee genomes have revealed that a significant portion of INDEL variation between chimpanzees and humans is attributable to endogenous retroviruses and may be of evolutionary significance.

Animals↗