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PubMed2005

Identification of the alternative promoters of the KChIP4 subfamily.

The subfamily of voltage-dependent potassium (Kv) channel interacting protein 4 (KChIP4) is made up of the auxiliary interacting protein of voltage-dependent potassium channels. In this study, the structure of four splicing variants of the human KChIP4 gene was analyzed. Three of the four isoforms of the KChIP4 gene, KChIP4.1, KChIP4.2 and KChIP4.4, were amplified from mouse and human fetal brain tissues by reverse transcription-polymerase chain reaction and then identified. Based on the bioinformatics analysis of the genomic sequences of the gene, we cloned and characterized two promoter fragments from the KChIP4 gene. One was a 325 bp fragment upstream of the 5' end of the KChIP4.1 mRNA sequence and the other was an 818 bp fragment located immediately at the 5' end of the KChIP4.4 variant. Both of them can initiate the transcription of the reporter gene in HT1080 cells and Sprague-Dawley (SD) rat fetal brain neurons, and they contain CG islands, except typical TATA boxes and CAAT boxes. This shows that the KChIP4 gene expression is regulated by an alternative promoter.

Amino Acid Sequence↗

PubMed2005

Advantage of dichromats over trichromats in discrimination of color-camouflaged stimuli in nonhuman primates.

Due to a middle- to long-wavelength-sensitive (M/LWS) cone opsin polymorphism, there is considerable phenotypic variation in the color vision of New World monkeys. Many females have trichromatic vision, whereas some females and all males have dichromatic vision. The selective pressures that maintain this polymorphism are unclear. In the present study we compared the performance of dichromats and trichromats in a discrimination task. We examined tri- and dichromatic individuals of two species: brown capuchin monkeys (Cebus apella) and long-tailed macaques (Macaca fascicularis). We also examined one protanomalous chimpanzee (Pan troglodytes). The subjects' task was to discriminate a circular pattern from other patterns in which textural elements differed in orientation and thickness from the background. After they were trained with stimuli of a single color, the subjects were presented with color-camouflaged stimuli with a green/red mosaic overlaid onto the pattern. The dichromatic monkeys and the protanomalous chimpanzee selected the correct stimulus under camouflaged conditions at rates significantly above chance levels, while the trichromats did not. These findings demonstrate that dichromatic nonhuman primates possess a superior visual ability to discriminate color-camouflaged stimuli, and that such an ability may confer selective advantages with respect to the detection of cryptic foods and/or predators.

Animals↗

PubMed2025

Genetic Conservation and Diversity of SARS-CoV-2 Envelope Gene Across Variants of Concern.

SARS-CoV-2 Envelope (E) protein is critical in viral assembly, release, and virulence. E gene was considered highly conserved and evolving slowly. Pan-sarbecoviruses-conserved regions in the E gene have been used as targets for various RT-PCR assays to detect SARS-CoV-2. It remains elusive whether SARS-CoV-2 variants of concern (VOCs) have accumulated significant E mutations that may affect protein stability and diagnostic RT-PCR assays. Herein we aimed to perform a comprehensive genetic analysis on the conservation and diversity of the E gene of SARS-CoV-2 and its VOCs in comparison with other human coronaviruses (HCoVs). In silico analysis of 20 326 HCoV E gene sequences retrieved from GenBank and GISAID suggests that SARS-CoV-2 E gene has multiple pan-HCoVs- and pan-SARS-CoV-2-conserved positions but accumulates significant mutations in VOC B.1.351 and Omicron strains. Mutations were often found in the 5' and 3' variable regions, whereas the central region is conserved. Nucleotide changes C109U and A114G may lead to potential failure of first-line SARS-CoV-2 diagnostic/screening assays. Nucleotide change C212U and its concomitant amino acid substitution Pro71Leu (i.e., C212U/Pro71Leu) is a hallmark mutation of B.1.351 variants, while C26U/Thr9Ile is characteristic of all Omicron variants. Later Omicron subvariants, such as XBB.1.5 and EG.5, additionally acquired the A31G/Thr11Ala mutation, as was confirmed by whole genome sequencing of SARS-CoV-2 in 118 pediatric cases. Wild-type E protein exhibits cytotoxicity to cells, but the mutations Thr9Ile, Thr11Ala, Thr9Ile + Thr11Ala, or Pro71Leu reduces its cytotoxicity. The Thr9Ile + Thr11Ala mutation stabilizes the E proteins of Omicron variants, while Pro71Leu alters the cellular distribution of the E protein, reducing its colocalization with the Golgi body. Altogether, this study not only sheds light on the conservation and diversity of the E gene in SARS-CoV-2 and its VOCs but also informs the improvement and development of SARS-CoV-2 or pan-HCoVs screening and diagnostic assays.

SARS-CoV-2↗

PubMed1989

Characterization of surface markers of bovine gut mucosal leukocytes using monoclonal antibodies.

The surface phenotypes of bovine intestinal leukocytes isolated from the intraepithelium (IEL), lamina propria (LPL) and Peyer's patches (PPL) of the small intestinal mucosa of normal adult cows were determined using monoclonal antibodies (mAb) specific to adult bovine peripheral blood leukocytes (PBL). Laser flow cytometric (LFC) analysis demonstrated that IEL contained significantly (P less than 0.1 to 0.02) fewer cells (26%) expressing the pan T cell phenotype in comparison to LPL (38%) and PPL (44%). Similarly, significantly (P less than 0.01 to 0.001) lower numbers of B cells were observed among IEL (10%) compared to LPL (28%) and PPL (33%). While approximately equal numbers of B7A1+ "null" cells (10%) and DH59B+ "Ia+ monocytes/granulocytes" (16.5%) were observed among the three intestinal cell populations, IEL contained significantly (P less than 0.1 to 0.05) lower numbers (19%) of T helper (Th) cells in comparison to LPL (44%) and PPL (38%). In contrast, lymphocytes with the T cytotoxic/suppressor (Tc/s) phenotype were significantly lower (P less than 0.01 to 0.001) among LPL (14.5%) compared to IEL (25%) and PPL (23%). While the numbers of cells expressing class I major histocompatibility complex (MHC) surface antigens (H58A+) were approximately equal among LPL (79%) and PPL (87%), a significant difference (P less than 0.02) was observed between IEL (71%) and PPL. Similarly, while approximately equal numbers of cells expressing the MHC class II surface phenotype were observed among LPL (42%) and PPL (46%), IEL contained significantly (P less than 0.01) fewer (31%) MHC class II cells in comparison to PPL. Enrichment for T cells by plastic adherence and Sephadex G-10/nylon wool fractionation revealed a significant (P less than 0.01) and proportional increase in T lymphocyte subsets expressing pan T, Th and Tc/s phenotypes among the three cell populations. Similarly, enrichment for B cells by the same techniques showed a significant (P less than 0.01) and proportional increase in cells expressing the panB cell phenotype among LPL and PPL. Marked differences in cell size distribution and cell surface density were observed when the three intestinal leukocyte populations were compared by LFC using monoclonal antibodies directed at various cell surface markers. Furthermore, considerable quantitative variations of each cell surface marker were observed among the individual animals tested. The results of this study indicate that bovine IEL, which contain a high percentage of cells (greater than 30%) with no known phenotype are significantly different from LPL and PPL which are phenotypically similar cell populations.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2005

Chronomics: circadian lead of extrapineal vs. pineal melatonin rhythms with an infradian hypothalamic exploration.

A circadian rhythm is documented for plasma, pineal, and hypothalamic melatonin of male and female rats kept on staggered lighting regimens. Log[_10]-transformation of the data usually normalizes, when need be, the distribution of residuals from the 24-hour cosine curve fits. A tentative circadian acrophase chart is presented that shows a lead in circadian acrophase of duodenal over pineal melatonin. The use of antiphasic lighting regimens facilitates circadian studies that can be carried out for several days, thereby allowing the assessment of infradian components such as a circasemiseptan variation in hypothalamic melatonin documented herein. The results are qualified by the presence of a second extremum of a double magnetic storm at the start of mapping.

Animals↗

PubMed2005

Goodness-of-fit methods for generalized linear mixed models.

We develop graphical and numerical methods for checking the adequacy of generalized linear mixed models (GLMMs). These methods are based on the cumulative sums of residuals over covariates or predicted values of the response variable. Under the assumed model, the asymptotic distributions of these stochastic processes can be approximated by certain zero-mean Gaussian processes, whose realizations can be generated through Monte Carlo simulation. Each observed process can then be compared, both visually and analytically, to a number of realizations simulated from the null distribution. These comparisons enable one to assess objectively whether the observed residual patterns reflect model misspecification or random variation. The proposed methods are particularly useful for checking the functional form of a covariate or the link function. Extensive simulation studies show that the proposed goodness-of-fit tests have proper sizes and are sensitive to model misspecification. Applications to two medical studies lead to improved models.

Anti-HIV Agents↗

PubMed2002

Mandibular variation among Chinese macaques.

In order to clarify the degree to which mandibular variation among Chinese macaques results from functional adaptation and phylogenetic inertia, 13 mandibular variables were analyzed by bivariate and multivariate techniques. The results indicate, not surprisingly, that the main differences in the mandible are associated with size. The study further implies that the variation between species is not closely associated with differences in functional adaptation even though the dietary and related differences are large compared to the situation in other macaques. The great variety in diet and related factors among Chinese macaques may not have yet resulted in a significant variation in the mandible. This may be because their radiation in Asia, though involving considerably greater differences in habitat, climate, and so on, has occurred more recently than for other macaque species in Southeast Asia. Mandibular variation between these species, therefore, is likely to be more closely tied to their immediate prior phylogenetic history. For example, the two stump-tailed macaques are closely similar and are also closely similar to the Assam species. Function in the mandible in these species is quite different. The results, therefore, seem to support the hypothesis that these three macaque species should be placed in a single species-group (sinica) as proposed by Delson [1980], Pan [1998], and Pan et al. [1998].

Animals↗

PubMed2006

Spatio-temporal expression of Prospero is finely tuned to allow the correct development and function of the nervous system in Drosophila melanogaster.

Adaptive animal behaviors depend upon the precise development of the nervous system that underlies them. In Drosophila melanogaster, the pan-neural prospero gene (pros), is involved in various aspects of neurogenesis including cell cycle control, axonal outgrowth, neuronal and glial cell differentiation. As these results have been generally obtained with null pros mutants inducing embryonic lethality, the role of pros during later development remains poorly known. Using several pros-Voila (prosV) alleles, that induce multiple developmental and behavioral anomalies in the larva and in adult, we explored the relationship between these phenotypes and the variation of pros expression in 5 different neural regions during pre-imaginal development. We found that the quantity of pros mRNA spliced variants and of Pros protein varied between these alleles in a tissue-specific and developmental way. Moreover, in prosV1 and prosV13 alleles, the respective decrease or increase of pros expression, affected (i) neuronal and glial cell composition, (ii) cell proliferation and death and (iii) axonal-dendritic outgrowth in a stage and cellular context dependant way. The various phenotypic consequences induced during development, related to more or less subtle differences in gene expression, indicate that Pros level needs a precise and specific adjustment in each neural organ to allow its proper function.

Animals↗

PubMed2005

Ancient haplotypes of the HLA Class II region.

Allelic variation in codons that specify amino acids that line the peptide-binding pockets of HLA's Class II antigen-presenting proteins is superimposed on strikingly few deeply diverged haplotypes. These haplotypes appear to have been evolving almost independently for tens of millions of years. By complete resequencing of 20 haplotypes across the approximately 100-kbp region that spans the HLA-DQA1, -DQB1, and -DRB1 genes, we provide a detailed view of the way in which the genome structure at this locus has been shaped by the interplay of selection, gene-gene interaction, and recombination.

Alleles↗

PubMedDate not supplied

Determination of moisture in cheese and cheese products.

Variables related to oven-drying samples of cheese and cheese products to determine moisture content were examined to provide more efficient and reproducible methods. Over 6500 samples of cheese were analyzed in an effort to modify the current AOAC procedure. The gravity atmospheric oven was unsuitable for use in accurate moisture analysis because of wide temperature differentials within the oven cavity. Use of this for oven moisture determination resulted in higher variance, which corresponded to the high temperature variation within the oven. Cheese sample preparation using an Oster blender yielded consistently lower variance in final moisture content than did preparation of cheese samples with a hand grater, rotary grater, and plug and plunger. Sample size of 3 +/- 0.25 g maximized surface area-to-volume ratios and yielded a lower error in final moisture content because of better control of ambient weight loss rates. Use of combination of disposable 5.5 cm diameter aluminum sample pans with 5.5 cm diameter glass fiber filter pads for covers produced a smaller standard deviation for moisture analysis than did the AOAC pan and insert cover and filter paper covers. All pans must be pre-dried for at least 3 h at 100 degrees C, and the glass fiber covers should be pre-dried for 1 h under the same conditions. All dried pans and covers must be stored in a desiccator with active desiccant. Equipment upgrades from the existing AOAC standard methods provide safer more efficient methods of analysis.

Algorithms↗

PubMed2003

Clinical brain MR imaging prescriptions in Talairach space: technologist- and computer-driven methods.

BACKGROUND AND PURPOSE: Variability in patient head positioning may yield substantial interstudy image variance in the clinical setting. We describe and test three-step technologist and computer-automated algorithms designed to image the brain in a standard reference system and reduce variance. METHODS: Triple oblique axial images obtained parallel to the Talairach anterior commissure (AC)-posterior commissure (PC) plane were reviewed in a prospective analysis of 126 consecutive patients. Requisite roll, yaw, and pitch correction, as three authors determined independently and subsequently by consensus, were compared with the technologists' actual graphical prescriptions and those generated by a novel computer automated three-step (CATS) program. Automated pitch determinations generated with Statistical Parametric Mapping '99 (SPM'99) were also compared. RESULTS: Requisite pitch correction (15.2 degrees +/- 10.2 degrees ) far exceeded that for roll (-0.6 degrees +/- 3.7 degrees ) and yaw (-0.9 degrees +/- 4.7 degrees ) in terms of magnitude and variance (P <.001). Technologist and computer-generated prescriptions substantially reduced interpatient image variance with regard to roll (3.4 degrees and 3.9 degrees vs 13.5 degrees ), yaw (0.6 degrees and 2.5 degrees vs 22.3 degrees ), and pitch (28.6 degrees, 18.5 degrees with CATS, and 59.3 degrees with SPM'99 vs 104 degrees ). CATS performed worse than the technologists in yaw prescription, and it was equivalent in roll and pitch prescriptions. Talairach prescriptions better approximated standard CT canthomeatal angulations (9 degrees vs 24 degrees ) and provided more efficient brain coverage than that of routine axial imaging. CONCLUSION: Brain MR prescriptions corrected for direct roll, yaw, and Talairach AC-PC pitch can be readily achieved by trained technologists or automated computer algorithms. This ability will substantially reduce interpatient variance, allow better approximation of standard CT angulation, and yield more efficient brain coverage than that of routine clinical axial imaging.

Adolescent↗

PubMed2003

Variability and phylogenetic incongruence of an SSU nrDNA group I intron in Artomyces, Auriscalpium, and Lentinellus (Auriscalpiaceae: Homobasidiomycetes).

Previous research has shown that a group I intron occurs in the SSU ribosomal DNA gene of isolates of Artomyces (Clavicorona, in part) and Lentinellus, but apparently it is absent in an Auriscalpium isolate. However, further investigation revealed that the intron is apparently absent in some species of Artomyces and Lentinellus and is present in at least one species of Auriscalpium. To examine this further, the presence or absence of the group I intron is reported for 13 species of Lentinellus, two species of Auriscalpium, and 16 species of Artomyces. The presence of the intron among the species was variable and is documented for seven species of Lentinellus, one species of Auriscalpium, and 12 species of Artomyces. Furthermore, the presence of the intron was variable among the isolates of several species, and variability of its presence was observed within single isolates, indicating inter-ribosomal repeat heterogeneity. Independent phylogenetic estimations were generated for the intron and nuclear ribosomal internal transcribed spacer regions (ITS). Tests of congruence for the two trees indicated that the data were heterogeneous. Some of the discontinuity between the two phylogenies is due to placement of the Ar. austropiperatus intron within the Lentinellus intron clade. Variability in the length of the intron was observed in populations of the pan-Northern Temperate species Ar. pyxidatus. This was due to the presence of an additional unknown insertional element found only within North American collections of Ar. pyxidatus and absent from European and Asian collections.

Basidiomycota↗

PubMed1998

HLA-H: a pseudogene with increased variation due to balancing selection at neighboring loci.

The HLA complex includes the most polymorphic genes in the human genome. However, the HLA class Ib loci have little, if any, nucleotide variation, presumably due to their specialized functions or perhaps due to a lack of function. This population genetic study of HLA-H, a class I pseudogene, was initiated to determine the pattern of variation at neutral sites within the HLA complex. We found that the pattern of variation for HLA-H is consistent with the neutral model. However, the amount of variation in HLA-H is significantly greater than estimates for other silent sites within the human genome outside of the MHC (theta = 0.0144, P < 0.000001). Our study further indicates that other possible causes of increased variation such as a high mutation rate for HLA-H, interlocus gene conversion, increased diversity in the sample population in general, and selection acting directly on HLA-H are unlikely. Instead, these data suggest that HLA-H has increased variation as a result of balancing selection acting on nearby loci such as HLA-A.

Animals↗

PubMed2002

Diurnal rhythm of H+-peptide cotransporter in rat small intestine.

In mammals, most physiological, biochemical, and behavioral processes show a circadian rhythm. In the present study, we examined the diurnal rhythm of the H+-peptide cotransporter (PEPT1), which transports small peptides and peptide-like drugs in the small intestine and kidney, using rats maintained in a 12-h photoperiod with free access to chow. The transport of [14C]glycylsarcosine (Gly-Sar), a typical substrate for PEPT1 by in situ intestinal loop and everted intestine, was greater in the dark phase than the light phase. PEPT1 protein and mRNA levels varied significantly, with a maximum at 2000 and minimum at 800. Similar functional and expressional diurnal variations were observed in the intestinal Na+-glucose cotransporter (SGLT1). In contrast, renal PEPT1 and SGLT1 showed little diurnal rhythmicity in protein and mRNA expression. These findings indicate that the intestinal PEPT1 undergoes diurnal regulation in its activity and expression, and this could affect the intestinal absorption of dietary protein.

Absorption↗

PubMed2026

Comprehensive characterization of MET exon 14 skipping mutations in non-small cell lung cancer.

BACKGROUND: MET exon 14 skipping mutation (METΔex14) is a key driver event in non-small cell lung cancer (NSCLC) and can emerge as an acquired drug resistance mechanism to MET, EGFR or ALK inhibitors. The clinical and genomic features of METΔex14 in NSCLC require further characterization. METHODS: Our study included a total of 585 patients with METΔex14 + NSCLC, comprising 556 baseline samples, 53 samples from patients exhibiting resistance to MET inhibitors, and 16 samples from patients resistant to EGFR/ALK inhibitors. Genomic data from targeted next-generation sequencing (NGS) of tissue and/or plasma samples using GeneseeqPrime™ (a 425 pan-cancer gene panel) were analyzed. RESULTS: Overall, METΔex14 exhibited a prevalence of 1.02% (n = 585) in the screened NSCLC population, with a higher incidence in patients with a sarcomatoid histology. METΔex14 was predominantly detected at the splice donor site, though the non-coding region adjacent to the splice acceptor site contributed considerably to the complexity of METΔex14. Common concurrent alterations identified at baseline included those in TP53 (40.8%), CDK4 (16%) and EGFR (12.4%). Concurrent MET amplification and cell cycle pathway mutations were both associated with worse outcomes in patients treated with crizotinib, with significant co-occurrences observed also among these concurrent genomic variations. In addition, increased chromosomal instability and intra-tumoral heterogeneity correlated with a poorer response to crizotinib. Mechanisms of acquired resistance to MET inhibitors were primarily attributed to on-target MET D1228X/Y1230X mutations or off-target alterations within genes in the RTK/RAS/MAPK and PI3K/AKT/mTOR pathways. Intriguingly, our exploratory analysis also identified the FGFR3::TACC3 fusion as a potential resistance mechanism to savolitinib. Moreover, METΔex14 was identified in 16 patients following progression on EGFR and ALK inhibitors, highlighting the need for developing tailored therapeutic strategies to overcome resistance. CONCLUSIONS: This study provides a comprehensive characterization of METΔex14 in NSCLC, revealing its dual role as a primary driver of oncogenesis and a potential resistance mechanism to EGFR/ALK inhibitors. The identification of concurrent genetic alterations and potential resistance mechanisms enhances our molecular understanding of treatment responses. These findings highlight the need for further investigation into targeted therapies that consider the genomic complexity of METΔex14 to improve treatment efficacy and patient outcomes.

Humans↗

PubMed2002

Conflict and post-conflict behavior in a small group of chimpanzees.

Chimpanzee research plays a central role in the discussions of conflict negotiation. Reconciliation, or the attraction and affiliation of former opponents following conflict, has been proposed as a central element of conflict negotiation in chimpanzees and various other taxa. In an attempt to expand the database of chimpanzee conflict resolution, conflict and post-conflict behavior were recorded for a small group of socially housed chimpanzees at the Chimpanzee and Human Communication Institute, at Central Washington University. Data were collected over six 6-week periods between 1997 and 2000, for a total of 840 hours of observation, resulting in a substantial post-conflict (PC) and matched control (MC) data set. The data demonstrate this group's tendencies to maintain visual contact and closer proximity after conflicts. Dyadic corrected conciliatory tendencies ranged between 0 - 37.5% and averaged 17.25% across all dyads. Individual corrected conciliatory tendencies ranged between 5.8 and 32%. The results of this study combined with recent publications on captive and free-ranging chimpanzee post-conflict behavior suggest that variation in post-conflict behavior may be important to our understanding of chimpanzee conflict negotiation, and may also have implications for the design and management of captive chimpanzee enclosures and social groups, respectively.

Aggression↗

PubMed1999

Determination of ancestral alleles for human single-nucleotide polymorphisms using high-density oligonucleotide arrays.

Here we report the application of high-density oligonucleotide array (DNA chip)-based analysis to determine the distant history of single nucleotide polymorphisms (SNPs) in current human populations. We analysed orthologues for 397 human SNP sites (identified in CEPH pedigrees from Amish, Venezuelan and Utah populations) from 23 common chimpanzee, 19 pygmy chimpanzee and 11 gorilla genomic DNA samples. From this data we determined 214 proposed ancestral alleles (the sequence found in the last common ancestor of humans and chimpanzees). In a diverse human population set, we found that SNP alleles with higher frequencies were more likely to be ancestral than less frequently occurring alleles. There were, however, exceptions. We also found three shared human/pygmy chimpanzee polymorphisms, all involving CpG dinucleotides, and two shared human/gorilla polymorphisms, one involving a CpG dinucleotide. We demonstrate that microarray-based assays allow rapid comparative sequence analysis of intra- and interspecies genetic variation.

Alleles↗

PubMed2004

Metastability of Helicobacter pylori bab adhesin genes and dynamics in Lewis b antigen binding.

Heterogeneity among Helicobacter pylori strains in gastric epithelial adherence is postulated to contribute to pathogen fitness in the physiologically diverse human population. H. pylori adherence to ABO and Lewis b (Leb) blood group antigens in the human stomach is mediated by the blood group antigen-binding adhesin BabA. Approximately 70% of Swedish and U.S. H. pylori clinical isolates exhibit Leb binding, but here we show that the babA gene is present in each of 10 Leb-nonbinding strains. Fluorescence microscopy identified occasional bacterial cells with a Leb-binding phenotype in populations of Leb-nonbinding strains. Thus, nonbinding seemed to be a metastable phenotype. To model metastable transition into the virulence-associated Leb-binding mode, Leb-binding clones were isolated from nonadherent strains by panning with Leb-magnetic beads and characterized. Strain 17875 has two babA genes, babA1 (silent) and babA2 (expressed). We found that a babA2-cam derivative of strain 17875 regained Leb binding by recombination of the formerly silent babA1 gene into the expressed and partially homologous babB locus. The chimeric BabB/A adhesin binds Leb with an affinity similar to that of wild-type BabA adhesin, but its expression level was lower and was subject to phase variation through slipped-strand mispairing. Equivalent results were obtained with strain NCTC11638. We propose that adhesin metastability and heterogeneity contributes to bacterial fitness and results in some clones having potential for periodic activation and deactivation of virulence appropriate for intensity of the host response to infection.

Adhesins, Bacterial↗