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PubMed2026

Pan-cancer analysis identifies APOC1 as a TAM-derived modulator of adaptive immune resistance and predictor of therapeutic response.

BACKGROUND: Apolipoprotein C1 (APOC1) has been implicated in several malignancies, yet its expression patterns, clinical significance, and immunomodulatory roles across cancer types remain poorly characterized. METHODS: We performed a comprehensive multi-omic analysis of APOC1 across 33 cancer types integrating transcriptomic, proteomic, genomic, epigenomic, and pharmacogenomic data from TCGA, GTEx, CPTAC, and multiple independent external cohorts. Immune infiltration was assessed using seven complementary algorithms. Spatial transcriptomics and single-cell RNA sequencing were employed to determine the cellular source of APOC1 expression. RESULTS: APOC1 upregulation in most cancers was associated with cancer type-specific prognosis. After adjustment for clinical covariates and macrophage infiltration, high APOC1 remained an independent adverse factor in KIRC, LGG, and STAD. APOC1 expression positively correlated with genomic instability hallmarks, including homologous recombination deficiency and aneuploidy, with these associations largely independent of immune infiltration; in contrast, associations with tumor mutational burden were substantially confounded by macrophage abundance. Immune infiltration analysis revealed a pattern consistent with adaptive immune resistance: APOC1 correlated positively with immune-activating signatures (STAT1, MHC-II, TCR signaling) and immunosuppressive M2 macrophages and Tregs, yet negatively with anti-tumor effectors (activated NK cells, dendritic cells). Spatial transcriptomics and single-cell RNA sequencing identified tumor-associated macrophages (TAMs) as the primary cellular source of APOC1, with transcripts co-localizing with CD68 in tissue sections. APOC1 expression correlated with multiple immune checkpoint molecules and was elevated in responders to immune checkpoint blockade, consistent with an inflamed yet regulated tumor microenvironment. Pharmacogenomic analyses revealed that APOC1-high tumors display distinct drug response profiles, characterized by resistance to MAPK pathway inhibitors and potential sensitivity to the HDAC inhibitor Entinostat. CONCLUSION: This pan-cancer analysis establishes APOC1 as a context-dependent biomarker and a TAM-derived modulator of adaptive immune resistance, with prognostic and therapeutic implications across malignancies. APOC1-expressing TAMs represent a potential target for combination immunotherapy strategies.

APOC1↗

PubMed2005

The effects of amplitude-spectrum statistics on foveal and peripheral discrimination of changes in natural images, and a multi-resolution model.

Psychophysical thresholds were measured for discriminating small changes in spatial features of naturalistic scenes (morph sequences), for foveal and peripheral vision, and under M-scaling. Sensitivity was greatest for scenes with near natural Fourier amplitude slope, perhaps implying that human vision is optimised for natural scene statistics. A low-level model calculated differences in local contrast between pairs of images within a few spatial frequency channels with bandwidth like neurons in V1. The model was "customised" to each observer's contrast sensitivity function for sinusoidal gratings, and it could replicate the "U-shaped" relationships between discrimination threshold and spectral slope, and many differences between picture sets and observers. A single-channel model and an ideal-observer analysis both failed to capture the U-shape.

Contrast Sensitivity↗

PubMed1991

Image processing in swallowing and speech research.

An image processing system for application to studies of the temporal and spatial parameters of movement during swallowing and speech is described. Image sequences from videotape are digitized for computerized manipulation and analysis in an attempt to improve on conventional visual inspection. The system is "interactive" or "event-driven": after executing a function, the computer waits for guidance from the user who controls the program through keyboard and mouse input, selecting options from menus and responding to prompts. The analyst alters image clarity by the application of filters and heightens contrast through video enhancement. A technique called "remapping" reduces head motion and provides uniform spatial scaling. Animated sequences of images are used, as opposed to frame-by-frame analysis, to preserve temporal context and increase efficiency of measurement. Low cost off-the-shelf personal computer hardware is used along with original software tailored to the application.

Deglutition↗

PubMed2003

Characterization and spatial distribution of ectomycorrhizas colonizing aspen clones released in an experimental field.

Ectomycorrhizas (EM) from aspen clones released on an experimental field were characterized by morphotyping, restriction analysis and internal transcribed spacer (ITS) sequencing. In addition, their community structure and spatial distribution was analyzed. Among the 23 observed morphotypes, six mycobionts dominated, forming roughly 90% of all ectomycorrhizas: Cenococcum geophilum, Laccaria sp., Phialocephala fortinii, two different Thelephoraceae, and one member of the Pezizales. The three most common morphotypes had an even spatial distribution, reflecting the high degree of homogeneity of the experimental field. The distribution of three other morphotypes was correlated with the distances to the spruce forest and deciduous trees bordering the experimental field. These two patterns allowed two invasion strategies of ectomycorrhizal fungi (EMF) to be recognized, the success of which depends on adaptation of the EMF to local ecological conditions.

Agaricales↗

PubMed2003

Interplay of negative and positive signals controls endoderm-specific expression of the ascidian Cititf1 gene promoter.

Cititf1 is an early and specific marker of endoderm development in Ciona intestinalis [ Development 126, 5149]. Here, we examine Cititf1 transcriptional regulation focusing in particular on its endodermal restricted expression. Through the analysis of Ciona embryos, electroporated with different portions of Cititf1 5'-flanking region fused to lacZ, we characterized a minimal 300-bp cis-regulatory sequence able to closely reproduce the spatial and temporal expression pattern of the endogenous gene. This enhancer contains at least three distinct regulatory regions, two of which are responsible for activation of transcription in the endoderm and in the mesenchyme, respectively, while the third is a negative control element that represses mesenchyme transcription. We have further defined the sequences responsible for transcriptional activation in the endoderm by clustered point mutations and DNA-binding assays.

Animals↗

PubMed1990

The endoplasmic reticulum retention signal of the E3/19K protein of adenovirus type 2 consists of three separate amino acid segments at the carboxy terminus.

The E3/19K protein of adenovirus type 2 is a resident of the ER. Immediately after synthesis it binds to human major histocompatibility complex class I antigens and prevents their departure from the ER compartment. The ER retention signal of the E3/19K protein is contained within the 15 amino acids that protrude on the cytoplasmic side at the carboxy terminus of the protein. To define the ER retention sequence in more detail, we have generated 10 mutants of the E3/19K protein that differ only within this segment. Analysis of the rate of intracellular transport and cell surface expression of HLA antigens associated to these mutants, show that the sequences Ser-Phe-Ile, located in the middle of the 15-residue segment and Met-Pro, at the extreme carboxy terminus, are crucial for retention. Four charged residues, Asp-Glu-Lys-Lys, are located between these two retention elements but are of little or no importance. The basic cluster of amino acids close to the membrane also has some effect on retention. Thus, the retention signal of the E3/19K protein is not a contiguous sequence of amino acids but has a complex spatial arrangement.

Adenovirus Early Proteins↗

PubMed1992

cDNA cloning and deduced amino acid sequence of a major, glycine-rich cuticular protein from the coleopteran Tenebrio molitor. Temporal and spatial distribution of the transcript during metamorphosis.

In Coleoptera, the elytra (forewings), with a very hard and thick cuticle, protect the membranous and delicate hindwings against mechanical stress. We have isolated and characterized a cDNA encoding a major cuticle protein in Tenebrio molitor, named ACP-20. The deduced amino acid sequence is roughly tripartite, with two terminal glycine-rich domains and a central region showing pronounced similarities with some other hard cuticle proteins. Northern blot and in situ hybridization analyses reveal that ACP-20 gene expression is developmentally regulated since transcript accumulation occurs only in epidermal regions synthesizing hard cuticle and is restricted to the period of preecdysial adult cuticle deposition. Moreover, application of a juvenile hormone analogue prevents the appearance of the transcript, indicating that juvenile hormone, a key molecule involved in the control of insect metamorphosis, negatively regulates the expression of the ACP-20 gene.

Amino Acid Sequence↗

PubMed2004

Large-scale isolation of ESTs from medaka embryos and its application to medaka developmental genetics.

The medaka is becoming an attractive model organism for the study of vertebrate early development and organogenesis and large-scale mutagenesis projects that are aimed at creating developmentally defective mutants are now being conducted by several groups in Japan. To strengthen the study of medaka developmental genetics, we have conducted a large-scale isolation of ESTs from medaka embryos and developed tools that facilitate mutant analysis. In this study, we have characterized a total of 132,082 sequences from both ends of cloned insert cDNAs from libraries generated at different stages of medaka embryo development. Clustering analysis with 3-prime sequences finally identified a total of 12,429 clusters. As a pilot analysis, 924 clusters were subjected to in situ hybridization to determine the spatial localization of their transcripts. Using EST sequence data generated in the present study, a 60-mer oligonucleotide microarray with 8,091 unigenes (Medaka Microarray 8K) was constructed and tested for its usefulness in expression profiling. Furthermore, we have developed a rapid and reliable mutant mapping system using a set of mapped EST markers (M-marker 2003) that covers the entire medaka genome. These resources will accelerate medaka mutant analyses and make an important contribution to the medaka genome project.

Animals↗

PubMed1999

Human chemokine receptors CCR5, CCR3 and CCR2B share common polarity motif in the first extracellular loop with other human G-protein coupled receptors implications for HIV-1 coreceptor function.

Chemokine receptors (CRs) are 7-helix membrane proteins from the family of G-protein coupled receptors (GPCRs). A few human CRs act as cofactors for macrophage-tropic (M-tropic) human immunodeficiency virus type-1 (HIV-1) entry into cells, while others do not. In this study, we describe an application of molecular modeling techniques to delineate common molecular determinants that might be related to coreceptor activity, and the use of the data to identify other GPCRs as putative cofactors for M-tropic HIV-1 entry. Subsequently, the results were confirmed by an experimental approach. The sequences of extracellular domains (ECDs) of CRs were employed in a compatibility search against a database of environmental profiles derived for proteins with known spatial structure. The best-scoring sequence-profile alignments obtained for each ECD were compared in pairs to check for common patterns in residue environments, and consensus sequence-profile fits for ECDs were also derived. Similar hydrophobicity motifs were found in the first extracellular loops of the CRs CCR5, CCR3, and CCR2B, and are all used by M-tropic HIV-1 for cell entry. In contrast, other CRs did not reveal common motifs. However, the same environmental pattern was also delineated in the first extracellular loop of some human GPCRs showing either high (group 1) or low (group 2) degree of similarity of their polarity patterns with those in HIV-1 coreceptors. To address the question of whether the delineated molecular determinant plays a critical role in the receptor-virus binding, three of the identified GPCRs, bradykinin receptor (BRB2) and G-protein receptor (GPR)-CY6 from group 1, and GPR8 from group 2, were cloned and transfected into HeLa-CD4 cells, which are nonpermissive to M-tropic HIV-1 infection. We demonstrate that, similar to CCR5, the two selected GPCRs from group 1 were capable of mediating M-tropic HIV-1 entry, whereas GPR8 from group 2 did not serve as HIV-1 coreceptor. The potential biological significance of the identified structural motif shared by the human CCR5, CCR3, CCR2B and other GPCRs is discussed.

Amino Acid Sequence↗

PubMed1990

Hox-2.3 upstream sequences mediate lacZ expression in intermediate mesoderm derivatives of transgenic mice.

The mouse Hox-2.3 gene contains an Antp-like homeobox sequence and is expressed in a spatially restricted anteroposterior domain during development. To study the molecular basis of this differential gene regulation, we set out to characterize the cis-regulatory elements mediating Hox-2.3 expression during embryogenesis. We show that a fragment extending 1316 base pairs (bp) upstream of the transcription start site, thus corresponding to the Hox-2.4/Hox-2.3 intergenic sequences is capable of mediating luciferase gene transcription in transfected cells in vitro and lacZ expression in transgenic mice. The beta-galactosidase-staining pattern in embryos was found to be strikingly similar to the Hox-2.3 in situ hybridization pattern in intermediate mesoderm derivatives: high levels of both Hox-2.3 transcripts and beta-galactosidase activity were found in the mesonephric duct-derived epithelium of the meso- and metanephric kidney and associated ducts, from the time these structures first appeared on throughout development. The transgene apparently lacks sequences needed for correct Hox-2.3 expression in somitic and lateral plate mesoderm and in neurectoderm. These results document the involvement of distinct regulatory elements in Hox gene expression in subsets of cells with distinct developmental fate, situated at similar positions along the anteroposterior axis of the embryo.

Animals↗

PubMed1999

Characterization of mouse cathepsin K gene, the gene promoter, and the gene expression.

Cathepsin K, a lysosomal cysteine protease, is abundantly and selectively expressed in osteoclasts and has a specialized role in osteoclast-mediated bone resorption. In contrast to function studies, transcription regulation of cathepsin K remains largely unknown. In this study, the gene encoding mouse cathepsin K and the promoter have been isolated and completely sequenced. In addition, the temporal and spatial expressions of cathepsin K have been characterized. Intrachromosomal mapping studies revealed that the gene contains eight exons and seven introns spanning approximately 10.6 kb of genomic DNA, a genomic organization that was highly conserved with respect to its human homology. Analysis of the 9 kb 5' flanking region indicates that this gene lacks canonical TATA and CAAT boxes and contains multiple putative transcription regulatory elements which are also present in the comparable position of 5' flanking region of human cathepsin K gene. Mouse cathepsin K was found to be a single-copy gene. Northern blot analysis of RNAs from a number of mouse tissues revealed that cathepsin K mRNA is selectively expressed in osteoclast. The selective expression of cathepsin K was confirmed by anticathepsin K immunohistochemical staining. The sequence of cathepsin K expression was linked to osteoclast differentiation in vivo and in vitro by a tartrate-resistant acid phosphatase-anticathepsin K dual immunostaining technique. Cathepsin K is initially expressed at the preosteoclast stage and throughout the mature osteoclast stage. The primer extension assay indicated a major transcription start site 58 bp upstream of the initiator Met codon. The characterization of the cathepsin K gene, its promoter, and the temporal and spatial expression may provide valuable insights into its osteoclast-specific expression and the molecular mechanisms responsible for osteoclast activation.

Amino Acid Sequence↗

PubMed2002

Three-dimensional spiral MR imaging: Application to renal multiphase contrast-enhanced angiography.

A fast MR pulse sequence with spiral in-plane readout and conventional 3D partition encoding was developed for multiphase contrast-enhanced magnetic resonance angiography (CE-MRA) of the renal vasculature. Compared to a standard multiphase 3D CE-MRA with FLASH readout, an isotropic in-plane spatial resolution of 1.4 x 1.4 mm(2) over 2.0 x 1.4 mm(2) could be achieved with a temporal resolution of 6 sec. The theoretical gain of spatial resolution by using the spiral pulse sequence and the performance in the presence of turbulent flow was evaluated in phantom measurements. Multiphase 3D CE-MRA of the renal arteries was performed in five healthy volunteers using both techniques. A deblurring technique was used to correct the spiral raw data. Thereby, the off-resonance frequencies were determined by minimizing the imaginary part of the data in image space. The chosen correction algorithm was able to reduce image blurring substantially in all MRA phases. The image quality of the spiral CE-MRA pulse sequence was comparable to that of the FLASH CE-MRA with increased spatial resolution and a 25% reduced contrast-to-noise ratio. Additionally, artifacts specific to spiral MRI could be observed which had no impact on the assessment of the renal arteries.

Adult↗

PubMed1990

The molecular evolution of bacterial alkaline phosphatase: correlating variation among enteric bacteria to experimental manipulations of the protein.

The phylogenetic distribution of the gene coding for bacterial alkaline phosphatase (phoA) was examined in nine species of enteric bacteria closely related to Escherichia coli. The nucleotide and protein sequences from the E. fergusonii and Serratia marcescens genes are presented. The spatial distribution of replaced amino acid residues in the aligned sequences is shown to be highly nonrandom and can be correlated with specific regions within the tertiary structure of the protein. There is an avoidance of replacements within the beta sheet of the protein, and there is an excess of replacements elsewhere, particularly in solvent-exposed residues. In addition, all positions across alpha helices do not accept replacements with equal frequency; there is a bias toward acceptance of replacements in the carboxyl ends of helices. To examine this further, mutations within the E. coli phoA gene were created using site-directed mutagenesis. The patterns seen from the sequence comparisons were verified in the laboratory-created mutants. The average activity of mutations within or near the beta sheet was approximately one-third of that within or near alpha helices, and multiple mutations within the carboxyl ends of alpha helices always possessed greater activity than did multiple mutations within the corresponding amino ends. The results indicate that identifiable regions within the protein are under different selective pressures and are therefore evolving at different rates.

Alkaline Phosphatase↗

PubMed1997

Cerebellar cognitive affective syndrome.

There has been persistent uncertainty as to whether lesions of the cerebellum are associated with clinically significant disturbances of behavior and cognition. To address this question, 20 patients with diseases confined to the cerebellum were studied prospectively over a 7-year period and the nature and severity of the changes in neurological and mental function were evaluated. Neurological examination, bedside mental state testing, neuropsychological studies, and anatomic neuroimaging were administered at the time of presentation and during follow-up assessments. Behavioral changes were clinically prominent in patients with lesions involving the posterior lobe of the cerebellum and the vermis and, in some cases, overwhelmed other aspects of the presentation. These changes were characterized by an impairment of working memory, planning, set shifting, verbal fluency, abstract reasoning, and perseveration; visual-spatial disorganization, visual memory deficits, and logical sequencing; and a bland or frankly inappropriate affect. Lesions of the anterior lobe of the cerebellum produced only minor changes in executive and visual-spatial functions. This newly defined clinical entity is called the cerebellar cognitive affective syndrome. The constellation of deficits is suggestive of disruption of the cerebellar modulation of neural circuits than link frontal, parietal, temporal, and limbic cortices with the cerebellum.

Adult↗

PubMed2002

Orientation dependent modulation of apparent speed: psychophysical evidence.

We report several experiments showing that a Gabor patch moving in apparent motion sequences appears much faster when its orientation is aligned with the motion path than when it is at an angle to it. This effect is very large and peaks at high speeds (64 degrees /s), decreases for higher and lower speeds and disappears at low speeds (4 degrees /s). This speed bias decreases as the angle between the motion axis and the orientation of the Gabor patch increases, but remains high for curvilinear paths, provided that element orientation is kept tangential to the motion trajectory. It is not accounted for by decision strategies relying on the overall length and duration of the motion sequence or the gap size (or spatial jump) between successive frames. We propose a simple explanation, thoroughly developed as a computational model in a companion paper (Seriès, Georges, Lorenceau & Frégnac: "Orientation dependent modulation of apparent speed: a model based on the dynamics of feedforward and horizontal connectivity in V1 cortex", this issue), according to which long-range horizontal connections in V1 elicit differential latency modulations in response to apparent motion sequences, whose read-out at an MT stage results in a perceptual speed bias. The consequences of these findings are discussed.

Analysis of Variance↗

PubMed1999

Ultrafast MR imaging of the pelvis.

MR gradient systems with higher slew rates and gradient amplitude enable certain forms of imaging that are not practical with older gradient systems. These newer pulse sequences include single shot half-Fourier T2-weighted images and echo planar imaging. More important in MR imaging of the pelvis, these gradient systems benefit more conventional imaging methods such as gadolinium-enhanced 3D MR angiography, dynamic gradient echo contrast-enhanced images, and T2-weighted fast spin echo images, by shortening echo times. For most MR imaging of the pelvis, spatial resolution is paramount, and therefore sequences such as half-Fourier acquisition Turbo spin echo (HASTE) and 3D gadolinium-enhanced dynamic imaging play a less important role than in the upper abdomen. The potential of these techniques for diffusion or perfusion studies in the pelvis has not been explored.

Contrast Media↗

PubMed1993

The P1 plasmid partition complex at parS. II. Analysis of ParB protein binding activity and specificity.

The P1 plasmid prophage is partitioned by a very high affinity protein complex at its partition site, parS, that contains the P1 ParB protein and Escherichia coli integration host factor (IHF). ParB binds to regions of parS that flank the IHF binding site. In this report, we have examined the sequences to which ParB binds, the spatial relationship between them, and the effect of IHF on ParB binding patterns. Methylation protection and interference experiments were performed on supercoiled plasmids. Mutations that interfered with the action of both proteins in vivo were identified following random mutagenesis of parS. These studies revealed that ParB binds to a complicated, nonsymmetrical region in the right side of parS. ParB recognizes a partial copy of this sequence, TCGCCA, in the left side of parS with much lower affinity. The presence of IHF greatly facilitates the interaction of ParB with parS such that both sides bind with an equal affinity that is much greater than to either side alone. The stimulation by IHF is strongly influenced by helical phasing. These observations support the proposal that ParB is directed, by the bend created by IHF, to bind simultaneously to properly placed sequences flanking the IHF site.

Bacterial Proteins↗

PubMed1997

Site-directed spin-labeling study of the structure and subunit interactions along a conserved sequence in the alpha-crystallin domain of heat-shock protein 27. Evidence of a conserved subunit interface.

Site-directed spin-labeling (SDSL) was used to investigate the secondary structure, solvent accessibility, and tertiary and quaternary interactions along the sequence located between residues 133 and 144 in the alpha-crystallin domain of human heat-shock protein 27 (HSP 27). The sequence is conserved among mammalian sHSP and shows similarity to the region of highest homology between alpha A- and alpha B-crystallins. Eleven sequential single cysteine mutants were prepared and reacted with a sulfhydryl-specific spin-label. The accessibilities of attached nitroxide side chains to a paramagnetic probe in the aqueous solution were determined. Spectral line shapes were analyzed in terms of side-chain mobility and spatial proximity to nearby nitroxides. The sequence-specific mobilities and accessibilities varied with a period of 2, consistent with the presence of a beta-strand along the sequence. At even sites, the nitroxide environment is highly ordered with virtually no accessibility to the hydrophilic probe, indicating that one face of the strand is buried. Furthermore, spin-spin interactions between nitroxides in the oligomeric structure strongly suggest that equivalent strands from different subunits are in close spatial proximity. These structural characteristics are remarkably similar to those of the equivalent sequence in alpha A-crystallin [Berengian, A. R., Bova, M. P., and Mchaourab, H. S. (1997) Biochemistry 36, 9951-9957]. In both proteins, a beta-strand spans the sequence and is located at a subunit interface, indicating that one set of interactions between subunits, and its associated symmetry, is conserved. This is the first report of sequence-specific structural similarity between alpha A-crystallin and HSP 27 and the first identification of a conserved secondary structural element in the alpha-crystallin domain.

Amino Acid Sequence↗