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PubMed1995

Orthotic management for children with osteogenesis imperfecta.

Fitting children and infants who have osteogenesis imperfecta (OI) with braces has posed substantial problems of implementation and patient management For the past twelve years bracing has been an important component of a patient research and management program conducted at the National Institutes of Health. By using the smallest manufactured parts and developing a wealth of experience, functional and well-fitting braces have been provided to a number of tiny and small children. Bracing allows these children to stand and walk earlier than would have otherwise been possible. Braces are used in conjunction with standing frames and parapodiums to increase a child's mobility. Less involved children have become good household and short distance ambulators with the use of braces.

Child↗
PubMed1991

Effect of circulating factors on vascular smooth muscle contraction and its calcium uptake in uremia.

Uremia is often associated with alterations in calcium metabolism and vascular smooth muscle function in hypertension and atherosclerosis. The ways in which these conditions inter-relate are not clearly understood. In order to study the possibility that circulating factors might influence smooth muscle function, experiments were performed on rat aortic strips. The serum from both uremic patients and rats enhanced the norepinephrine-induced contraction (NEIC) and net 45-calcium uptake in rat aortic strips. In a similar manner, the serum of parathyroidectomized uremic rats also increased the NEIC, whereas verapamil reduced the aortic response to levels below those of the control, in the presence of uremic serum. These findings suggest that in both chronic (patients) and early (rats) stages of uremia, there is a circulating factor, different from parathyroid hormone, that affects calcium uptake and vascular smooth muscle contraction.

Adult↗
PubMed2026

SSB deficiency-induced R-loop accumulation triggers podocyte inflammation in DKD.

INTRODUCTION: Diabetic kidney disease (DKD) is fundamentally a podocytopathy in which sterile inflammation plays a central pathogenic role, yet the upstream triggers that initiate inflammatory cascades in podocytes remain elusive. R-loops are critical regulators of genomic stability, and their pathological accumulation triggers DNA damage and innate immune activation. Whether R-loop dysregulation contributes to podocyte-driven inflammation in DKD is unknown. METHODS: We integrated single-cell transcriptomic profiling, dual machine learning algorithms, and functional experiments to dissect the R-loop regulatory network in the diabetic kidney. RESULTS: Integrated analysis of human diabetic kidney single-cell RNA-seq data revealed a globally compromised R-loop regulatory network selectively within podocytes. Intersection of podocyte-specific transcriptomic shifts with validated R-loop regulators identified 93 candidate genes, from which dual machine learning algorithms pinpointed SSB (Sjögren syndrome antigen B) as the principal podocyte-selective R-loop resolver and a superior diagnostic biomarker (AUC = 0.983). SSB expression was selectively downregulated in diabetic podocytes and showed the strongest positive correlation with the R-loop resolution module. Mechanistically, SSB loss impaired RNA splicing and stability pathways, leading to aberrant R-loop accumulation that activated the cGAS-dependent inflammatory signaling in podocytes. In two murine DKD models and high glucose-challenged podocytes, SSB was markedly reduced. Remarkably, SSB knockdown in podocytes alone sufficed to trigger R-loop accumulation and pro-inflammatory cytokine expression, whereas both RNase H1-mediated R-loop removal and cGAS co-depletion blunted this response. DISCUSSION: These findings suggest that an SSB-governed R-loop -cGAS -inflammatory signaling axis may link genomic instability to podocyte inflammation and contribute to DKD progression, nominating R-loop homeostasis as a previously unrecognized potential therapeutic target.

Podocytes↗
PubMed2026

Efferocytosis related KCTD12 is a clinico-immune target in lung adenocarcinoma.

BACKGROUND: Efferocytosis, the clearance of apoptotic cells by phagocytes, contributes to immune homeostasis but may also promote tumor immune tolerance. However, its transcriptional landscape and clinical relevance in lung adenocarcinoma (LUAD) remain incompletely understood. METHODS: We systematically analyzed efferocytosis-associated genes across TCGA and multiple GEO datasets to classify LUAD subtypes and construct a prognostic risk model. The prognostic and immunological relevance of this model was validated in four independent cohorts and further assessed through immune infiltration, genomic, and immunotherapy datasets. Functional and pharmacogenomic analyses were performed to identify potential therapeutic vulnerabilities, and the efferocytosis-associated signature gene KCTD12 was subsequently validated in vitro. RESULTS: Unsupervised clustering identified two efferocytosis-based LUAD subtypes with distinct prognostic and immune-metabolic characteristics. The derived risk model robustly predicted overall survival across validation cohorts. Among the model genes, KCTD12 emerged as an efferocytosis-associated candidate linked to an immune-active tumor microenvironment. Across the analyzed single-cell, spatial transcriptomic, and immunotherapy-treated cohorts, higher KCTD12 expression was associated with enhanced cytotoxic T-cell activity and more favorable treatment outcomes. Functional experiments confirmed that KCTD12 suppresses tumor cell proliferation, reduces colony formation, and enhances OT-1 CD8+ T-cell activation and cytotoxicity. CONCLUSIONS: Our study identifies an efferocytosis-associated transcriptional program linked to immune heterogeneity and prognosis in LUAD. The efferocytosis-related risk signature provides a framework for prognostic and immune stratification, while KCTD12 represents a candidate biomarker associated with immune activation and clinical outcomes in immunotherapy-treated cohorts. Its treatment-specific predictive value requires prospective validation in appropriately controlled studies.

KCTD12↗
PubMed2026

Mechanism of Action of Hedyotis diffusa Extract in a Rat Model of Acute Lung Injury Based on Transcriptomic Analysis.

OBJECTIVE: This study established a rat model of lipopolysaccharide (LPS)-induced acute lung injury (ALI) to evaluate pathological damage, collagen deposition, inflammatory cytokine levels, and key gene/protein expression following Hedyotis diffusa water extract (HDWE) intervention. Combined with ultra-high-performance liquid chromatography-quadrupole Orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS), transcriptomic analysis, and molecular simulation, this study identified the bioactive components of HDWE, evaluated their potential interactions with ALI-related targets, and explored the multi-omics-based protective mechanisms of HDWE. METHODS: Thirty-six Sprague-Dawley (SD) rats were randomly divided into six groups: Control group, ALI group, DXMS group, HDWE-L group (100 mg/kg), HDWE-M group (200 mg/kg), and HDWE-H group (300 mg/kg). Hematoxylin and eosin (H&E) and Masson's trichrome staining were used to evaluate lung pathological changes and collagen deposition. Enzyme-linked immunosorbent assay (ELISA) was used to measure serum tumor necrosis factor-α TNF-α interleukin-1β IL-1β, erleukin-6 (IL-6), and interleukin-10 (IL-10) levels. Transcriptomic analysis identified differentially expressed genes (DEGs), followed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), receiver operating characteristic (ROC), and immune infiltration analyses. Quantitative real-time polymerase chain reaction (qRT-PCR) detected the mRNA expression levels of SPHK1, RELA, and NFKBIA. Immunohistochemistry evaluated the expression of eight hub targets, including endothelin-1 (EDN1), sphingosine kinase 1 (SPHK1), intercellular adhesion molecule 1 (ICAM1), interleukin-17 (IL-17), prostaglandin-endoperoxide synthase 2 (PTGS2/COX-2), NF-κB p65 (encoded by RELA), WT1-associated protein (WTAP), and myeloperoxidase (MPO). UHPLC-Q-Orbitrap HRMS characterized HDWE constituents. Molecular docking analysis was performed between 22 compounds and eight hub targets, followed by 100 ns molecular dynamics simulations and molecular mechanics-Poisson-Boltzmann surface area (MM/PBSA) binding free energy calculations for five core targets. Compared with the control group, the ALI group showed increased levels of TNF-α (86%), IL-1β (107%), and IL-6 (66%), accompanied by a 43% reduction in IL-10 and a 300% increase in lung collagen deposition. All HDWE doses alleviated inflammatory responses, with medium-dose HDWE showing the most pronounced effects. Specifically, medium-dose HDWE increased IL-10 levels by 52% and reduced IL-6, TNF-α, and IL-1β levels by 18%, 22%, and 11%, respectively. Transcriptomic analysis identified 2512 DEGs between the control group and ALI groups, 832 exclusive DEGs between the ALI group and HDWE-M groups, and 876 overlapping DEGs enriched in TNF, IL-17, and NF-κB signaling pathways. The eight-hub-gene diagnostic model achieved an area under the curve (AUC) of 0.969. RELA, SPHK1, and four other hub genes showed positive correlations with Th1, Th17, and neutrophil infiltration. In the ALI group, SPHK1, RELA, and NFKBIA mRNA expression levels were 1.30-, 0.96-, and 0.71-fold of those in the control group, respectively. Compared with the ALI group, high-dose HDWE treatment and low-dose HDWE treatment reduced SPHK1 expression to 0.62- and 0.57-fold, respectively, and increased NFKBIA expression to 1.68- and 1.58-fold, respectively. High-dose HDWE treatment reduced RELA expression to 0.43-fold. The expression levels of inflammation-related proteins were increased in the ALI group and were reduced after HDWE treatment. Twenty-two HDWE components were identified, 16 of which met the docking criteria. Asperulosidic acid exhibited favorable predicted binding affinities with all eight targets, with calculated binding free energies of -14.74, -14.92, -17.58, -23.04, and -16.10 kcal/mol for MPO, IL-17, NF-κB p65, PTGS2/COX-2, and SPHK1, respectively. CONCLUSIONS: This study provides systematic in vivo pharmacodynamic and in silico component-target evidence regarding the protective effects of HDWE against LPS-induced ALI. HDWE treatment increased NFKBIA expression and reduced SPHK1, RELA, and multiple inflammatory protein levels, suggesting that HDWE may regulate the IL-17/NF-κB-associated inflammatory network, although direct causal relationships require further validation. Asperulosidic acid may represent a key bioactive component with broad target-binding potential. This study was limited by the use of an LPS-induced rat ALI model without gene knockout or target inhibitor validation; therefore, further functional experiments are required to confirm the proposed regulatory mechanisms.

Hedyotis diffusa↗
PubMed1990

An examination of the continuous distractor task and the "long-term recency effect".

The continuous distractor task has yielded a so-called "long-term recency effect" that appears to call into question the dual-storage explanation of serial position effects in free recall. In this study, we show that the "long-term recency effect" is really a short-term storage effect, resulting from adaptation to the repeated presentation of a particular type of distractor throughout the list. This adaptation, a time-sharing process, permits short-term storage to carry out its normal functions. Experiment 1 shows that an appropriate postlist distractor task does in fact eliminate the "long-term recency effect." This finding supports the assertion that the effect is a product of short-term storage. Experiment 2 demonstrates the benefits and costs of the time-sharing process, relative to standard free recall, for both long-term and short-term storage. The findings support the time-sharing hypothesis. Experiment 3 replicates Experiment 2, with a change in procedure that rules out output interference as a mechanism responsible for the results of Experiment 2. Data are also presented on the development of the adaptation over trials. It is concluded that the adaptation and time-sharing processes need to be included in the dual-storage model of short-term storage.

Adult↗
PubMed2026

Placenta-derived Exosomes Mitigate Hypoxia-Induced Trophoblast Apoptosis and Inflammatory Progression via SASH1.

SASH1 is a signal adaptor protein involved in cell growth, apoptosis, and immune regulation, and has been increasingly studied in tumor and immune cells. Emerging evidence suggests that SASH1 plays an important role in inflammatory responses and cellular homeostasis, processes that are closely associated with the development of PE. This study aimed to determine whether SASH1 contributes to trophoblast apoptosis and inflammatory responses in PE and whether P-EXOS exerts protective effects through SASH1 regulation. In this study, three PE-related transcriptomic datasets (GSE75010, GSE10588, and GSE60438) were analyzed to identify shared differentially expressed genes (DEGs), followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Machine learning algorithms were further applied to screen key candidate genes, and single-cell RNA sequencing data were used to characterize cellular heterogeneity in placental tissue and to determine cell type-specific expression patterns. SASH1 was identified as a consensus candidate gene and was significantly upregulated in trophoblast cells from PE samples. In vitro, a hypoxia-treated HTR-8/SVneo trophoblast cell model was established, combined with SASH1 knockdown, SASH1 overexpression, and co-culture with P-EXOS. Functional experiments showed that knockdown of SASH1 significantly suppressed hypoxia-induced trophoblast apoptosis and reduced the secretion of pro-inflammatory cytokines, including IL-6, IL-1β, and TNF-α, whereas SASH1 overexpression promoted apoptosis and inflammatory responses. In addition, P-EXOS treatment markedly reduced SASH1 expression at both mRNA and protein levels and attenuated hypoxia-induced trophoblast injury, while SASH1 overexpression largely abolished these protective effects. Taken together, these findings indicate that SASH1 plays a critical role in trophoblast apoptosis and inflammatory responses in PE. P-EXOS may alleviate hypoxia-induced trophoblastic injury by suppressing SASH1 expression, providing new insights into the molecular mechanisms and potential therapeutic targets for PE.

Trophoblasts↗
PubMed2004

Transient and selective NF-kappa B p65 serine 536 phosphorylation induced by T cell costimulation is mediated by I kappa B kinase beta and controls the kinetics of p65 nuclear import.

Full transcriptional activity of the nuclear, DNA-bound form of NF-kappaB requires additional posttranslational modifications. In this study, we systematically mapped the T cell costimulation-induced phosphorylation sites within the C-terminal half of the strongly trans-activating NF-kappaB p65 subunit and identified serine 536 as the main phosphorylation site. The transient kinetics of serine 536 phosphorylation paralleled the kinetics of IkappaBalpha and IkappaB kinase (IKK) phosphorylation and also mirrored the principle of T cell costimulation. The TCR-induced pathway leading to serine 536 phosphorylation is regulated by the kinases Cot (Tpl2), receptor interacting protein, protein kinase Ctheta, and NF-kappaB-inducing kinase, but is independent from the phosphatidylinositol 3-kinase/Akt signaling pathway. Loss-of-function and gain-of-function experiments showed phosphorylation of p65 serine 536 by IKKbeta, but not by IKKalpha. Phosphorylation occurs within the cytoplasmic and intact NF-kappaB/IkappaBalpha complex and requires prior phosphorylation of IkappaBalpha at serines 32 and 36. Reconstitution of p65(-/-) cells either with wild-type p65 or a p65 mutant containing a serine to alanine mutation revealed the importance of this phosphorylation site for cytosolic IkappaBalpha localization and the kinetics of p65 nuclear import.

Active Transport, Cell Nucleus↗
PubMed2004

Constitutive expression of CCR7 directs effector CD8 T cells into the splenic white pulp and impairs functional activity.

Antigenic stimulation down-regulates CCR7 on effector T cells. To analyze the importance of CCR7 down-regulation, transgenic (tg) mice constitutively expressing CCR7 were generated. CD8 T cells with defined Ag specificity were obtained by breeding CCR7-tg mice with P14 TCR-tg mice specific for lymphocytic choriomeningitis virus. Transgenic CCR7 expression did not impair proliferation of P14.CCR7 T cells induced by lymphocytic choriomeningitis virus infection, but prevented CCR7 down-regulation. Compared with wild-type P14 effector cells, P14.CCR7 effector cells, expressing the CCR7 transgene, were increased in the spleen, but decreased in blood and peripheral tissues. Moreover, P14.CCR7 effector cells localized almost exclusively in the splenic white pulp, whereas P14 effector cells were excluded from splenic white pulp cords and were found preferentially in the red pulp. Functional experiments further revealed that P14.CCR7 effector cells were impaired in rapid viral clearance and in inducing Ag-specific delayed-type hypersensitivity reactions. Thus, the present study demonstrates that down-regulation of CCR7 during CD8 T cell activation is important to release effector cells from the white pulp of the spleen, and highlights the importance of effector cell localization in providing rapid immunity.

Animals↗
PubMed2002

New insights to the functional role of the T cell-antigen presenting cell immunological synapse.

Three innovative and complementary morphological approaches were employed to study the T cell/antigen presenting cell (APC) interaction: (i) high resolution three-dimensional confocal microscopy of the T cell-APC contact site; (ii) time lapse video recording in living T cells of [Ca2+]I and changes in distribution of various GFP fusion proteins with TCR/CD3-zeta complex associated- and other signaling components; (iii) measurement of lateral TCR mobility and that of recruited signaling components using techniques based on fluorescence recovery after photo-bleaching. These approaches were combined with biochemical and functional experiments to investigate two principal issues: (A) Recruitment and the three-dimensional arrangement of receptors and signaling components at the contact site between human CD4+ T lymphocytes and APCs, (B) Structure of the immunological synapse formed at the contact site between cytotoxic T lymphocytes (CTLs) and target cells. We discuss evidence indicating that TCR engagement and triggering can occur in the absence of large-scale molecular segregation into the T cell-APC contact site. Taken together our results indicate that although not required for TCR engagement and triggering, formation of the IS is important to reinforce TCR-mediated signal transduction and achieve full T cell activation.

Animals↗
PubMed1999

Ex-chiral pool synthesis and pharmacological aspects of 3-pyrrolidinylisoxazoles.

Employing the dopamine autoreceptor agonist (-)-3-PPP (3) as well as the cholinergic receptor ligands 4 and 5 as lead compounds the 3-pyrrolidinylisoxazoles 2a,b as well as its optical antipodes ent 2a,b were synthesized from (R)-aspartic acid (6) and (S)-aspartic acid (ent-6), respectively. Pharmacological properties of the target compounds were evaluated employing dopamine D2 receptor binding studies and functional experiments on muscarinic M2 receptors.

Animals↗
PubMedDate not supplied

Effects of oxamate, an inhibitor of lactate dahydrogenase, upon the spontaneous or oxytocin-induced motility and over pyruvate levels of uterine horns isolated from ovariectomized or estrus rats.

The stability with time of the spontaneous as well as the oxytocin-triggered functional activity of uterine borns isolated from induced estrus rats and immersed in a medium with lactate as the substrate was not affected by the presence of oxomate (an inhibitor of lactate dehydrogenase) at 10 or 20mM. On the contrary, the oxytocin-driven and the spontaneous motility of preparations obtained from 15 days castrated rats diminished significantly following in addition of the enzyme inhibitor. Furthermore, uterine borns from ovariectomized animals injected with 17-beta estradiol, regain the lack of functional sensivity towards oxamate. In addition, determinations of pyruvate levels in homogenates of uterine tissue, previously suspended in lactate medium (as in the functional experiments), demonstrate to be significantly reduced, following oxamate. Several possible reasons, attempting to explain these findings, are discussed.

Amino Acids↗
PubMed1999

Middle ear defects associated with the double knock out mutation of murine goosecoid and Msx1 genes.

A number of developmental regulatory genes, including homeobox genes, are dynamically expressed in the mammalian cephalic ectomesenchyme during craniofacial morphogenesis. Owing to the vast amount of gene knock out experiments, functions of such genes are now being revealed in the mammalian skeletal patterning process. The murine goosecoid (Gsc) and Msx1 genes are expressed during craniofacial development and each mutant mouse displays intriguing facial abnormalities including those of middle ear ossicles, suggesting that both genes play roles in spatial programming of craniofacial regions. In order to examine whether these genes could function in concert to direct particular craniofacial morphogenesis, double knock out mice were analyzed. The phenotype of the double mutant mice was restricted to the first arch derivatives and was apparently additive of the single gene mutant mice, implying region specific genetic interactions of these homeobox genes expressed in overlapping regions of middle ear forming ectomesenchyme. Our results also suggested that the patterning of distal portions of the malleus depends on the tympanic membrane, for which normal expressions of both the genes are prerequisite.

Animals↗
PubMed1999

Alpha(1)-adrenoceptor subtypes mediating inotropic responses in rat heart.

We studied the distribution of alpha(1)-adrenoceptor subtypes by radioligand binding assays using (125)I-labeled 2-beta(4-hydroxyphenyl)-ethylaminomethyl)-tetralone (BE2254) and RNase protection assays, and determined the role of each subtype in mediating the inotropic response in rat heart. Chlorethylclonidine preincubation causes a approximately 72% decrease in the maximal binding capacity (B(max)). On the other hand, protection from phenoxybenzamine alkylation by 5-methyl-urapidil or BMY7378 decreased B(max) by 59 and 70%. By competitive inhibition, we have identified 19 to 28% and 30% high-affinity binding sites for the alpha(1A)- and alpha(1D)-selective antagonists in rat ventricles, with the alpha(1B)-adrenoceptor estimated as 45%. Consistent with the receptor-binding result, a similar distribution of mRNAs encoding alpha(1A), alpha(1B,) and alpha(1D) (22, 39, and 39%), based on RNase protection assays, was observed. In addition, we demonstrated that the noradrenaline response through alpha(1)-adrenoceptor was antagonisted by 5-methyl-urapidil, RS-17053, BMY7378, and WB4101 in contraction functional experiments. K(I) values for the above compounds were defined for all three alpha(1)-adrenoceptor subtypes expressed in the human embryonic kidney 293 cell stably, and were further compared with the corresponding pA(2) values. Interestingly, the correlation was significantly higher for alpha(1A) (r(2) = 0.73) and alpha(1B) (r(2) = 0.66) than alpha(1D) (r(2) = 0.35) in these experiments. Because the potential of alpha(1D) measured to be 21% based on protection from phenoxybenzamine-caused inhibition by BMY7378, the combined potential of alpha(1A) and alpha(1B) can be estimated as approximately 80%. Taken together, these results suggest that the three alpha(1)-adrenoceptor subtypes coexist in rat heart, with alpha(1A) and alpha(1B) playing a more prominent role in the positive inotropic response to noradrenaline.

Adrenergic alpha-Agonists↗
PubMed2000

Cyclooxygenase-2 is highly expressed in microglial-like cells in a murine model of prion disease.

Prion diseases, or transmissible spongiform encephalopathies, are a relatively rare group of chronic degenerative disorders afflicting both animals and humans, characterized by typical histopathological signs such as amyloid deposition, neuronal loss and spongiform changes. Despite the absence of a typical acute inflammatory response, the consistent microglial activation and astrocytosis, that are found in human pathologies as well as in animal models, suggests the existence of an ongoing inflammatory response in these neurodegenerative diseases. To investigate the role of cyclooxygenase-2 (COX-2) activity in the pathogenesis of chronic neurodegenerative diseases, we studied immunohistochemically the expression of this key enzyme in the formation of prostaglandins during inflammatory responses in a well characterized murine model of prion disease. We found that COX-2 is selectively up-regulated in glial cells presenting the typical morphology of activated microglia and that the number of COX-2-positive cells increases with the progression of the disease. The extensive microglial expression of COX-2, that is likely to be followed by a sustained enzymatic activity leading to the generation of prostaglandins as well as of oxygen free radicals, might have important effects on chronic neurodegeneration. Further functional experiments are required to elucidate the role of COX-2 activity in the pathogenesis of chronic neurodegenerative diseases.

Animals↗
PubMedDate not supplied

[The affinity of m-cholinomimetics for the m-cholinoreceptors in different tissues].

The affinities of some cholinomimetics (acetylcholine, methacholine, carbachol, oxotremorine, aceclidine and pilocarpine) for muscarinic acetylcholine receptors of various isolated tissues (rat spontaneously beating atria, rat electrically stimulated left atrium, segment of rat aorta precontracted by PGF2 alpha, rat trachea and guinea pig trachea) was estimated in functional experiments. It was established that each of full agonists (acetylcholine, methacholine, carbachol, oxotremorine and aceclidine) has lower affinities for muscarinic M2 receptors of rat atria as compared with its affinity for muscarinic M3 receptors of rat aorta. The partial agonist pilocarpine has similar affinities for muscarinic receptors of rat atria and rat aorta. It was shown that contractile response of guinea pig tracheal smooth muscle is two-staged. It was found that rat and guinea pig tracheal smooth muscle contractions are mediated primarily by muscarinic M3 cholinoceptors and partially by M2 cholinoceptors.

Animals↗
PubMed2000

Dissociable neural responses in human reward systems.

Reward is one of the most important influences shaping behavior. Single-unit recording and lesion studies in experimental animals have implicated a number of regions in response to reinforcing stimuli, in particular regions of the extended limbic system and the ventral striatum. In this experiment, functional neuroimaging was used to assess neural response within human reward systems under different psychological contexts. Nine healthy volunteers were scanned using functional magnetic resonance imaging during the performance of a gambling task with financial rewards and penalties. We demonstrated neural sensitivity of midbrain and ventral striatal regions to financial rewards and hippocampal sensitivity to financial penalties. Furthermore, we show that neural responses in globus pallidus, thalamus, and subgenual cingulate were specific to high reward levels occurring in the context of increasing reward. Responses to both reward level in the context of increasing reward and penalty level in the context of increasing penalty were seen in caudate, insula, and ventral prefrontal cortex. These results demonstrate dissociable neural responses to rewards and penalties that are dependent on the psychological context in which they are experienced.

Brain↗
PubMed2000

The architectural transcription factor high mobility group I(Y) participates in photoreceptor-specific gene expression.

The nonhistone chromosomal proteins high mobility group I(Y) [HMG I(Y)] have been shown to function as architectural transcription factors facilitating enhanceosome formation on a variety of mammalian promoters. Specifically, they have been shown to act as a "molecular glue" mediating protein-protein and protein-DNA contacts within the enhanceosome complex. HMG I(Y) proteins are expressed at high levels in embryonic and transformed cells and have been implicated in transcriptional regulation in these cells. Terminally differentiated cells, however, have been reported to express only minimal, if any, HMG I(Y). In contrast to these observations, we show here that adult mouse retinal photoreceptors, which are terminally differentiated cells, express high levels of these proteins. Using retinoblastoma cells as an approximate model, we further demonstrate in transiently transfected cells that inhibition of HMG I(Y) expression and mutation of HMG I(Y) binding sites significantly reduce rhodopsin promoter activity. DNase I footprint analysis indicates that HMG I protein interacts with a discrete site within the rhodopsin proximal promoter. This site overlaps with the binding site for Crx, a paired-like homeodomain transcription factor that is essential for photoreceptor functioning and that when mutated causes several forms of human photoreceptor degeneration. Both biochemical and functional experiments demonstrate that HMG I(Y) physically associate with Crx and that their interaction with DNA is required for high-level transcription of the rhodopsin gene. These data provide the first demonstration that HMG I(Y) can be important for gene activation in terminally differentiated cells.

Animals↗