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PubMed2001

Genetic susceptibility to macrovascular complications of type 2 diabetes mellitus.

Patients with type 2 diabetes mellitus have a threefold increased risk of developing macrovascular disease such that 75% of such patients will die of cardiovascular complications. This increased risk is, however, not completely explained by traditional risk factors such as smoking, hypercholesterolaemia, hypertension and glycaemic control. Moreover, the fact that not all patients with type 2 diabetes develop these complications, together with evidence of family clustering (a heritability of 50%), suggests that a proportion of the susceptibility to ischaemic heart disease in type 2 diabetes may be genetic. Unravelling the polygenic susceptibility factors for the complications of a disease that itself has multifactorial inheritance has proved difficult and has focused largely on the candidate gene approach. A review of some of the studies testing candidate genes specifically in patients with both type 2 diabetes and ischaemic heart disease is presented. These studies focus largely on four main areas: lipoprotein metabolism, glycation and oxidation pathways, haemostatic cascade, and other candidate genes.

Diabetes Mellitus, Type 2↗

PubMed2005

Sindbis virus translation is inhibited by a PKR/RNase L-independent effector induced by alpha/beta interferon priming of dendritic cells.

The tropism of Sindbis virus (SB) for cells of the dendritic cell (DC) lineage and the virulence of SB in vivo are largely determined by the efficacy of alpha/beta interferon (IFN-alpha/beta)-mediated antiviral responses. These responses are essentially intact in the absence of PKR and/or RNase L (K. D. Ryman, L. J. White, R. E. Johnston, and W. B. Klimstra, Viral Immunol. 15:53-76, 2002). In the present studies, we investigated the nature of antiviral effects and identity of antiviral effectors primed by IFN-alpha/beta treatment of bone marrow-derived DCs (BMDCs) generated from mice deficient in PKR and RNase L (TD). IFN-alpha/beta priming exerted significant antiviral activity at very early stages of SB replication and most likely inhibited the initial translation of infecting genomes. The early effect targeted cap-dependent translation as protein synthesis from an SB-like and a simple RNA were inhibited by interferon treatment, but an encephalomyocarditis virus internal ribosome entry site-driven element exhibited no inhibition. Phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 was defective after virus infection of TD cells, suggesting other mechanisms of translation inhibition. To identify components of these alternative antiviral pathway(s), we have compared global gene regulation in BMDCs derived from normal 129 Sv/Ev, IFNAR1-/-, and TD mice following infection with SB or treatment with IFN-alpha/beta. Candidate effectors of alternative antiviral pathways were those genes induced by virus infection or IFN-alpha/beta treatment in 129 Sv/Ev and TD-derived BMDC but not in virus-infected or IFN-alpha/beta-treated IFNAR1-/- cells. Statistical analyses of gene array data identified 44 genes that met these criteria which are discussed.

ATP-Binding Cassette Transporters↗

PubMed1982

Evidence for a glycinergic cortico-lateral hypothalamic inhibitory pathway in the rat.

To determine the neurotransmitter involved in the frontal cortex (FC)-lateral hypothalamic (LHA) inhibitory pathway, the effects of transmitter candidates and their antagonists on FC-evoked inhibitions in LHA neurons were analyzed using multibarrel iontophoretic and extracellular recording methods. The result suggests that glycine is involved in this inhibitory pathway.

Animals↗

PubMed2025

Genomic analysis of Dasiphora on the Qinghai-Tibet Plateau provides insights into genetic divergence and flower color variation.

The Qinghai-Tibet Plateau (QTP) harbors diverse alpine flora, including the ecologically significant shrubs Dasiphora fruticosa and D. glabra, for which taxonomic uncertainties remain and adaptive mechanisms are still poorly understood. Based on high-quality genome assembly, population resequencing, and multi-omics integration, we elucidated their evolutionary divergence and flower color genetics. Chromosome-level haplotype-resolved genomes were assembled: autotetraploid D. fruticosa (929.99 Mb) and diploid D. glabra (450.89 Mb). Phylogenetic analysis showed that the tetraploid D. fruticosa and D. glabra in this study clustered together, while the diploid D. fruticosa sequenced by previous research formed a distinct lineage clustered outside. Consistently, population structure analysis of 55 samples revealed three major clades, with D. fruticosa further subdivided into two divergent branches. Additionally, hybridization events detected by Admixture, coupled with ploidy complexity identified via flow cytometry highlight the intricate genetic relationships within this genus. Adaptive gene families expanded in antioxidant (flavonoid synthesis) and secondary metabolism pathways, adapting to ultraviolet radiation and cold stress. Natural selection analysis identified 193 candidate genes (e.g., TFB5 in the DNA repair pathway), predominantly localized to chromosome 5, which are potential candidates for high-altitude adaptation. Transcriptome and metabolome analyses showed D. fruticosa's yellow petals derive from flavonol (quercetin) accumulation, while D. glabra's white petals result from proanthocyanidin biosynthesis via high LAR/ANR expression. This study provides insights into the taxonomic revision and adaptive genetic divergence of alpine plants, and offers a foundation for horticultural improvement of Dasiphora.

Flowers↗

PubMed2003

Signal transduction pathways in mast cell granule-mediated endothelial cell activation.

BACKGROUND: We have previously shown that incubation of human endothelial cells with mast cell granules results in potentiation of lipopolysaccharide-induced production of interleukin-6 and interleukin-8. AIMS: The objective of the present study was to identify candidate molecules and signal transduction pathways involved in the synergy between mast cell granules and lipopolysaccharide on endothelial cell activation. METHODS: Human umbilical vein endothelial cells were incubated with rat mast cell granules in the presence and absence of lipopolysaccharide, and IL-6 production was quantified. The status of c-Jun amino-terminal kinase and extracellular signal-regulated kinase 1/2 activation, nuclear factor-kappaB translocation and intracellular calcium levels were determined to identify the mechanism of synergy between mast cell granules and lipopolysaccaride. RESULTS: Mast cell granules induced low levels of interleukin-6 production by endothelial cells, and this effect was markedly enhanced by lipopolysaccharide. The results revealed that both serine proteases and histamine present in mast cell granules were involved in this activation process. Mast cell granules increased intracellular calcium, and activated c-Jun amino-terminal kinase and extracellular signal-regulated kinase 1/2. The combination of lipopolysaccharide and mast cell granules prolonged c-Jun amino-terminal kinase activity beyond the duration of induction by either stimulant alone and was entirely due to active proteases. However, both proteases and histamine contributed to calcium mobilization and extracellular signal-regulated kinase 1/2 activation. The nuclear translocation of nuclear factor-kappaB proteins was of greater magnitude in endothelial cells treated with the combination of mast cell granules and lipopolysaccharide. CONCLUSIONS: Mast cell granule serine proteases and histamine can amplify lipopolysaccharide-induced endothelial cell activation, which involves calcium mobilization, mitogen-activated protein kinase activation and nuclear factor-kappaB translocation.

Animals↗

PubMed2005

Genetic tests of biologic systems in affective disorders.

To liberate candidate gene analyses from criticisms of inexhaustiveness of examination of specific candidate genes, or incompleteness in the choice of candidate genes to study for specific neurobiological pathways, study of sizeable sets of genes pertinent to each putative pathophysiological pathway is required. For many years, genes have been tested in a 'one by one' manner for association with major affective disorders, primarily bipolar illness. However, it is conceivable that not individual genes but abnormalities in several genes within a system or in several neuronal, neural, or hormonal systems are implicated in the functional hypotheses for etiology of affective disorders. Compilation of candidate genes for entire pathways is a challenge, but can reasonably be carried out for the major affective disorders as discussed here. We present here five groupings of genes implicated by neuropharmacological and other evidence, which suggest 252 candidate genes worth examining. Inexhaustiveness of gene interrogation would apply to many studies in which only one polymorphism per gene is analyzed. In contrast to whole-genome association studies, a study of a limited number of candidate genes can readily exploit information on genomic sequence variations obtained from databases and/or resequencing, and has an advantage of not having the complication of an extremely stringent statistical criterion for association.

Bipolar Disorder↗

PubMed2003

Apoptosis, chemoresistance, and breast cancer: insights from the MCF-7 cell model system.

The MCF-7 cell line was derived from a patient with metastatic breast cancer in 1970. Since then it has become a prominent model system for the study of estrogen receptor-positive breast cancer. With this model as a focus, this review summarizes important studies addressing tumor necrosis factor-alpha as a prototypical apoptosis-inducing cytokine in MCF-7 cells. Both survival and death receptor signaling pathways are discussed in terms of their role in chemotherapy-induced apoptosis as well as in chemoresistance. Novel therapeutic approaches to the treatment of breast cancer are proposed utilizing knowledge of these signaling pathways as targets. Specifically, ceramide metabolism is proposed as a novel target for chemosensitivity, perhaps combined with selective inhibitors of Bcl-2 or PI3K/Akt/nuclear factor-kappaB. Suggested areas of future research include translational studies manipulating candidate survival and death signaling pathways.

Apoptosis↗

PubMed2004

Proteomic identification of Bcl2-associated athanogene 2 as a novel MAPK-activated protein kinase 2 substrate.

The p38 MAPK cascade is activated by various stresses or cytokines. Downstream of p38 MAPKs, there are diversification and extensive branching of signaling pathways. Fluorescent two-dimensional difference gel electrophoresis of phosphoprotein-enriched samples from HeLa cells in which p38 MAPK activity was either suppressed or activated enabled us to detect approximately 90 candidate spots for factors involved in p38-dependent pathways. Among these candidates, here we identified four proteins including Bcl-2-associated athanogene 2 (BAG2) by peptide mass fingerprintings. BAG family proteins are highly conserved throughout eukaryotes and regulate Hsc/Hsp70-mediated molecular chaperone activities and apoptosis. The results of two-dimensional immunoblots suggested that the phosphorylation of BAG2 was specifically controlled in a p38 MAPK-dependent manner. Furthermore, BAG2 was directly phosphorylated at serine 20 in vitro by MAPK-activated protein kinase 2 (MAPKAP kinase 2), which is known as a primary substrate of p38 MAPK and mediates several p38 MAPK-dependent processes. We confirmed that MAPKAP kinase 2 is also required for phosphorylation of BAG2 in vivo. Thus, p38 MAPK-MAPKAP kinase 2-BAG2 phosphorylation cascade may be a novel signaling pathway for response to extracellular stresses.

Electrophoresis, Gel, Two-Dimensional↗

PubMed2002

N-O glucuronidation: a major human metabolic pathway in the elimination of two novel anti-convulsant drug candidates.

1. The urinary metabolites of the anti-convulsant compound 4-amino-1-(2,6-difluorobenzyl)-1H-1,2,3-triazolo[4,5-c]-pyridine hydrochloride (GI265080) obtained following a single oral dose to man have been detected and quantified relative to each other using 19F-NMR spectroscopy. 2. The human urinary metabolites of GI265080 were isolated using semipreparative HPLC and unequivocally characterized using 1H-NMR spectroscopy, two-dimensional heteronuclear NMR spectroscopy and mass spectrometry. The assignments of the N-(5)-oxide and the N-(5)-O-glucuronide metabolites of GI265080 were further confirmed by independent synthesis. The urinary metabolites obtained following single oral doses to dog and rat have also been isolated and characterized. 3. The human urinary metabolites of GI265080 comprise the N-(5)-oxide, the quaternary N+-(5)-glucuronide, the 7-hydroxy glucuronide and a glucuronide conjugate of the N-(5)-oxide. The N-(5)-O-glucuronide conjugate is a novel species in human metabolism and is a significant route of elimination of GI265080 in man. 4. The urinary metabolites of the potential anti-convulsant GW273293 (6-amino-3-(2,3,5-trichlorophenyl)pyrazin-2-ylamine) obtained following a single oral dose to man have also been isolated and characterized. The formation of a novel N-O-glucuronide was also observed and was shown to constitute a significant route of elimination of GW273293 in man.

Animals↗

PubMedDate not supplied

Comparison of ultrasound, CT, and MR imaging in the evaluation of candidates for TIPS.

To compare ultrasound (US), CT, and MRI in the evaluation of hepatic vascular anatomy, portal and splenic venous flow, and collateral pathways (varices and spontaneous shunts) in candidates for transjugular intrahepatic portosystemic shunting (TIPS), 17 patients with history of refractory variceal bleeding or intractable ascites underwent duplex US, contrast-enhanced CT, and MRI before TIPS. The appearance of portal and hepatic anatomy was graded from 1 (not visible) to 4 (excellent visualization) independently by four radiologists. Presence and direction of portal and splenic venous flow, and presence and location of varices and spontaneous portosystemic shunts were also assessed. Results and effects of interobserver variation were assessed for significance using Friedman's ANOVA and Wilcoxon's signed-rank test. MRI yielded higher scores than CT or US for hepatic veins (P < .0001) and inferior vena cava (P < .0001). MRI and CT scored better than US for portal vein branches (P = .012) and splenic vein (P = .0038). All tests demonstrated the main portal vein well, with no statistically significant difference. US and MRI were more sensitive than CT for detecting portal vein flow and direction (US 76%, CT 0%, MRI 82%). MRI was most sensitive for splenic vein flow and direction (US 41%, CT 0%, MRI 76%). CT and MRI were more sensitive than US in detecting varices (US 5%, CT 50%, MRI 58%) and spontaneous shunts (US 13%, CT 75%, MRI 75%). Interobserver variation did not influence results significantly P = .3691). MRI provides the most useful information and may be the preferred single imaging test prior to TIPS.

Adolescent↗

PubMed1998

Analysis of epithelial-mesenchymal interactions in the initial morphogenesis of the mammalian tooth.

Epithelial-mesenchymal interactions govern the development of epidermal organs such as teeth. During the early stages of tooth development, a local ectodermal thickening which expresses several signaling molecules appears. It is believed that these in turn signal to the underlying mesenchyme triggering mesenchymal condensation and tooth development. For example, epithelially expressed Bmp4 induces Msx1 and Lef1 as well as itself in the underlying mesenchyme. In this paper we have investigated the role of four epithelial signaling molecules, Bmp2, Shh, Wnt10a, and Wnt10b, in the early inductive cascades that govern tooth development. We show that all four genes are specifically expressed in the epithelium between E11.0 and E12.0 when tooth morphogenesis is first apparent. Although Shh, Bmp2, and Wnt10b have similar, if not identical, expression patterns, each signal has a distinct molecular action on the jaw mesenchyme. Whereas Shh and Wnt10b can induce general Hedgehog and Wnt targets, Ptc and Gli for Shh and Lef1 for Wnt10b, only Bmp2 is able to induce tooth-specific expression of Msx1. Thus, there are distinct targets for all three pathways. Interestingly, both Bmp and Wnt signaling activate Lef1, making it a candidate for integrating the two distinct signaling pathways.

3T3 Cells↗

PubMed1997

Up-regulation of thymidine phosphorylase expression is associated with a discrete pattern of angiogenesis in ductal carcinomas in situ of the breast.

Angiogenesis is essential for tumour growth and metastasis. Although vascular density as a measure of angiogenesis is an important prognostic factor in invasive breast carcinoma, the mechanism of a switch to an angiogenic phenotype in ductal in situ breast carcinomas (DCIS) has yet to be identified. Nevertheless, two distinct vascular patterns have been reported in DCIS: a diffuse increase of stromal vascularity and a dense rim of microvessels close to the basement membrane of involved ducts. This suggests that tumour angiogenesis in invasive breast cancer arises from two different angiogenic pathways. Platelet-derived endothelial cell growth factor, now known to be thymidine phosphorylase (TP), is a candidate for initiating one of these pathways, since it is important in remodelling the existing vasculature through its chemotactic non-mitogenic properties and is expressed early in breast cancer development. The expression of TP was therefore examined in 75 formalin-fixed, paraffin-embedded specimens of DCIS by immunohistochemistry, using the monoclonal antibody PGF44c to detect TP. The results were correlated with blood vessel staining by polyclonal antibodies to von Willebrand factor (Factor VIII-related antigen, FVIIIrAg) and other clinicopathological variables. TP expression was nuclear and/or cytoplasmic and was observed in all subtypes of DCIS. High TP expression was demonstrated in 36 per cent (27/75) of tumours. This was not limited to the neoplastic cells, but was also present in stroma, endothelium, and tumour-associated macrophages. There was no correlation between high TP and DCIS subtype (P > 0.05). There was a significant correlation between TP expression and the presence of a dense vascular rim (P = 0.042; chi 2 = 4.1), but not with an increase in stromal vascularity (P = 0.800; chi 2 = 0.1). There was no significant correlation between tumour TP expression and relapse-free survival (P = 0.662; chi 2 = 0.2). These findings suggest that remodelling of the pre-existing vascular network induced by TP is important in generating a dense rim of microvessels around DCIS.

Adult↗

PubMed2003

Obesity--is it a genetic disorder?

Obesity is one of the most pressing problems in the industrialized world. Twin, adoption and family studies have shown that genetic factors play a significant role in the pathogenesis of obesity. Rare mutations in humans and model organisms have provided insights into the pathways involved in body weight regulation. Studies of candidate genes indicate that some of the genes involved in pathways regulating energy expenditure and food intake may play a role in the predisposition to obesity. Amongst these genes, sequence variations in the adrenergic receptors, uncoupling proteins, peroxisome proliferator-activated receptor, and the leptin receptor genes are of particular relevance. Results that have been replicated in at least three genome-wide scans suggest that key genes are located on chromosomes 2p, 3q, 5p, 6p, 7q, 10p, 11q, 17p and 20q. We conclude that the currently available evidence suggests four levels of genetic determination of obesity: genetic obesity, strong genetic predisposition, slight genetic predisposition, and genetically resistant. This growing body of research may help in the development of anti-obesity agents and perhaps genetic tests to predict the risk for obesity.

Environment↗

PubMed2026

Prenatal BPA exposure perturbs RNA-binding protein-mediated splicing regulation and synaptogenesis in the developing cerebellum in a sex-dependent manner.

BACKGROUND: Autism spectrum disorder (ASD) is a pervasive neurodevelopmental condition characterized by social communication deficits, exhibiting a male bias in prevalence. Emerging evidence suggests that prenatal exposure to bisphenol A (BPA) may perturb neurodevelopmental trajectories relevant to ASD. While the cerebellum is increasingly recognized as a brain region implicated in ASD pathophysiology, the impact of gestational BPA exposure on its post-transcriptional alternative splicing machinery remains fundamentally undefined. METHODS: Here, we investigated sex-dependent effects of prenatal BPA exposure on the alternative splicing landscape of the neonatal rat cerebellum. We utilized RNA-seq to profile differential alternative splicing (DAS) events. Ingenuity Pathway Analysis (IPA) was used to predict biological functions and canonical pathways, and to construct the interactome network of DAS genes. To explore candidate upstream regulatory mechanisms, we performed in silico molecular docking and used high-resolution melting (HRM) qRT-PCR to validate selected splicing events. Furthermore, we assessed in vitro cellular phenotypes in primary cerebellar neurons by measuring MTS-based viability and Syn1/Psd95 puncta colocalization. RESULTS: Prenatal BPA exposure was associated with widespread DAS in genes enriched for ASD-relevant pathways in the neonatal rat cerebellum. To our knowledge, this study is the first to report molecular docking analyses predicting favorable interactions between BPA and several candidate RNA-binding proteins (RBPs), including CPEB1, RALYL, HNRNPDL, and ACO1. Our findings support a model in which BPA may perturb RBP-associated splicing regulation, including altered splicing of chromatin regulators such as Ccar1 in males. These molecular and cellular findings were accompanied by sex-stratified differences in neuronal viability and synaptic puncta measurements. BPA exposure was associated with an increased MTS viability signal in male primary cerebellar neurons, together with significant reductions in Psd95 and Syn1 puncta density, whereas female neurons showed significantly increased synaptic puncta colocalization together with reduced viability. CONCLUSIONS: In this study, we propose that prenatal BPA may be relevant to ASD-related neurodevelopmental pathways through sex-dependent changes in RBP-associated alternative splicing, including altered splicing of Ccar1 in males, together with distinct cellular outcomes. Together, these findings identify the developing cerebellum as a sensitive target of prenatal BPA exposure and highlight alternative splicing as a candidate pathway relevant to ASD biology.

Animals↗

PubMed1995

Induction of a secondary embryonic axis in zebrafish occurs following the overexpression of beta-catenin.

Formation of the vertebrate axis may involve a Wnt signaling cascade similar to the Drosophila wingless pathway. Zebrafish wnt8 is a candidate for involvement in axis specification insofar as it is expressed maternally and when overexpressed it can induce goosecoid, a transcription factor normally expressed in the embryonic shield. In this study we demonstrate that beta-catenin, a cadherin associated protein in the Wnt pathway, is expressed maternally in zebrafish and is widely distributed in the early embryo. Overexpressing beta-catenin in early zebrafish embryos induces goosecoid and ntl, ultimately leading to a duplication of a complete secondary axis. These data are consistent with the involvement of beta-catenin in a Wnt signaling pathway which is involved in mesoderm induction in zebrafish.

Amino Acid Sequence↗

PubMed2003

Identification of four genes necessary for biosynthesis of the modified nucleoside queuosine.

Queuosine (Q) is a hypermodified 7-deazaguanosine nucleoside located in the anticodon wobble position of four amino acid-specific tRNAs. In bacteria, Q is produced de novo from GTP via the 7-deazaguanosine precursor preQ1 (7-aminoethyl 7-deazaguanine) by an uncharacterized pathway. PreQ1 is subsequently transferred to its specific tRNA by a tRNA-guanine transglycosylase (TGT) and then further modified in situ to produce Q. Here we use comparative genomics to implicate four gene families (best exemplified by the B. subtilis operon ykvJKLM) as candidates in the preQ1 biosynthetic pathway. Deletions were constructed in genes for each of the four orthologs in Acinetobacter. High pressure liquid chromatography analysis showed the Q nucleoside was absent from the tRNAs of each of four deletion strains. Electrospray ionization mass spectrometry confirmed the absence of Q in each mutant strain. Finally, introduction of the Bacillus subtilis ykvJKLM operon in trans complemented the Q deficiency of the two deletion mutants that were tested. Thus, the products of these four genes (named queC, -D, -E, and -F) are essential for the Q biosynthetic pathway.

Acinetobacter↗

PubMed2005

Activation pathways implicate anti-HLA-DP and anti-LFA-1 antibodies as lead candidates for intervention in chronic berylliosis.

CD4(+) T cells play a key role in granulomatous inflammation in the lung of patients with chronic beryllium disease. The goal of this study was to characterize activation pathways of beryllium-responsive bronchoalveolar lavage (BAL) CD4(+) T cells from chronic beryllium disease patients to identify possible therapeutic interventional strategies. Our results demonstrate that in the presence of APCs, beryllium induced strong proliferation responses of BAL CD4(+) T cells, production of superoptimal concentrations of secreted proinflammatory cytokines, IFN-gamma, TNF-alpha,and IL-2, and up-regulation of numerous T cell surface markers that would promote T-T Ag presentation. Ab blocking experiments revealed that anti-HLA-DP or anti-LFA-1 Ab strongly reduced proliferation responses and cytokine secretion by BAL CD4(+) T cells. In contrast, anti-HLA-DR or anti-OX40 ligand Ab mainly affected beryllium-induced proliferation responses with little impact on cytokines other than IL-2, thus implying that nonproliferating BAL CD4(+) T cells may still contribute to inflammation. Blockade with CTLA4-Ig had a minimal effect on proliferation and cytokine responses, confirming that activation was independent of B7/CD28 costimulation. These results indicate a prominent role for HLA-DP and LFA-1 in BAL CD4(+) T cell activation and further suggest that specific Abs to these molecules could serve as a possible therapy for chronic beryllium disease.

Antibodies, Monoclonal↗

PubMed1998

The gene for the human Src-like adaptor protein (hSLAP) is located within the 64-kb intron of the thyroglobulin gene.

In this study, we describe the molecular cloning and characterization of a Src-like adaptor protein gene embedded within the genomic organization of the human thyroglobulin (Tg) gene. This gene was identified by exon trapping on overlapping cosmids encompassing the largest Tg intron. A 2.6-kb transcript, with the highest levels of expression in fetal brain and lung, was detected on Northern blots. Two full-length cDNAs (one alternatively spliced) were isolated from a fetal brain library, both containing an open reading frame of 276 amino acids, but lacking a catalytic tyrosine kinase domain. The gene shows a high degree of cross-species similarity and appears to be transcribed in the direction opposite to Tg. This gene, designated hslap, appears to be the human ortholog of the recently described gene for the murine Src-like adaptor protein (mSLAP), a candidate intermediate in the signal-transduction pathway of the Eck receptor tyrosine kinase. Human slap is located in the candidate region for a recessive demyelinating neuropathy on chromosome 8q24, but sequence analysis failed to identify mutations, suggesting that it is not the gene for this disease.

Adaptor Proteins, Signal Transducing↗