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Y Xiong

Publications and source records attributed to Y Xiong.

At least 109 records · Page 6Linked to original sources
PubMed1998

The expressed alpha domain of mouse metallothionein-I from Escherichia coli displays independent structure and function.

The alpha domain of mouse metallothionein-I (mMT-I) was expressed in E. coli as a C-terminus of the 26 KD glutathione-S-transferase and purified from the cell lysates. The amino acid composition and molecular weight of the expressed protein are as expected. The metal-binding stoichimetry was determined to show that divalent metals bind to the expressed alpha domain at the desired ratio of 4:1. The ultraviolet absorbance, circular dichroism spectra and the atomic force microscopy indicate that it can form the proper metal-thiolate structure as in the whole MT molecule. The apparent affinity of the expressed alpha domain to bind cadmium is 1.8-fold stronger than the recombinant mMT-I when detected by the reaction with DTNB. The ability to scavenge hydroxyl free radicals remains higher than the whole MT molecule. All the results demonstrate that the expressed alpha-domain from E. coli exhibits independent biochemical and physiological structure/function without the assistance of beta domain.

Amino Acids↗
PubMed1998

Mitochondrial dysfunction after experimental traumatic brain injury: combined efficacy of SNX-111 and U-101033E.

We recently demonstrated that posttraumatic administration of the N-type calcium channel blocker SNX-111 (S) and a novel blood-brain barrier penetrating antioxidant U-101033E (U), significantly alleviated mitochondrial dysfunction induced by traumatic brain injury (TBI) in rats. The present study was designed to determine whether a combination of S and U, which act on different biochemical mechanisms of secondary brain injury, would be more efficacious than either drug alone. Brain mitochondria from injured and uninjured hemispheres were isolated and examined at 12 h post TBI induced by a severe controlled cortical impact injury. S at 1.0 mg/kg significantly increased both State 3 and 4 rates and produced a slight increase in P/O ratio, and there was virtually no change in RCI. U at 1.0 mg/kg did not show any protection. However, the combined treatment of S at 1.0 mg/kg and U at 1.0 mg/kg eliminated the uncoupling effect of S, and restored not only State 3 rates and P/O ratios but also RCI to near sham values. These results provide further evidence that both reactive oxygen species and perturbation of cellular calcium homeostasis participate in the pathogenesis of TBI-induced mitochondrial dysfunction, and support the idea of using combined therapy with lower drug doses.

Analysis of Variance↗
PubMed1998

Coupled transcriptional and translational control of cyclin-dependent kinase inhibitor p18INK4c expression during myogenesis.

Terminal differentiation of many cell types involves permanent withdrawal from the cell division cycle. The p18INK4c protein, a member of the p16/INK4 cyclin-dependent kinase (CDK) inhibitor family, is induced more than 50-fold during myogenic differentiation of mouse C2C12 myoblasts to become the predominant CDK inhibitor complexed with CDK4 and CDK6 in terminally differentiated myotubes. We have found that the p18INK4c gene expresses two mRNA transcripts--a 2.4-kb transcript, p18(L), and a 1.2-kb transcript, p18(S). In proliferating C2C12 myoblasts, only the larger p18(L) transcript is expressed from an upstream promoter. As C2C12 cells are induced to differentiate into permanently arrested myotubes, the abundance of the p18(L) transcript decreases. The smaller p18(S) transcript expressed from a downstream promoter becomes detectable by 12 h postinduction and is the predominant transcript expressed in terminally differentiated myotubes. Both transcripts contain coding exons 2 and 3, but p18(L) uniquely contains an additional noncoding 1.2-kb exon, exon 1, corresponding exclusively to the 5' untranslated region (5' UTR). The expression pattern of the shorter p18(S) transcript, but not that of the longer p18(L) transcript, correlates with terminal differentiation of muscle, lung, liver, thymus, and eye lens cells during mouse embryo development. The presence of the long 5' UTR in exon 1 attenuated the translation of p18(L) transcript, while its absence from the shorter p18(S) transcript resulted in significantly more efficient translation of the p18 protein. Our results demonstrate that during terminal muscle cell differentiation, induction of the p18 protein is regulated by promoter switching coupled with translational control.

3T3 Cells↗
PubMed1998

Human CUL-1, but not other cullin family members, selectively interacts with SKP1 to form a complex with SKP2 and cyclin A.

The budding yeast gene product, CDC53p, forms E3-like SCF complexes with SKP1 and F-box-containing proteins to mediate the ubiquitin-dependent degradation of G1 cyclins and cyclin-dependent kinase (CDK) inhibitors. Cdc53 represents a multigene family, the human homologues of which, the cullin family, include at least six distinct members. We have found that human cullin 1, but not the other closely related cullins 2, 3, 4A, and 5, selectively interacts with human SKP1. This CUL1-SKP1 interaction is mediated by the NH2-terminal domains of both proteins, and the association appears to be required for the interaction of CUL1 with SKP2, an essential element of the S-phase cyclin A-CDK2 kinase. In an asynchronous population of dividing cells, a minor amount of CUL1 specifically associates with cyclin A but not with other cyclins or CDK inhibitors. The steady-state levels of both CUL1 and SKP1 as well as their association with one another remain relatively constant throughout the cell cycle and in postmitotic cells. Our findings indicate that the SCF pathway, although similarly used by the mammalian cullin 1, is not shared by other cullin members. This implies that most cullins may use a SKP1/F-box-independent pathway to facilitate protein degradation.

Animals↗
PubMed1998

Regulation of cyclin-dependent kinase 4 during adipogenesis involves switching of cyclin D subunits and concurrent binding of p18INK4c and p27Kip1.

Terminal differentiation of many cell lineages involves an exit from the mitotic cycle and entry into, and maintenance of, a permanent state of G1 arrest. We found that during terminal differentiation of mouse 3T3-L1 preadipocytes, the level of cyclin-dependent kinase 4 (CDK4) remained constant, but the subunit composition of the CDK4 complex underwent a dynamic rearrangement. As 3T3-L1 cells differentiated, the levels of cyclin D1 and cyclin D1-CDK4 complexes declined to negligible levels. Meanwhile, cyclins D2 and D3 levels and their associations with CDK4 increased transiently and persistently, respectively, with cyclin D3 becoming the predominant cyclin partner of CDK4 in mature adipocytes. At least five CDK inhibitors are expressed during the differentiation program of 3T3-L1 cells. Both p15INK4b and p16INK4a continuously declined to undetectable levels immediately after differentiation induction. p21 was transiently expressed during the exit of 3T3-L1 cells from mitotic clonal expansion and then decreased to undetectable levels in mature adipocytes. The level of p27KiP1 and p27-CDK4 complexes remain high during differentiation and in mature adipocytes. Distinctly, there is a remarkable induction of p18INK4c mRNA and protein that was not seen in the closely related nondifferentiating 3T3-C2 cell line, suggesting that p18 induction in 3T3-L1 cells is related to cell differentiation, not cell cycle arrest. The pRb kinase activity of cyclin D3 and CDK4 was not detected in quiescent 3T3-L1 cells and was then induced as the cells entered the mitotic clonal expansion phase. Unexpectedly, cyclin D3 and CDK4 pRb kinase activity remained high after 3T3-L1 cells completed their mitotic division and was still readily detectable in mature adipocytes. Our study reveals an active regulation, rather than passive inhibition, of CDK4 activity during adipocyte differentiation. Two central features of this complex regulation are switching of activating cyclin D subunits and concurrent binding by the p18 and p27 CDK inhibitors.

3T3 Cells↗
PubMed1997

Extracellular cysteines of the corticotropin-releasing factor receptor are critical for ligand interaction.

The corticotropin-releasing factor receptor (CRF-R) contains six conserved cysteines in its amino-terminal domain (C30, C44, C54, C68, C87, and C102) and one cysteine in its first and second extracellular loops (C188 and C258, respectively). Additionally, several other cysteines are located in the transmembrane domains (C128, C211, C233, and C364) and first intracellular loop (C150). Reduction of disulfide bonds with DTT decreased CRF binding to detergent-solubilized membranes, suggesting an important role for disulfide bonds in ligand recognition. Therefore, site-directed mutagenesis was used to introduce single and paired Cys (C) to Ser (S) or Ala (A) mutations. A silent nine amino acid tag from c myc was introduced in the amino terminus of the mouse CRF-R. With the exception of C258S and C188S/C258S mutations, all C to S or to A receptor mutants had good surface expression that was at least 52.5% of control. C30S, C54S, and C30S/C54S mutations had good CRF binding and CRF-stimulated cAMP accumulation. No CRF binding was detected for the C44S, C68S, C87S, C102S, C188S, C258S, C30S/C44S, C30S/C68S, C54S/C68S, C87S/C102S, and C188S/C258S mutants, while CRF-stimulated cAMP accumulation occurred with high EC50 values. In particular, receptors carrying double mutations, C44S/C102S and C68S/C87S, had an improved signaling property as compared to receptors carrying the respective single cysteine mutations. These data, together with the effects of DTT on CRF binding, indicate that disulfide bridges are important for receptor functions. Functional data from single and paired cysteine mutations suggest potential pairings between C44 and C102, C68 and C87, and C188 and C258 that are critical for ligand-receptor interactions.

Amino Acid Sequence↗
PubMed1997

Trimeresurus stejnegeri snake venom plasminogen activator. Site-directed mutagenesis and molecular modeling.

The specific plasminogen activator from Trimeresurus stejnegeri venom (TSV-PA) is a serine proteinase presenting 23% sequence identity with the proteinase domain of tissue type plasminogen activator, and 63% with batroxobin, a fibrinogen clotting enzyme from Bothrops atrox venom that does not activate plasminogen. TSV-PA contains six disulfide bonds and has been successfully overexpressed in Escherichia coli (Zhang, Y., Wisner, A., Xiong, Y. L., and Bon, C. (1995) J. Biol. Chem. 270, 10246-10255). To identify the functional domains of TSV-PA, we focused on three short peptide fragments of TSV-PA showing important sequence differences with batroxobin and other venom serine proteinases. Molecular modeling shows that these sequences are located in surface loop regions, one of which is next to the catalytic site. When these sequences were replaced in TSV-PA by the equivalent batroxobin residues none generated either fibrinogen-clotting or direct fibrinogenolytic activity. Two of the replacements had little effect in general and are not critical to the specificity of TSV-PA for plasminogen. Nevertheless, the third replacement, produced by the conversion of the sequence DDE 96a-98 to NVI, significantly increased the Km for some tripeptide chromogenic substrates and resulted in undetectable plasminogen activation, indicating the key role that the sequence plays in substrate recognition by the enzyme.

Amino Acid Sequence↗
PubMed1997

Differential effects of tumor necrosis factor-alpha and interleukin-1 on 3 beta-hydroxysteroid dehydrogenase/delta 5-->delta 4 isomerase expression in mouse Leydig cells.

Immune-endocrine interactions are important to the regulation of Leydig cell steroidogenesis. We have shown previously that both tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1-beta) inhibit 8-bromo-cAMP-(8-Br-cAMP)-stimulated steroidogenesis in mouse Leydig cells. TNF and IL-1 both inhibit cAMP-stimulated testosterone production as well as mRNA and protein levels of cholesterol side chain cleavage enzyme (P450scc) and 17 alpha-hydroxylase/C17,20 lyase (P450c17) in mouse Leydig cells. Neither TNF nor IL-1 affects basal levels of P450scc mRNA and protein. In the present study, we tested the effects of TNF and IL-1 on basal testosterone production and 8-Br-cAMP-stimulated 3 beta-hydroxysteroid dehydrogenase/delta 5-->delta 4 isomerase (3 beta HSD) expression in Leydig cells. Purified and macrophage-depleted Leydig cells were cultured for 5 d with daily changes of media, and then treated with increasing concentrations of recombinant mouse TNF or IL-1 in the presence or absence of 8-Br-cAMP (50 microM) for 24 h. The media were collected for testosterone RIA and RNA and protein were extracted from cells. Basal testosterone production was inhibited by TNF, but not IL-1. Treatment of Leydig cells with 8-Br-cAMP alone caused a marked increase in 3 beta HSD mRNA, and protein levels. Both TNF and IL-1 inhibited cAMP-stimulated 3 beta HSD mRNA and protein levels, but only TNF inhibited basal 3 beta HSD expression. These results demonstrate that TNF and IL-1 have different effects on basal steroidogenesis in Leydig cells and suggest that TNF-mediated inhibition of basal testosterone production may be owing to the inhibition of basal 3 beta-HSD expression in Leydig cells.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1997

Preliminary studies on the relationship between autoantibodies to heat stress proteins and heat injury of pilots during acute heat stress.

Comparison in the heart rate, oral temperature and lymphocyte DNA damage during heat stress was made in pilots with negative antibodies to heat stress proteins (HSPs) and those with positive antibodies in the man-made climate room with Western blot and comet assay. Our results showed that the increase in oral temperature, heart rate and lymphocyte DNA damage in pilots with the positive antibodies to HSPs were higher than those in pilots with the negative antibodies during heat stress. These results indicated that the presence of autoantibodies in plasma of pilots might reflect heat damage and high sensitivity to heat.

Adult↗
PubMed1997

Induction of cell cycle arrest and B cell terminal differentiation by CDK inhibitor p18(INK4c) and IL-6.

Cell cycle arrest and cell death are tightly coupled to terminal differentiation of B cells to plasma cells in vivo. This process was recapitulated in vitro by stimulation of IgG-bearing human B lymphoblastoid cells with interleukin-6 (IL-6), which led to orderly cell cycle arrest, differentiation, and apoptosis. In terminally differentiated plasmacytoid cells, phosphorylation of pRb was suppressed, correlating with the activation of the D-type cyclin-dependent kinase (CDK) inhibitors p18(INK4c) and p21(WAF1/CIP1). The expression of CDK6, however, remained unchanged. Activation of p18 by IL-6 was rapid, concomitant with marked enhancement of its association with CDK6 and cell cycle arrest. Overexpression of p18 in IgM-bearing lymphoblastoid cells, which differentiated in response to IL-6 but did not exit the cell cycle, reconstituted coupled differentiation and cell cycle arrest. Thus, CDK inhibitors, in particular p18, are likely to play a pivotal role in controlling cell cycle arrest and cell death in terminal differentiation of late-stage B cells to plasma cells via inhibition of pRb phosphorylation by CDK6.

Apoptosis↗
PubMed1997

Mitochondrial dysfunction after experimental and human brain injury and its possible reversal with a selective N-type calcium channel antagonist (SNX-111).

We have recently demonstrated in a rat model that traumatic brain injury induces perturbation of cellular calcium homeostasis with an overload of cytosolic calcium and excessive calcium adsorbed on the mitochondrial membrane, consequently the mitochondrial respiratory chain-linked oxidative phosphorylation was impaired. We report the effect of a selective N-type calcium channel blocker, SNX-111 on mitochondrial dysfunction induced by a controlled cortical impact. Intravenous administration of SNX-111 at varying times post injury was made. The concentration titration profile revealed SNX-111 at 4 mg kg-1 to be optimal, and the time window to be administration at 4 h post-injury, in line with that reported on the effect of SNX-111 in experimental stroke. Under optimal conditions, SNX-111 significantly improved the mitochondrial respiratory chain-linked functions, such as the electron transfer activities with both succinate and NAD-linked substrates, and the accompanied energy coupling capacities measured as respiratory control indices (RCI) and ATP synthesis (P/O ratio), and the energy linked Ca2+ transport. In order to assess the applicability of these data to the clinical setting, we have initiated studies with brain tissue which has to be resected during surgical treatment. Five patients suffered from brain trauma, one from intracranial hypertension due to stroke (noninfarcted tissue was taken), and one from epilepsy. Our data revealed that brain mitochondria derived from the patient with intracranial hypertension and the patient with epilepsy were tightly coupled with good respiratory rates with glutamate and malate as substrates, and high P/O ratios. The rates of respiration and ATP synthesis were severely impaired in the brain mitochondria isolated from traumatized patients. These results indicate that investigation of brain mitochondrial functions can be used as a measure for trauma-induced impairment of brain energy metabolism. The time window for the effect of SNX-111 in mitochondrial function and the (preliminary) similarity between mitochondrial dysfunction in experimental animals and humans make the drug appear to be well suited for clinical trials in severe head injury.

Animals↗
PubMed1997

Interleukin-1beta is differentially expressed by human dermal papilla cells in response to PKC activation and is a potent inhibitor of human hair follicle growth in organ culture.

The dermal papilla plays an important role in the regulation of hair follicle matrix cell proliferation and hair fiber production, at least in part through mesenchymal-epithelial interactions. In the present study, we have investigated the regulation of interleukin-1 (IL-1) production by protein kinase C in cultured human dermal papilla cells. Treatment of dermal papilla cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) elicited the rapid and transient production of mature (17 kDa) cytosolic IL-1beta protein, but not IL-1alpha, with maximal levels achieved after 12 h. Rapid secretion of IL-1beta into the medium occurred subsequent to increased intracellular cytokine levels, after which medium IL-1beta protein levels were stable for 4 days. Northern blot analysis showed that TPA treatment elicited a transient induction of IL-1beta mRNA expression, maximal after 12 h, indicating that TPA regulates dermal papilla cell IL-1beta production at the transcriptional level. Pretreatment of dermal papilla cells with Ro 31-7549, a selective protein kinase C inhibitor, dose dependently and completely reversed phorbol-induced IL-1beta protein production. In addition, we demonstrated that IL-1beta is a highly potent inhibitor of the growth of human hair follicles in whole-organ culture, with an IC50 value of approximately 5 pg/ml. These findings, taken together with a previous report that follicular matrix cells express type I IL-1 receptors but dermal papilla cells do not, raise the possibility that dermal papilla cell-derived IL-1beta may act as a negative paracrine factor in the regulation of matrix cell proliferation.

Cells, Cultured↗
PubMed1997

Acetaminophen cytotoxicity in mouse eye: mitochondria in anterior tissues are the primary target.

Acetaminophen (APAP) injected into C57BL/6 mice (cytochrome P450 inducer-responsive strain) that had been pretreated with b-naphthoflavone (BNF) produced ocular tissue damage, including cataract. Our previous histocytochemical studies showed that tissue damage spread in association with the flow of the aqueous humor and appeared first in the ciliary epithelium, followed by the iris and corneal endothelium and, finally, the lens. The neural retina, retinal pigmented epithelium and choroid remained unaffected. A close examination of the affected tissues indicated that mitochondria are the primary target of APAP cytotoxicity. In order to investigate whether the respiratory capacity of mitochondria is more sensitive to APAP cytotoxicity than mitochondrial morphology, we determined in this work the oxygen uptake by eye tissues dissected from BNF-pretreated and APAP-injected C57BL/6 mice. Oxygen uptake by the ciliary body/iris decreased about 60% at 90 min and 85% at 120 min after APAP administration. The oxygen uptake was inhibited about 50% by 10 microM rotenone. Since the earliest sign of mitochondrial damage was noted at 120 min, the result indicates that mitochondrial energy dysfunction precedes morphological alterations. It was also observed that oxygen uptake by the retina remained unaffected at least for 120 min after APAP administration; therefore, it is evident that the retina and, possibly, other posterior tissues as well are resistant to APAP cytotoxicity, not only in their morphology but, also, in their capacity of mitochondrial energy metabolism.

Acetaminophen↗
PubMed1997

Mitochondrial dysfunction and calcium perturbation induced by traumatic brain injury.

Traumatic brain injury (TBI) is associated with primary and secondary injury. A thorough understanding of secondary injury will help to develop effective treatments and improve patient outcome. In this study, the GM model of controlled cortical impact injury (CCII) of Lighthall (1988) was used with modification to induce lateral TBI in rats. Forebrain mitochondria isolated from ipsilateral (IH) and contralateral (CH) hemispheres to impact showed a distinct difference. With glutamate + malate as substrates, mitochondria from the IH showed a significant decrease in State 3 respiratory rates, respiratory control indices (RCI), and P/O ratios. This decrease occurred as early as 1 h and persisted for at least 14 days following TBI. The State 3 respiratory rates, RCI, and P/O ratios could be restored to sham values by the addition of EGTA to the assay mixture. A significant amount of Ca2+ was found to be adsorbed to the mitochondria of both the IH and the CH with higher values seen in the IH. The rate of energy-linked Ca2+ transport in the IH was significantly decreased at 6 and 12 h. These data indicate that CCII-induced TBI perturbs cellular Ca2+ homeostasis and results in excessive Ca2+ adsorption to the mitochondrial membrane, which subsequently inhibits the respiratory chain-linked electron transfer and energy transduction.

Animals↗
PubMed1997

Amelioration of mitochondrial function by a novel antioxidant U-101033E following traumatic brain injury in rats.

In the present study, a severe traumatic brain injury (TBI) was produced over the right parietal cortex of rats using the controlled cortical impact injury (CCII) model. TBI perturbed calcium homeostasis and impaired electron transfer and energy coupling activities of forebrain mitochondria isolated from injured hemispheres with a maximal injury at 12-72 h. Efficacy of the blood-brain barrier penetrating antioxidant U-101033E on TBI-induced mitochondrial impairment was evaluated. In the dose-response experiment, two i.v. boluses (vehicle or 1-10 mg/kg of U-101033E) were administered at 5 min and 2h post-TBI. Forebrain mitochondria from each hemisphere were examined at 12 h post-injury. With respect to forebrain mitochondrial dysfunction, the drug showed a bell-shaped dose-response curve with an optimal dose of 3 mg/kg (n = 5, p < 0.05 vs. vehicle). In the time-course experiment, two i.v. boluses of 3 mg U-101033E/kg (the optimal dose) were given at 5 min and 2 h post-injury and forebrain mitochondria were examined at 6 h-14 days post-injury. U-101033E significantly restored electron transfer, energy coupling capacity, and Ca2+ transport capacity during 6 h to 14 days post-injury. Our data indicate that the antioxidant U-101033E administered post-injury at proper dosage can effectively restore TBI-induced mitochondrial dysfunction and support the contention that oxidative stress plays an important role in the pathogenesis of TBI.

Animals↗
PubMed1997

Purification and characteristics of recombinant mouse metallothionein-I from Escherichia coli.

The mouse metallothionein-I (mMT-I) cDNA was amplified by polymerase chain reaction (PCR), inserted into vector pGEX-4T-1, and expressed in Escherichia coli as a carboxyl terminal extension of the 26-kDa glutathione-S-transferase (GST). Analyzed by SDS-PAGE, the amount of the expressed fusion protein GST-MT was over 50% of total cellular proteins. After the fusion protein had been digested with thrombin on a Glutathione-Sepharose 4B affinity chromatography column, recombinant mMT-I was purified by gel filtration on Sephadex G50. The results of molecular mass, amino acid composition and sequence of 10 amino acids at the N-terminus of the recombinant mMT-I demonstrate that the purified protein is the one we desired. The ratios of metal:protein and thiol:protein are the same as those of wild-type MT. The half-dissociation pHs of Cd, Cu, and Zn from recombinant mMT-I were 3.57, 1.40, and 5.20, respectively, which are in agreement with those from native rabbit MT-I. The ultraviolet absorbance and circular dichroism (CD) spectra at pH 8.0 and pH 2.0 were all similar to those of native MT, indicating that they have the same metal-thiolate structure even though six amino acid residues have been added at the N-terminus of the recombinant protein.

Amino Acid Sequence↗
PubMed1997

Differences in the density of barosensitive neurons in the medulla of spontaneously hypertensive and Wistar-Kyoto rats.

1. The density of barosensitive neurons in the medulla was examined in spontaneously hypertensive rats (SHR) and in normotensive Wistar-Kyoto (WKY) rats. In control experiments, rats were sham-operated, while in test experiments arterial baroreceptors were stimulated by pressor responses to i.v. administration of phenylephrine and the density of c-Fos-labelled neurons was immunocytologically examined. 2. In both control and test experiments, c-Fos-labelled neurons were distributed in cardiovascular control sites: the nucleus tractus solitarii (NTS) and the caudal and rostral ventrolateral medullas (CVLM/RVLM). 3. In both WKY rats and in SHR, the total density of labelled neurons in test experiments was significantly higher than in control experiments. 4. In control experiments, no significant difference was found in the distribution and density of labelled neurons in the NTS and in the CVLM/RVLM between rats and SHR. 5. In test experiments, no significant difference was found in the distribution and density of labelled neurons in the NTS between WKY rats and SHR. 6. In test experiments in SHR, the density of labelled neurons in the CVLM just caudal to the obex level was significantly higher than that in WKY rats, whereas the density of labelled neurons in WKY rats in the RVLM just rostral to the obex level was significantly higher than that in SHR. 7. These results indicate that stimulation of the arterial baroreceptor induces strain-specific differences in the density of barosensitive neurons in the CVLM/RVLM near the obex level.

Animals↗