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PubMed1994

Technical considerations in two-stage functioning free muscle transplantation reconstruction of both flexor and extensor functions of the forearm.

We report on two patients with severe injuries of the forearm who were reconstructed using functioning free muscle transplantation (FFMT) for individual replacement of flexor and extensor function. In both cases a two-stage procedure was performed: The extensor reconstruction preceded the flexor reconstruction by 4-6 months. The extensor digitorum communis and flexor digitorum profundus were successfully reconstructed in both cases using bilateral gracilis FFMT. In one case the flexor pollicis longus and extensor pollicis longus were also reconstructed using the adductor longus in addition to the gracilis. Clinical follow-up was a minimum of 2 years. Both patients achieved wrist control, excellent finger flexion, and metacarpophalangeal joint extension. One patient also had good interphalangeal finger extension, but the other developed a persistent claw deformity due to the lack of recovery of ulnar nerve function. Performing the extensor reconstruction prior to the flexor reconstruction theoretically allows a more rapid return of function and a shorter rehabilitation period than using the converse sequence.

Adult↗

PubMed1997

The functional scout image: immediate mapping of cortical function at 4 Tesla using receiver phase cycling.

A rapid method of generating functional scout images to map cortical activity is presented. Maps were produced immediately "on-line" on the scanner's console using fast low-angle shot gradient-recalled echo and echo-planar imaging sequences without special hardware. To demonstrate the technique, raw data collected during photic stimulation and dark control periods were subtracted through phase alternation of the receiver with constant transmitted radio frequency phase. A blood oxygen level-dependent signal difference map was produced by magnitude reconstruction of the resulting complex-difference data. Maps improved in contrast with an increasing number of stimulation-control cycles and showed similar areas of activation to traditional fMRI processing methods. Such a functional scout procedure allows rapid localization of brain function within the anatomical region of interest. From these functional scout images, slices or voxels may be planned by using the scanner manufacturers prescription tools for further specialized studies.

Brain Mapping↗

PubMed1996

Mapping the functional surface of insulin by design: structure and function of a novel A-chain analogue.

Functional surfaces of a protein are often mapped by combination of X-ray crystallography and mutagenesis. Such studies of insulin have yielded paradoxical results, suggesting that the native state is inactive and reorganizes on receptor binding. Of particular interest is the N-terminal alpha-helix of the A-chain. Does this segment function as an alpha-helix or reorganize as recently proposed in a prohormone-convertase complex? To correlate structure and function, we describe a mapping strategy based on protein design. The solution structure of an engineered monomer ([AspB10, LysB28, ProB29]-human insulin) is determined at neutral pH as a template for synthesis of a novel A-chain analogue. Designed by analogy to a protein-folding intermediate, the analogue lacks the A6-A11 disulphide bridge; the cysteine residues are replaced by serine. Its solution structure is remarkable for segmental unfolding of the N-terminal A-chain alpha-helix (A1 to A8) in an otherwise native subdomain. The structure demonstrates that the overall orientation of the A and B chains is consistent with reorganization of the A-chain's N-terminal segment. Nevertheless, the analogue's low biological activity suggests that this segment, a site of clinical mutation causing diabetes mellitus, functions as a preformed recognition alpha-helix.

Amino Acid Sequence↗

PubMed2003

An algorithm for rapid calculation of a probabilistic functional atlas of subcortical structures from electrophysiological data collected during functional neurosurgery procedures.

The paper introduces an optimal algorithm for rapid calculation of a probabilistic functional atlas (PFA) of subcortical structures from data collected during functional neurosurgery procedures. The PFA is calculated based on combined intraoperative electrophysiology, pre- and intraoperative neuroimaging, and postoperative neurological verification. The algorithm converts the coordinates of the neurologically most effective contacts into probabilistic functional maps taking into account the geometry of a stimulating electrode. The PFA calculation comprises the reconstruction of the contact coordinates from two orthogonal projections, normalizing (warping) the contacts modeled as cylinders, voxelizing the contact models, calculating the atlas, and computing probability. In addition, an analytical representation of the PFA is formulated based on Gaussian modeling. The initial PFA has been calculated from the data collected during the treatment of 274 Parkinson's disease patients, most of them operated bilaterally (487 operated hemispheres). It contains the most popular stereotactic targets, the subthalamic nucleus, globus pallidus internus, and ventral intermedius nucleus. The key application of the algorithm is targeting in stereotactic and functional neurosurgery, and it also can be employed in human and animal brain research.

Algorithms↗

PubMed1990

Modulation of endothelial function by hypoxia: perturbation of barrier and anticoagulant function, and induction of a novel factor X activator.

Exposure of the vessel wall to hypoxemia is a central feature of ischemic cardiovascular disease. This led us to examine the perturbation of endothelial cell properties under hypoxia. An atmosphere of pO2 of 12 mmHg is not lethal to the endothelial cells for up to five days, but barrier function was impaired. Increased passage of macromolecule tracers were observed in time- and dose-dependent manner and electron microscopy demonstrated small gaps (0.5-1.0 micron) between cells. Expression of the anticoagulant cofactor thrombomodulin was also perturbed: thrombomodulin activity and antigen decreased in parallel. Northern blots showed almost complete suppression of thrombomodulin in hypoxic culture. Furthermore, synthesis of other proteins, such as fibronectin, was slightly enhanced under hypoxia. In addition to the suppression of these anticoagulant cofactor, hypoxic endothelial cell displayed a noval procoagulant activity distinct from tissue factor. Further study revealed that hypoxic endothelial cultures directly activated Factor X, as assessed by functional assays and SDS-PAGE. In addition to this no activation of Factor IX or prothrombin was observed. The hypoxia-induced Factor X activator was membrane-associated, required calcium to form Factor Xa, was inhibited by HgCl2 but not by PMSF, and had Km approximately 25 micrograms/ml. Co-incubation of hypoxic cultures with cycloheximide prevented the expression of this activity, suggesting that protein synthesis is required for its expression. These functional perturbations of endothelial cells were reversible following reoxygenation. These data indicate that hypoxia imposes a selective perturbation on endothelial cell function, suggesting the possible contribution of hypoxemia to vascular dysfunction in ischemia.

Animals↗

PubMed1991

Acquisition of mature functional responsiveness in T cells: programming for function via signaling.

The results discussed here provide strong evidence that different T-cell effector gene programs are activated by different signals, and that in several cases their responses to the same exogenous stimuli shift during the development and antigen responses of the cells. T-cell responses are thus conditional and plastic at the individual cell level. In the formalism of the introductory section, the results support elements of Models 2 and 3, and suggest a fusion between them as differentiation is explained in terms of alteration in the relative strengths of different intracellular signaling pathways. Returning to an initial question, how are different functional capabilities assigned nonrandomly to cells with different antigen recognition specificities? This question has not been answered, but it can be reformulated. If all virgin T cells can transiently make IL-2, then we must ask what features of cell biology explain the preferential preservation of IL-2 inducibility in CD4+ cells as opposed to CD8+ cells. If the capacity to induce IL-4 expression is not acquired in the thymus, then we may ask whether the initial opening of this locus depends on a CD4-transmitted signal. Similarly, the CD8 molecule itself might participate in inducing the initial differentiation events that render CTL-p inducible for granzyme C and perforin. This would be in accord with a large literature showing that CD8 engagement is much more important in the initial induction of CTL activity than in the exercise of function by pre-primed CTL effectors. The subtext of each of these "questions", however, is that intrathymic events may not directly affect the genes used by terminal effectors for function at all. They may instead bias a cell's complement of triggering receptors, thus rendering it differentially sensitive to particular signals generated during antigen reception. This view is extreme, and will probably turn out to be an overstatement. But it does inspire a unique set of investigations into the basis of T-cell function. It lends urgency to the question of whether CD4+ and CD8+ cells differ in their G proteins, kinases, or inducible proto-oncogenes. If they do, we can then ask whether such differences themselves arise in the periphery, or whether they can be traced back to thymocytes fresh from positive selection--or before.

Animals↗

PubMed1982

A scintillation camera technique for measurements of the reticuloendothelial function - comparison of different methods for measuring RES function.

A highly standardized 99mTc-sulphur colloid was used to evaluate reticuloendothelial system (RES)-function in the normal rat and after RE blockade by gelatin (Haemaccel). Activity distribution in the animals was measured with a scintillation camera technique. Total uptake of activity in the liver was estimated. From the time-activity curves over the liver, the phagocytic index (kphag) was evaluated. Estimation of the uptake rate of the labelled colloid into the liver and into other parts of the RES was also performed using a two-compartment model. Different methods of evaluation of RE function were compared. It was shown that for a proper estimation of the RE function, the whole uptake curve must be considered. Gelatin (Haemaccel) significantly reduced the total colloid uptake by the liver. The colloid uptake rate into the liver was also significantly reduced. Liver specimens after colloid injection were examined by light and electron microscopy showing vacuolation of hepatocytes and sinusoidal cells probably due to pinocytosis. The technique described enables functional studies of the RES. It has the advantage of noninvasive registrations and is based on the same technical facilities as used for routine liver scintigraphy.

Animals↗

PubMedDate not supplied

The effect of magnesium added to secondary cardioplegia on postischemic myocardial metabolism and contractile function--a 31P NMR spectroscopy and functional study in the isolated pig heart.

This study investigated whether increasing the magnesium concentration during secondary cardioplegia improves postischemic myocardial recovery. Twenty-four isolated pig hearts were divided into four groups. All hearts were initially subjected to control perfusion with modified Krebs-Henseleit solution for 30 min, followed by a single infusion of St. Thomas' solution #2. The hearts were then maintained without perfusion at 12 degrees C for 4 h. Following this hypothermic preservation, the hearts in group I were reperfused with modified Krebs-Henseleit solution for 50 min, while hearts in group II and III were reperfused with a secondary cardioplegic solution containing 16 or 0 mmol/L magnesium, respectively, for 20 min followed by 30 min of perfusion with modified Krebs-Henseleit solution. In group IV, the hearts were initially reperfused with Krebs-Henseleit solution containing 16 mmol/L potassium for 20 min, followed by 30 min of reperfusion with modified Krebs-Henseleit solution. The changes in high-energy phosphates and intracellular pH were monitored throughout the experiments using 31P nuclear magnetic resonance (NMR) spectroscopy. Heart rate, left-ventricular systolic developed pressure, and rates of pressure increase and decrease were measured during control perfusion and reperfusion to calculate the percent contractile functional recovery. Needle biopsies for measurement of energy metabolites with high performance liquid chromatography were performed at the end of preservation and reperfusion to confirm the NMR measurements. All six hearts in group I showed significantly less recovery of contractile function during reperfusion when compared to the hearts in groups II, III, IV (p less than 0.05). There was no difference in either recovery of metabolism or mechanical function among the latter three groups of hearts. None of hearts in groups II, III, and IV showed ventricular fibrillation, which occurred in all six hearts of group I upon reperfusion. The results suggest that a short period of re-arrest perfusion following ischemia ("secondary cardioplegia") improves postischemic contractile functional recovery and prevents reperfusion-induced ventricular fibrillation. Increased magnesium concentration in the secondary cardioplegia did not provide additional benefit to the ischemic myocardium, possibly due to the low permeability of the sarcolemmal membrane to magnesium.

Animals↗

PubMed1998

Prospective study of morphologic and functional changes with time in the mucosa of the ileoanal pouch: functional appraisal using transmucosal potential differences.

PURPOSE: This study was undertaken to investigate the morphologic and functional changes with time in the mucosa of the ileoanal pouch. METHODS: A morphologic study by histopathologic analysis, mucosal morphometry, and mucin histochemistry and a functional study by analysis of transmucosal potential difference were performed in 27 patients with an ileoanal J-pouch after restorative proctocolectomy for ulcerative colitis. In 19 patients with a normal ileoanal pouch, two prospective follow-up analyses were performed after median functional pouch times of 14 and 39 months. We also evaluated eight patients with the diagnosis of pouchitis (median follow-up, 52.5 months). RESULTS: In the normal ileoanal pouch group, some degree of chronic and acute inflammatory infiltration was identified in 100 percent and 63.2 percent of cases, respectively, with no significant differences being observed between the two follow-up analyses. The mean villous atrophy index at the first and second follow-up was 0.54 and 0.52, respectively, significantly lower (P < 0.001; an indication of a greater degree of villous atrophy) than the value obtained from the control group with a healthy terminal ileum (0.77). The group of patients with pouchitis exhibited statistically significant differences in the degree of acute and chronic inflammatory infiltration, the extent of ulceration, the crypt depth, and the villous atrophy index, compared with patients without pouchitis. In the normal ileoanal pouch group, the median percentage of sulfomucin with each degree of atrophy (1=mild; 2=moderate; and 3=severe) was 2.6, 4.5, and 20.9 percent, respectively. In patients with pouchitis, the median percentage of sulfomucin was 5.9 percent. The mean transmucosal potential difference at the first follow-up (-25.3 mV) was significantly lower (P=0.001) than at the second (-30.4 mV). Significant differences were apparent with respect to both the normal ileum (-8.9 mV) and the normal rectum (-40.2 mV). CONCLUSION: These results suggest that the ileal pouch behaves as a neorectum, with different degrees of colonic metaplasia from a morphologic and a functional perspective.

Adult↗

PubMed1991

Functional hepatic imaging with receptor-binding radiopharmaceutical: clinical potential as a measure of functioning hepatocyte mass.

Asialoglycoprotein receptor (ASGP-R) is a hepatic cell surface receptor specific for galactose-terminated glycoproteins. Technetium-99m diethylenetriaminepentaacetic acid-galactosyl human serum albumin (TcGSA) is a newly developed analog ligand to ASGP-R. Fourteen human subjects were studied: three normal volunteers, one with chronic hepatitis, 6 with liver cirrhosis, and 4 with hepatocellular carcinoma associated with liver cirrhosis. The receptor index parameter (LHL15), was obtained from the liver and heart time-activity data as the ratio of radioactivity of the liver over that of the liver plus heart at 15 min after intravenous injection of 1 mg of TcGSA. Means +/- standard deviations of LHL15 in normal volunteers (3 cases), patients with mild (4 cases), moderate (2 cases), and severe liver damage (5 cases) were 0.933 +/- 0.006, 0.789 +/- 0.045, 0.723 +/- 0.033, and 0.488 +/- 0.094, respectively. The difference between the mean values of each group was statistically significant (P less than 0.05). LHL15 correlated well with classical indicators for hepatic functional capacity such as serum albumin level, serum bilirubin level, prothrombin time, ICG R15 or Child-Turcotte criteria score. Our preliminary experiences of high correlations of TcGSA functional imaging data with clinical data suggest that the dynamic data using this receptor-binding radiopharmaceutical provides invaluable information with regard to liver function, and thus, the TcGSA study is potentially a noninvasive practical tool to measure functioning hepatocyte mass.

Asialoglycoprotein Receptor↗

PubMed1999

Evaluation of a German version of the Bath Ankylosing Spondylitis Functional Index (BASFI) and Dougados Functional Index (D-FI).

OBJECTIVE: Transcultural adaptation of the two most widely used and accepted functional indices in ankylosing spondylitis, the Bath Ankylosing Spondylitis Functional Index (BASFI) and Dougados Functional Index (D-FI). METHODS: The instruments were translated and tested for internal consistency (Cronbach's coefficient alpha), test-retest reliability (intraclass correlation coefficient, ICC), construct validity (testing for association with Schober's test, finger floor distance, occiput wall distance, frequency and duration of awakenings at night, and a visual analog scale pain), and responsiveness (standardized response mean, SRM). RESULTS: The study sample consisted of 72 patients of a randomized, controlled clinical trial receiving either Diclofenac or placebo. Visual assessment of distribution patterns revealed a ceiling effect of both instruments. Both questionnaires had a high internal consistency (Cronbach alpha: 0.81 [BASFI], 0.85 [D-FI] and a high test-retest reliability (ICC: 0.92 [BASFI], 0.89 [D-FI]). The limited responsiveness to Diclofenac treatment (SRM: 0.46 [BASFI], 0. 33 [D-FI]) may be related to the selected study sample. The BASFI was significantly correlated with all tested validation parameters. The D-FI was only significantly correlated with finger floor distance, occiput wall distance, and duration of awakenings at night. CONCLUSION: The transculturally adapted version of both functional indices are valid, reliable, and internally consistent. Because of psychometric advantages, the BASFI may be preferred in clinical trial settings.

Activities of Daily Living↗

PubMed1986

A comparative study on the effects of inhibitors of the lipoxygenase pathway on neutrophil function. Inhibitory effects on neutrophil function may not be attributed to inhibition of the lipoxygenase pathway.

The effects of five inhibitors of the lipoxygenase pathway were evaluated on oxygen radical production, degranulation, chemotaxis, leukotriene B4 (LTB4) production by neutrophils. The lipoxygenase inhibitors tested were nordihydroguaiaretic acid (NDGA), esculetin, eicosatetraynoic acid (ETYA), 2-(12-hydroxydodeca-5,10-diynyl)-3,5,6-trimethyl-1,4-benzoqu inone (AA-861), and 6,9-deepoxy-6, 9-(phenylimino)-delta 6.8-prostaglandin I1 (U-60,257). Neutrophils were activated by n-formyl-methionyl-leucyl-phenylalanine (fMLP), phorbol myristate acetate (PMA), A23187, or platelet activating factor (PAF). The effects of these inhibitors on NADPH oxidase activity and phospholipase A2 activity of isolated particulate fraction of neutrophils were also evaluated. ETYA inhibited neutrophil function induced by all the stimulators except PMA. AA-681 was unique in that it did not inhibit PAF-induced neutrophil activation. U-60,257 had virtually no effect on oxygen radical production and degranulation, but chemotaxis was moderately suppressed. NDGA effectively inhibited neutrophil function, except for chemotaxis. Esculetin inhibited only oxygen radical production, but this was due to inhibition on NADPH oxidase activity of neutrophil membrane. The inhibitory effect on neutrophil function and that of LTB4 production were not closely correlated. It is suggested that lipoxygenase inhibitors may modify neutrophil function by the mechanism not involving the lipoxygenase pathway. It is also suggested that LTB4 may not be a mediator in neutrophil oxygen radical production and degranulation induced by the stimulators used in the present study.

5,8,11,14-Eicosatetraynoic Acid↗

PubMed1996

Aminotetralin drugs and D3 receptor functions. What may partially selective D3 receptor ligands tell us about dopamine D3 receptor functions?

The dopamine D3 receptor gene was identified by Sokoloff and colleagues in 1990. This finding rapidly gained the interest of the scientific community because this unexpected dopamine receptor subtype may play an important role in the antipsychotic activity of neuroleptic drugs. It recognizes most neuroleptics with a high affinity, and its brain distribution is restricted mainly to the ventral part of the striatal complex. However, the characterization and the subsequent identification of functions of the D3 receptor were hampered initially by at least four important factors that are still partially unresolved: (1) the absence of selective drugs that can discriminate between the D2 and D3 receptor subtype functions in vivo, (2) the lack of apparent coupling with GTP-dependent proteins, (3) the absence of effects on second messenger systems, and (4) the low level of expression of this receptor in brain tissue; these factors have contributed to tempering the interest of scientists. However, this situation has begun to change with the identification of [3H]7-hydroxy-N,N-(di-n-propyl)-2-aminotetralin ([3H]7-OH-DPAT), the first selective ligand for the dopamine D3 receptor. Although its binding selectivity for the D3 versus the D2 receptor is somewhat artificial, the potentially important impact of identification of a function for the D3 receptor encouraged scientists to use this aminotetralin compound for in vivo studies with, however, limited success. This commentary is focused on the impact and controversies generated by the use of 7-OH-DPAT and its congeners, on new conceptual views that may arise from this research, and on what partially selective D3 receptor ligands may tell us about dopamine D3 receptor functions.

Animals↗

PubMed1990

Functional substitution of the basic domain of the HIV-1 trans-activator, Tat, with the basic domain of the functionally heterologous Rev.

The tat gene of HIV is a strong activator of the viral LTR. The Tat protein contains a highly basic domain that is important for its transport to the nuclear/nucleolar locations. The Tat basic domain when fused to Escherichia coli beta-galactosidase directed the chimeric protein to the nucleus and nucleolus. Tat mutants lacking the entire basic domain were severely defective in trans-activation. Substitution of the basic domain of Tat with that of the functionally unrelated HIV-1 Rev protein targeted the chimeric protein to the nucleolus and restored the function of Tat. In contrast, substitution with the nuclear targeting signal (NLS) of SV40 T antigen targeted the chimeric protein to the nucleus and accumulation in the nucleolar region was excluded. The Tat-NLS chimeric protein did not restore the trans-activation function of Tat efficiently. These results indicate that the arginine-rich basic domain of the trans-activator, Tat, and post-transcriptional trans-regulator, Rev, are functionally similar with regard to trans-activation of HIV-1 LTR.

Amino Acid Sequence↗

PubMed1991

Phenotypic and functional characteristics of activated CD8+ cells: a CD11b-CD28- subset mediates noncytolytic functional suppression.

Freshly isolated human CD8+ cells can be divided into mutually exclusive subsets bearing the phenotypes CD11b+(CD28-) or CD28+(CD11b-). We found that activation of CD8+ cells with anti-CD3 mAb and IL-2 preferentially expanded the CD11b-(CD28+) subset. This subset, when separated and activated independently, mediated both functional suppression and lectin-dependent cell cytotoxicity (LDCC). CD28- cells, prepared by elimination of the CD 28+ cells from expanded unfractionated CD8+ cell cultures, retained functional suppressor activity but demonstrated reduced LDCC compared to either the CD28+(CD11b-)-enriched fraction or the unfractionated CD8+ population. The majority of the CD28- cells were also CD11b-, reflecting the observation that initially CD11b+ cells lose CD11b expression following activation with anti-CD3 mAb and IL-2. Our results therefore indicate that CD8+ cells deriving from the CD11b+CD28- subset, but expressing neither CD11b nor CD28 after activation, represent the main noncytotoxic functional suppressor cell in the mitogen "activated" suppressor assay. The preferential expansion of CD8+CD28+ cells relative to CD8+CD28- cells, if occurring in vivo in the central nervous system (CNS) compartment, would be consistent with observed phenotypic analysis of cerebrospinal fluid-derived T cells and might contribute to the reduced functional suppressor activity previously found for CNS compared to peripheral blood-derived lymphocytes.

Antibodies, Monoclonal↗

PubMed1983

(--)-alpha-Acetylmethadol effects on alcohol and diazepam use, sexual function and cardiac function.

Selected behavioral and physiological effects of maintenance on (--)-alpha-acetylmethadol (LAAM) were examined for 67 men beginning LAAM maintenance. Thirty-four began LAAM maintenance after 1 month or more on methadone; 33 others were using street heroin immediately before beginning LAAM. Subjects were followed for 20 weeks on LAAM; assessment focused on changes in alcohol and diazepam use, sexual behavior and testicular function, and cardiovascular function. There was a trend toward increased alcoholism-related behaviors, but not consumption of alcohol, when on LAAM. Use of diazepam remained low. Subjects reported slightly enhanced sexual activity: reported number of ejaculations tended to increase, although interest in sexual activity remained constant. Semen volume values remained in the low normal range. In contrast to an earlier published report of reduced sperm motility in methadone and heroin users, normal motility was noted in this sample. The incidence of abnormal sperm morphology decreased from baseline to the end of the study. Cardiovascular function, as assessed by response to standard exercise, was unchanged during LAAM maintenance. Electrocardiograms revealed minor abnormalities prior to beginning LAAM maintenance; but these abnormalities did not consistently change during treatment. There is little evidence that the effects of LAAM maintenance differ from the effects of methadone maintenance on these behavioral and physiological functions.

Adult↗

PubMed1994

Sertoli cell function declines earlier than Leydig cell function in aging Japanese men.

In order to evaluate the age-related changes in Leydig cell and Sertoli cell function, we measured serum levels of total testosterone (TT), free testosterone (FT), inhibin, LH and FSH in 116 healthy Japanese men, aged 24-92 years. Serum TT remained constant up to the age of 80 years and decreased thereafter. Serum FT declined linearly with aging and was significantly lower in men in their forties than in younger men (24-39 years old). Serum inhibin levels also declined with aging, with serum concentrations significantly lower in men older than 40 and markedly lower in men over 80 years old. LH and FSH were elevated in men over 60 and 40 years old, respectively. We also examined relationships between gonadotropins and gonadal hormones in these men divided into three age groups, young (24-39 years old), middle aged (40-59 years old) and aged (60-92 years old) men. Although there was a significant inverse correlation between LH and TT or FT for the entire population, subset analysis demonstrated that this inverse correlation was confined to men over 60 years old. In fact, in young men, TT and FT were positively correlated with LH. Overall, there was also an inverse correlation between FSH and inhibin. In subset analysis this relationship was present in both middle aged and aged men. These findings suggest that in Japanese men testicular endocrine functions decline after the fourth decade of life, and that Sertoli cell function declines earlier than Leydig cell function.

Adult↗

PubMed2026

Divergent PXR function in seals: Endocrine adaptation or functional loss?

Seals accumulate xenobiotics through dietary biomagnification and exposure to polluted marine environments, with contaminants concentrating in their blubber. Biotransformation mitigates xenobiotic toxicity by converting lipophilic compounds into excretable hydrophilic metabolites, a process coordinated by nuclear receptors including the Pregnane X Receptor (PXR), whose plastic ligand-binding domain enables broad xenobiotic sensing. By examining PXR in pinnipeds, we investigated the evolutionary conservation and functional characterization of PXR using genomic sequence analysis, protein structural prediction, and transactivation assays, revealing broadly conserved structural features alongside species-specific functional divergence in receptor responsiveness to environmental stressors. Specifically, the obtained results highlight divergent gene and functional landscapes with ORF-disrupting mutations identified in Monachus monachus and Neomonachus schauinslandi that abolish receptor activation toward known PXR ligands. In contrast, Leptonychotes weddelli retained an intact PXR ORF but showed reduced receptor activity, revealing functional divergence in PXR among pinnipeds.

Biotransformation↗