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BACKGROUND: To review the treatment and the causes of postoperative epidural hematoma (PEDH) after intracranial tumor resection. METHOD: A retrospective case study was conducted to examine a series of patients who developed PEDH as a complication following intracranial tumor resection between January 2016 and June 2021. The study collected data from hospital charts, including clinical status at admission, imaging results, histopathologic findings, surgical management, complications, and outcomes. Causes of PEDH were evaluated through a review of operative notes and discussions with the surgical team. RESULTS: Twenty-five patients (10 males, 15 females; median age 42 years, range 11-61 years; median medical history 27 months, range 1-96 months) were enrolled in the study. Regarding tumor location, 16 cases exhibited supratentorial brain tumors, 4 cases had infratentorial brain tumors, 2 cases of tumors occurred in the petroclival region, 2 cases in the peritorcular region, and 1 case in the pineal region. Four of these cases were complicated with supratentorial hydrocephalus. The 25 cases in this study were classified into four types based on location. Type 1 refers to EDHs that occur at the adjacent site of the operative field without involvement of the surgical area. Type 2 includes hematomas that occur at the adjacent site of the surgical area and the surgical area. Type 3 includes EDHs that occur in distant areas, and type 4 involves EDHs in the surgical field. The numbers of cases of types 1, 2, 3, and 4 PEDHs were 16, 2, 3, and 4 cases, respectively. Most PEDHs were associated with reduced ICP after craniotomy due to intracranial tumor resection and substantial loss of CSF. All patients achieved satisfactory outcomes after hematoma evacuation. CONCLUSION: The decrease in ICP resulting from intracranial tumor resection and CSF loss might lead to PEDHs. By employing optimized surgical techniques and meticulous patient management to prevent rapid decreases in ICP and dural detachment, we can potentially lower the incidence of PEDHs. Additionally, prompt evacuation of hematomas can contribute to positive outcomes.
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As a primitive driving force for biological reproduction, sexual behavior (and its associated mechanisms) is extremely complex, and orgasm plays an essential role. The limbic system plays a very important role in regulating human sexual behavior. However, it is not clear which components of the limbic system are related to orgasm sensation. We studied a rare case of spontaneous orgasmic aura in a male patient with temporal lobe epilepsy. Stereoelectroencephalography (SEEG) revealed that the right amygdala was the origin of orgasmic aura. Surgical removal of the medial temporal lobe, including the right amygdala, completely eliminated the patient's seizures. This study demonstrates the critical role of the amygdala in human male orgasm.
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Epilepsia del Lóbulo Temporal , Masculino , Humanos , Femenino , Epilepsia del Lóbulo Temporal/diagnóstico por imagen , Epilepsia del Lóbulo Temporal/cirugía , Orgasmo , Amígdala del Cerebelo/diagnóstico por imagen , Amígdala del Cerebelo/cirugía , Convulsiones , Lóbulo TemporalRESUMEN
Polarizing beam splitters (PBSs) play an important role in applications requiring polarization multiplexing or high polarization purity. Traditional prism-based PBSs usually have large volumes, which hampers their further applications in ultracompact integrated optical systems. Here, we demonstrate a single-layer silicon metasurface-based PBS with the ability to deflect two orthogonally linearly polarized infrared light beams to on-demand angles. The metasurface consists of silicon anisotropic microstructures, which can provide different phase profiles for the two orthogonal polarization states. In experiments, two metasurfaces designed with arbitrary deflection angles for x- and y-polarized light exhibit good splitting performance at an infrared wavelength of 10â µm. We envision that this type of planar and thin PBS can be used in a series of compact thermal infrared systems.
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The western corn rootworm (WCR), Diabrotica virgifera virgifera LeConte, is a major corn pest of significant economic importance in the United States. The continuous need to control this corn maize pest and the development of field-evolved resistance toward all existing transgenic maize (Zea mays L.) expressing Bacillus thuringiensis (Bt) insecticidal proteins against WCR has prompted the development of new insect-protected crops expressing distinct structural classes of insecticidal proteins. In this current study, we describe the crystal structure and functional characterization of Mpp75Aa1.1, which represents the first corn rootworm (CRW) active insecticidal protein member of the ETX_MTX2 sub-family of beta-pore forming proteins (ß-PFPs), and provides new and effective protection against WCR feeding. The Mpp75Aa1.1 crystal structure was solved at 1.94 Å resolution. The Mpp75Aa1.1 is processed at its carboxyl-terminus by WCR midgut proteases, forms an oligomer, and specifically interacts with putative membrane-associated binding partners on the midgut apical microvilli to cause cellular tissue damage resulting in insect death. Alanine substitution of the surface-exposed amino acids W206, Y212, and G217 within the Mpp75Aa1.1 putative receptor binding domain I demonstrates that at least these three amino acids are required for WCR activity. The distinctive spatial arrangement of these amino acids suggests that they are part of a receptor binding epitope, which may be unique to Mpp75Aa1.1 and not present in other ETX_MTX2 proteins that do not have WCR activity. Overall, this work establishes that Mpp75Aa1.1 shares a mode of action consistent with traditional WCR-active Bt proteins despite significant structural differences.
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Bacillus thuringiensis/metabolismo , Proteínas Bacterianas/farmacología , Insecticidas/farmacología , Control Biológico de Vectores/métodos , Plantas Modificadas Genéticamente , Zea mays , Animales , Proteínas Bacterianas/genética , Escarabajos/efectos de los fármacos , Resistencia a los Insecticidas/efectos de los fármacos , Plantas Modificadas Genéticamente/genética , Plantas Modificadas Genéticamente/metabolismo , Zea mays/genética , Zea mays/metabolismoRESUMEN
Considering spectrally resolved absorption and temperature distribution, a physical model is established to describe the laser kinetic and thermodynamic processes of an exciplex pumped Rb vapor laser. A comparison with Carroll's model is made. Influences of pump intensity, temperature, reflectivity of output coupler, and number density of Kr on the performance of CW Rb-Kr XPAL with uniform temperature distribution are calculated and analyzed. Besides, with the heat accumulation considered, the temperature distribution was calculated, and the maximal optical-to-optical efficiency about 5.7% can be achieved at the condition of pump intensity I0 = 5.2 × 1010 W/m2 and flow velocity u = 250 m/s.
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A physical model combining rate, power propagation, and transient heat conduction equations for diode-pumped alkali vapor lasers (DPAL) is applied to a pulsed Rb-CH4 DPAL, which agrees well with the time evolution of laser power and temperature measured by K absorption spectroscopy. The output feature and temperature rise of a multi-pulse DPAL are also calculated in the time domain, showing that if we energize the pump light when the temperature rise decays to 1/2, rather than 1/e of its maximum, we can increase the duty cycle and obtain more output energy. The repetition rate of >100Hz is high enough to achieve QCW (quasi-continuous-wave) laser pulses.
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Comprehensive analysis of kinetic and fluid dynamic processes in flowing-gas diode-pumped alkali vapor amplifiers is reported. Taking into account effects of the temperature, the amplified spontaneous emission, the saturation power, the excitation of the alkali atoms to high electronic levels and the ionization, a detailed physical model is established to simulate the output performance of flowing-gas diode-pumped alkali vapor amplifiers. Influences of the flow velocity and the pump power on the amplified power are calculated and analyzed. Comparisons between single and double amplifier, longitudinal and transverse flow are made. Results show that end-pumped cascaded amplifier can provide higher output power under the same total pump power and the cell length, while output powers achieved by single- and double-end pumped, double-side pumped amplifiers with longitudinal or transverse flow have a complicated but valuable relation. Thus the model is extremely helpful for designing high-power flowing-gas diode-pumped alkali vapor amplifiers.
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Considering the amplified spontaneous emission, the saturation effect and the energy distributions of the incident pump and seed lasers, a physical model is established to describe the kinetic process and the output performance of a four sided diode pumped alkali vapor laser amplifier. According to the experimental parameters of a single-side pumped configuration with a diffuse type hollow cylinder cavity, energy distributions in the cell and influences of several important factors are simulated and analyzed. The model is validated by comparing the simulation result with the experimental data, which shows the model can provide an effective way for designing an efficient diode four-side symmetrically pumped alkali vapor laser amplifier.
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Here, we report the isolation and functional characterization of mAbs against two murine norovirus (MNV) strains, MNV-1 and WU20, which were isolated following oral infection of mice. The mAbs were screened for reactivity against the respective homologous and heterologous MNV strain by ELISA. Selected mAbs were of IgA, IgG1, IgG2a or IgG2b isotype and showed a range of Western blot reactivities from non-binding to strong binding, suggesting recognition of conformational and linear epitopes. Some of the anti-MNV-1 antibodies neutralized both MNV-1 and WU20 infections in culture and in mice, but none of the anti-WU20 mAbs neutralized either virus. The non-neutralizing anti-MNV-1 IgG2b antibody 5C4.10 was mapped to the S domain of the MNV-1 capsid, whilst the epitopes of the neutralizing anti-MNV-1 IgA antibodies 2D3.7 and 4F9.4 were mapped to the P domain. Generation of neutralization escape viruses showed that two mutations (V339I and D348E) in the C'D' loop of the MNV-1 P domain mediated escape from mAb 2D3.7 and 4F9.4 neutralization. These findings broaden the known neutralizing epitopes of MNV to the main surface-exposed loops of the P domain. In addition, the current panel of antibodies provides valuable reagents for studying norovirus biology and development of diagnostic tools.
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Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Proteínas de la Cápside/inmunología , Norovirus/inmunología , Secuencia de Aminoácidos , Animales , Anticuerpos Monoclonales/genética , Anticuerpos Neutralizantes/genética , Especificidad de Anticuerpos , Infecciones por Caliciviridae/inmunología , Cápside/inmunología , Línea Celular , Epítopos/inmunología , Células HEK293 , Humanos , Inmunoglobulina A/inmunología , Inmunoglobulina G/inmunología , Macrófagos , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Datos de Secuencia Molecular , Mutación , Pruebas de Neutralización , Norovirus/genética , Alineación de Secuencia , Análisis de Secuencia de ADN , Carga ViralRESUMEN
UNLABELLED: New human norovirus strains emerge every 2 to 3 years, partly due to mutations in the viral capsid that allow escape from antibody neutralization and herd immunity. To understand how noroviruses evolve antibody resistance, we investigated the structural basis for the escape of murine norovirus (MNV) from antibody neutralization. To identify specific residues in the MNV-1 protruding (P) domain of the capsid that play a role in escape from the neutralizing monoclonal antibody (MAb) A6.2, 22 recombinant MNVs were generated with amino acid substitutions in the A'B' and E'F' loops. Six mutations in the E'F' loop (V378F, A382K, A382P, A382R, D385G, and L386F) mediated escape from MAb A6.2 neutralization. To elucidate underlying structural mechanisms for these results, the atomic structure of the A6.2 Fab was determined and fitted into the previously generated pseudoatomic model of the A6.2 Fab/MNV-1 virion complex. Previously, two distinct conformations, A and B, of the atomic structures of the MNV-1 P domain were identified due to flexibility in the two P domain loops. A superior stereochemical fit of the A6.2 Fab to the A conformation of the MNV P domain was observed. Structural analysis of our observed escape mutants indicates changes toward the less-preferred B conformation of the P domain. The shift in the structural equilibrium of the P domain toward the conformation with poor structural complementarity to the antibody strongly supports a unique mechanism for antibody escape that occurs via antigen flexibility instead of direct antibody-antigen binding. IMPORTANCE: Human noroviruses cause the majority of all nonbacterial gastroenteritis worldwide. New epidemic strains arise in part by mutations in the viral capsid leading to escape from antibody neutralization. Herein, we identify a series of point mutations in a norovirus capsid that mediate escape from antibody neutralization and determine the structure of a neutralizing antibody. Fitting of the antibody structure into the virion/antibody complex identifies two conformations of the antibody binding domain of the viral capsid: one with a superior fit and the other with an inferior fit to the antibody. These data suggest a unique mode of antibody neutralization. In contrast to other viruses that largely escape antibody neutralization through direct disruption of the antibody-virus interface, we identify mutations that acted indirectly by limiting the conformation of the antibody binding loop in the viral capsid and drive the antibody binding domain into the conformation unable to be bound by the antibody.
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Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Infecciones por Caliciviridae/inmunología , Proteínas de la Cápside/química , Proteínas de la Cápside/inmunología , Norovirus/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Infecciones por Caliciviridae/virología , Proteínas de la Cápside/genética , Línea Celular , Humanos , Evasión Inmune , Ratones , Ratones Noqueados , Pruebas de Neutralización , Norovirus/química , Norovirus/genéticaRESUMEN
ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events), the phase 3 morbidity and mortality trial of torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, identified previously undescribed changes in plasma levels of potassium, sodium, bicarbonate, and aldosterone. A key question after this trial is whether the failure of torcetrapib was a result of CETP inhibition or of some other pharmacology of the molecule. The direct effects of torcetrapib and related molecules on adrenal steroid production were assessed in cell culture using the H295R as well as the newly developed HAC15 human adrenal carcinoma cell lines. Torcetrapib induced the synthesis of both aldosterone and cortisol in these two in vitro cell systems. Analysis of steroidogenic gene expression indicated that torcetrapib significantly induced the expression of CYP11B2 and CYP11B1, two enzymes in the last step of aldosterone and cortisol biosynthesis pathway, respectively. Transcription profiling indicated that torcetrapib and angiotensin II share overlapping pathways in regulating adrenal steroid biosynthesis. Hormone-induced steroid production is mainly mediated by two messengers, calcium and cAMP. An increase of intracellular calcium was observed after torcetrapib treatment, whereas cAMP was unchanged. Consistent with intracellular calcium being the key mediator of torcetrapib's effect in adrenal cells, calcium channel blockers completely blocked torcetrapib-induced corticoid release and calcium increase. A series of compounds structurally related to torcetrapib as well as structurally distinct compounds were profiled. The results indicate that the pressor and adrenal effects observed with torcetrapib and related molecules are independent of CETP inhibition.
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Aldosterona/metabolismo , Señalización del Calcio/fisiología , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Hidrocortisona/metabolismo , Quinolinas/farmacología , Neoplasias de las Glándulas Suprarrenales/genética , Neoplasias de las Glándulas Suprarrenales/metabolismo , Neoplasias de las Glándulas Suprarrenales/patología , Anticolesterolemiantes/efectos adversos , Anticolesterolemiantes/química , Anticolesterolemiantes/farmacología , Presión Sanguínea/efectos de los fármacos , Señalización del Calcio/efectos de los fármacos , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/patología , Línea Celular Tumoral , Citocromo P-450 CYP11B2/genética , Citocromo P-450 CYP11B2/metabolismo , Evaluación Preclínica de Medicamentos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Líquido Intracelular/efectos de los fármacos , Líquido Intracelular/metabolismo , Modelos Biológicos , Quinolinas/efectos adversos , Quinolinas/química , Esteroide 11-beta-Hidroxilasa/genética , Esteroide 11-beta-Hidroxilasa/metabolismo , Relación Estructura-ActividadRESUMEN
Calcium channel blockers are widely used antihypertensives. Mineralocorticoid receptor antagonists are also used to treat hypertension and heart failure. We report here that a number of widely used dihydropyridine class calcium channel blockers are able to inhibit aldosterone-induced activation of mineralocorticoid receptor. These dihydropyridines varied in the extent of their effect on mineralocorticoid receptor, with nimodipine and felodipine the most potent and amlodipine the least. In contrast, both diltiazem and verapamil, nondihydropyridine calcium channel blockers, had no effect on mineralocorticoid receptor. These dihydropyridines compete with aldosterone for binding and block aldosterone-induced coactivator recruitment to mineralocorticoid receptor. The mineralocorticoid receptor S810L mutant, which is activated by steroidal mineralocorticoid receptor antagonist such as eplerenone, is inhibited by these drugs. Furthermore, nimodipine decreased aldosterone-induced expression of the mineralocorticoid receptor target gene epithelial sodium channel gamma subunit in adrenalectomized rats, demonstrating that dihydropyridine calcium channel blockers can function as mineralocorticoid receptor antagonists in vivo. Molecular modeling indicates that dihydropyridines dock into the ligand binding domain of mineralocorticoid receptor in a consensus pose that partially overlaps with steroidal mineralocorticoid receptor antagonists. Together, our data suggest that, in addition to their calcium channel blocking activity, a number of dihydropyridine calcium channel blockers also have mineralocorticoid receptor antagonist activity at high doses, a finding which may thus prove useful for the design of novel antihypertensive drugs in the future.
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Bloqueadores de los Canales de Calcio/farmacología , Dihidropiridinas/farmacología , Antagonistas de Receptores de Mineralocorticoides , Adrenalectomía , Aldosterona/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Canales Epiteliales de Sodio/metabolismo , Masculino , Modelos Moleculares , Mutación , Nimodipina/farmacología , Unión Proteica , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Receptores de Mineralocorticoides/genética , Receptores de Mineralocorticoides/metabolismoRESUMEN
We investigated the coregulator (coactivator and corepressor) interactions with the mineralocorticoid receptor (MR) that lead to activation and inhibition of the receptor in the presence of agonist and/or antagonist. Our results indicate that MR ligand binding domain (LBD) interacts strongly with only a few specific coactivator peptides in the presence of the agonist aldosterone and that these interactions are blocked by the antagonist eplerenone. We also discovered that cortisol, the preferred physiological ligand for the glucocorticoid receptor in humans, is a partial MR agonist/antagonist, providing a possible molecular explanation of the tissue-selective effects of glucocorticoids on MR. However, when we examined the coactivator and corepressor peptide interactions in the presence of cortisol, we found that MR bound with cortisol or aldosterone interacted with the same set of peptides. Thus, the partial agonism shown by cortisol is unlikely to be the result of differential interaction with known coactivators and corepressors. On the other hand, we have identified coactivator binding groove mutations that are critical for cortisol activation but not for aldosterone activation, suggesting that the two steroids induce different MR LBD conformations. In addition, we also show that cortisol becomes full agonist when S810L mutation is introduced in the LBD of MR. Interestingly, MR antagonists, such as eplerenone and progesterone, become partial agonist/antagonist of S810L but are still able to recruit LXXLL peptides to the mutant receptor. Together, these findings suggest a model to explain the MR activation by various ligands.
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Regulación de la Expresión Génica , Receptores de Mineralocorticoides/metabolismo , Aldosterona/metabolismo , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Línea Celular , Células Cultivadas , Relación Dosis-Respuesta a Droga , Eplerenona , Transferencia Resonante de Energía de Fluorescencia , Glucocorticoides/metabolismo , Humanos , Hidrocortisona/química , Hidrocortisona/metabolismo , Ligandos , Modelos Biológicos , Datos de Secuencia Molecular , Mutación , Péptidos/química , Unión Proteica , Conformación Proteica , Estructura Terciaria de Proteína , Homología de Secuencia de Aminoácido , Espironolactona/análogos & derivados , Espironolactona/química , Transcripción Genética , TransfecciónRESUMEN
Liver X receptors (LXRs) are members of the nuclear receptor superfamily that regulate gene expression in response to oxysterols and play a critical role in cholesterol homeostasis by regulating genes that are involved in cholesterol transport, catabolism, and triglyceride synthesis. Oxysterols and synthetic agonists bind LXRs and activate transcription by recruiting coactivator proteins. The role of LXRs in regulating target gene expression in the absence of ligand is unknown. Here we show that LXRs interact with corepressors, N-CoR (nuclear receptor corepressor) and SMRT (silent mediator of retinoic acid receptor and thyroid receptor), which are released upon binding agonists. The LXR-corepressor interaction is isoform selective, wherein LXRalpha has a very strong interaction with corepressors and LXRbeta only shows weak interaction. LXRs also exhibit a preference for interacting with N-CoR vs. SMRT. Similar to other nuclear receptors, mutations in the LXR helix 3 and 4 region abolish corepressor interaction. Using a transient transfection assay, we demonstrate that LXR represses transcription that can be further increased by cotransfecting N-CoR into cells. Chromatin immunoprecipitation experiments further indicated that N-CoR is recruited onto endogenous LXR target genes, and addition of LXR agonists releases N-CoR from their promoters. Collectively, these results suggest that corepressors play an important role in regulating LXR target gene expression.
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Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica/fisiología , Proteínas Nucleares/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Proteínas Represoras/metabolismo , Animales , Células Cultivadas , Humanos , Receptores X del Hígado , Co-Represor 1 de Receptor Nuclear , Co-Represor 2 de Receptor Nuclear , Receptores Nucleares Huérfanos , Unión Proteica/fisiología , Isoformas de Proteínas/metabolismo , Transcripción Genética/fisiologíaRESUMEN
Ayurveda, the ancient Indian system of health care and medicine, has a well-organized materia medica in which plants form a dominant part. A key illustration of the exploitation of this knowledge toward the development of a modern drug is the isolation and characterization of two antihyperlipidemic compounds, Z-, and E-guggulsterone from the tree Commiphora mukul, the exudate of which has been traditionally used for mitigating lipid disorders. Here, we demonstrate that Z-guggulsterone and an analog, 80-574 currently in clinical trials, act as antagonists of the bile acid receptor (BAR), a member of the intracellular receptor superfamily. These compounds antagonize the activity of BAR in vitro, and in cell culture systems on promoters and endogenous target genes. In biochemical assays, they are able to displace coactivator peptides from the receptor in a dose-dependent manner. The mechanism by which they act as BAR antagonists is likely through their inability to recruit coactivator proteins, failure to release corepressor proteins from unliganded receptor, and ability to compete with BAR agonists to block coactivator recruitment. Our data suggest these compounds may mediate at least some of their effects via the BAR.
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Proteínas de Unión al ADN/antagonistas & inhibidores , Hidroxiesteroide Deshidrogenasas , Hipolipemiantes/farmacología , Glicoproteínas de Membrana , Pregnenodionas/farmacología , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Factores de Transcripción/antagonistas & inhibidores , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Células Cultivadas , Colesterol 7-alfa-Hidroxilasa/efectos de los fármacos , Colesterol 7-alfa-Hidroxilasa/genética , Proteínas de Unión al ADN/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Isoxazoles/farmacología , Ligandos , Hígado/efectos de los fármacos , Hígado/metabolismo , Subunidad 1 del Complejo Mediador , Proteínas Nucleares/efectos de los fármacos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Co-Represor 1 de Receptor Nuclear , Pregnadienos/farmacología , Receptores Citoplasmáticos y Nucleares/efectos de los fármacos , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores de Hormona Tiroidea/efectos de los fármacos , Receptores de Hormona Tiroidea/metabolismo , Proteínas Represoras/efectos de los fármacos , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Factores de Transcripción/efectos de los fármacos , Factores de Transcripción/metabolismoRESUMEN
The liver X receptors (LXRs), members of the nuclear receptor superfamily, play an important role in controlling lipid homeostasis by activating several genes involved in reverse cholesterol transport. These include members of the ATP binding cassette (ABC) superfamily of transporter proteins ABCA1 and ABCG1, surface constituents of plasma lipoproteins like apolipoprotein E, and cholesterol ester transport protein. They also play an important role in fatty acid metabolism by activating the sterol regulatory element-binding protein 1c gene. Here, we identify human LXRalpha (hLXRalpha) as an autoinducible gene. Induction in response to LXR ligands is observed in multiple human cell types including macrophages and occurs within 2--4 h. Analysis of the hLXRalpha promoter revealed three LXR response elements (LXREs); one exhibits strong affinity for both LXRalpha:RXR and LXRbeta:RXR (a type I LXRE), and deletion and mutational studies indicate it plays a critical role in LXR-mediated induction. The other two LXREs are identical to each other, exist within highly conserved Alu repeats, and exhibit selective binding to LXRalpha:RXR (type II LXREs). In transfections, the type I LXRE acts as a strong mediator of both LXRalpha and LXRbeta activity, whereas the type II LXRE acts as a weaker and selective mediator of LXRalpha activity. Our data suggest a model in which LXR ligands trigger an autoregulatory loop leading to selective induction of hLXRalpha gene expression. This would lead to increased hLXRalpha levels and transcription of its downstream target genes such as ABCA1, providing a simple yet exquisite mechanism for cells to respond to LXR ligands and cholesterol loading.