Showing papers by "University of Texas Southwestern Medical Center published in 2000"
TL;DR: The identification of a novel protein, Smac, which promotes caspase activation in the cytochrome c/Apaf-1/caspase-9 pathway and increases cells' sensitivity to apoptotic stimuli is reported.
3,515 citations
TL;DR: In patients with persistently active rheumatoid arthritis despite methotrexate therapy, repeated doses of infliximab in combination with methotRexate provided clinical benefit and halted the progression of joint damage.
Abstract: Background Neutralization of tumor necrosis factor α (TNF-α) for three to six months reduces the symptoms and signs of rheumatoid arthritis. However, the capacity of this approach to effect a more sustained benefit and its effect on joint damage are not known. Methods We treated 428 patients who had active rheumatoid arthritis despite methotrexate therapy with placebo or infliximab, a chimeric monoclonal antibody against TNF-α, in intravenous doses of 3 or 10 mg per kilogram of body weight every 4 or 8 weeks in combination with oral methotrexate for 54 weeks. We assessed clinical responses with use of the criteria of the American College of Rheumatology, the quality of life with a health-status questionnaire, and the effect on joint damage radiographically. Results The combination of infliximab and methotrexate was well tolerated and resulted in a sustained reduction in the symptoms and signs of rheumatoid arthritis that was significantly greater than the reduction associated with methotrexate therapy alo...
3,060 citations
TL;DR: The results show that MMP-9 is a component of theAngiogenic switch, and MMP inhibitors reduce angiogenic switching, and tumour number and growth, as does genetic ablation of M MP-9.
Abstract: During carcinogenesis of pancreatic islets in transgenic mice, an angiogenic switch activates the quiescent vasculature Paradoxically, vascular endothelial growth factor (VEGF) and its receptors are expressed constitutively Nevertheless, a synthetic inhibitor (SU5416) of VEGF signalling impairs angiogenic switching and tumour growth Two metalloproteinases, MMP-2/gelatinase-A and MMP-9/gelatinase-B, are upregulated in angiogenic lesions MMP-9 can render normal islets angiogenic, releasing VEGF MMP inhibitors reduce angiogenic switching, and tumour number and growth, as does genetic ablation of MMP-9 Absence of MMP-2 does not impair induction of angiogenesis, but retards tumour growth, whereas lack of urokinase has no effect Our results show that MMP-9 is a component of the angiogenic switch
2,657 citations
TL;DR: It is found that TRAF6, a RING domain protein, functions together with Ubc13/Uev1A to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63 (K63) of ubiquitin.
1,853 citations
TL;DR: It is shown that S1P and S2P are required for the ER stress response as well as for lipid synthesis, and ATF6 processing did not require SCAP, which is essential for SREBP processing.
1,691 citations
TL;DR: A novel LXR target is described, the sterol regulatory element-binding protein-1c gene (SREBP-1C), which encodes a membrane-bound transcription factor of the basic helix-loop-helix-leucine zipper family and reveals a unique regulatory interplay between cholesterol and fatty acid metabolism.
Abstract: The liver X receptors (LXRs) are members of the nuclear hormone receptor superfamily that are bound and activated by oxysterols. These receptors serve as sterol sensors to regulate the transcription of gene products that control intracellular cholesterol homeostasis through catabolism and transport. In this report, we describe a novel LXR target, the sterol regulatory element-binding protein-1c gene (SREBP-1c), which encodes a membrane-bound transcription factor of the basic helix-loop-helix-leucine zipper family. SREBP-1c expression was markedly increased in mouse tissues in an LXR-dependent manner by dietary cholesterol and synthetic agonists for both LXR and its heterodimer partner, the retinoid X receptor (RXR). Expression of the related gene products, SREBP-1a and SREBP-2, were not increased. Analysis of the mouse SREBP-1c gene promoter revealed an RXR/LXR DNA-binding site that is essential for this regulation. The transcriptional increase in SREBP-1c mRNA by RXR/LXR was accompanied by a similar increase in the level of the nuclear, active form of the SREBP-1c protein and an increase in fatty acid synthesis. Because this active form of SREBP-1c controls the transcription of genes involved in fatty acid biosynthesis, our results reveal a unique regulatory interplay between cholesterol and fatty acid metabolism.
1,580 citations
TL;DR: Data suggest that ABCG5 and ABCG8 normally cooperate to limit intestinal absorption and to promote biliary excretion of sterols, and that mutated forms of these transporters predispose to sterol accumulation and atherosclerosis.
Abstract: In healthy individuals, acute changes in cholesterol intake produce modest changes in plasma cholesterol levels. A striking exception occurs in sitosterolemia, an autosomal recessive disorder characterized by increased intestinal absorption and decreased biliary excretion of dietary sterols, hypercholesterolemia, and premature coronary atherosclerosis. We identified seven different mutations in two adjacent, oppositely oriented genes that encode new members of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter family (six mutations in ABCG8 and one in ABCG5) in nine patients with sitosterolemia. The two genes are expressed at highest levels in liver and intestine and, in mice, cholesterol feeding up-regulates expressions of both genes. These data suggest that ABCG5 and ABCG8 normally cooperate to limit intestinal absorption and to promote biliary excretion of sterols, and that mutated forms of these transporters predispose to sterol accumulation and atherosclerosis.
1,575 citations
TL;DR: An elaborate autoregulatory cascade mediated by nuclear receptors for the maintenance of hepatic cholesterol catabolism is revealed, showing that repression is coordinately regulated by a triumvirate of nuclear receptors, including the bile acid receptor, FXR, and the promoter-specific repressor, SHP.
1,385 citations
TL;DR: This research is supported by grants from the National Institutes of Health (HL20948) and the Perot Family Foundation.
1,361 citations
TL;DR: Synaptic connectivity does not depend on neurotransmitter secretion, but its maintenance does, and neurotransmitter secretion probably functions to validate already established synaptic connections.
Abstract: Brain function requires precisely orchestrated connectivity between neurons. Establishment of these connections is believed to require signals secreted from outgrowing axons, followed by synapse formation between selected neurons. Deletion of a single protein, Munc18-1, in mice leads to a complete loss of neurotransmitter secretion from synaptic vesicles throughout development. However, this does not prevent normal brain assembly, including formation of layered structures, fiber pathways, and morphologically defined synapses. After assembly is completed, neurons undergo apoptosis, leading to widespread neurodegeneration. Thus, synaptic connectivity does not depend on neurotransmitter secretion, but its maintenance does. Neurotransmitter secretion probably functions to validate already established synaptic connections.
1,302 citations
TL;DR: Several nuclear hormone receptors involved in lipid metabolism form obligate heterodimers with retinoid X receptors (RXRs) and are activated by RXR agonists such as rexinoids and serve as key regulators of cholesterol homeostasis by governing reverse cholesterol transport from peripheral tissues, bile acid synthesis in liver, and cholesterol absorption in intestine.
Abstract: Several nuclear hormone receptors involved in lipid metabolism form obligate heterodimers with retinoid X receptors (RXRs) and are activated by RXR agonists such as rexinoids. Animals treated with rexinoids exhibited marked changes in cholesterol balance, including inhibition of cholesterol absorption and repressed bile acid synthesis. Studies with receptor-selective agonists revealed that oxysterol receptors (LXRs) and the bile acid receptor (FXR) are the RXR heterodimeric partners that mediate these effects by regulating expression of the reverse cholesterol transporter, ABC1, and the rate-limiting enzyme of bile acid synthesis, CYP7A1, respectively. Thus, these RXR heterodimers serve as key regulators of cholesterol homeostasis by governing reverse cholesterol transport from peripheral tissues, bile acid synthesis in liver, and cholesterol absorption in intestine.
Brown University1, Virginia Commonwealth University2, Stony Brook University3, Stanford University4, University of Washington5, University of Arizona6, Cornell University7, Emory University8, University of Texas Medical Branch9, University of Pittsburgh10, University of Texas Southwestern Medical Center11, Rush University Medical Center12
TL;DR: Although about half of patients with chronic forms of major depression have a response to short-term treatment with either nefazodone or a cognitive behavioral-analysis system of psychotherapy, the combination of the two is significantly more efficacious than either treatment alone.
Abstract: Background Patients with chronic forms of major depression are difficult to treat, and the relative efficacy of medications and psychotherapy is uncertain. Methods We randomly assigned 681 adults with a chronic nonpsychotic major depressive disorder to 12 weeks of outpatient treatment with nefazodone (maximal dose, 600 mg per day), the cognitive behavioral-analysis system of psychotherapy (16 to 20 sessions), or both. At base line, all patients had scores of at least 20 on the 24-item Hamilton Rating Scale for Depression (indicating clinically significant depression). Remission was defined as a score of 8 or less at weeks 10 and 12. For patients who did not have remission, a satisfactory response was defined as a reduction in the score by at least 50 percent from base line and a score of 15 or less. Raters were unaware of the patients' treatment assignments. Results Of the 681 patients, 662 attended at least one treatment session and were included in the analysis of response. The overall rate of response ...
TL;DR: Cardiac dysfunction in obesity is caused by lipoapoptosis and is prevented by reducing cardiac lipids and Troglitazone therapy lowered myocardial TG and ceramide and completely prevented DNA laddering and loss of cardiac function.
Abstract: To determine the mechanism of the cardiac dilatation and reduced contractility of obese Zucker Diabetic Fatty rats, myocardial triacylglycerol (TG) was assayed chemically and morphologically. TG was high because of underexpression of fatty acid oxidative enzymes and their transcription factor, peroxisome proliferator-activated receptor-α. Levels of ceramide, a mediator of apoptosis, were 2–3 times those of controls and inducible nitric oxide synthase levels were 4 times greater than normal. Myocardial DNA laddering, an index of apoptosis, reached 20 times the normal level. Troglitazone therapy lowered myocardial TG and ceramide and completely prevented DNA laddering and loss of cardiac function. In this paper, we conclude that cardiac dysfunction in obesity is caused by lipoapoptosis and is prevented by reducing cardiac lipids.
TL;DR: Prenatal diagnosis by direct mutation detection permits prenatal treatment of affected females with severe, classic 21-hydroxylase deficiency to minimize genital virilization, reducing mortality from this condition.
Abstract: More than 90% of cases of congenital adrenal hyperplasia (CAH, the inherited inability to synthesize cortisol) are caused by 21-hydroxylase deficiency. Females with severe, classic 21-hydroxylase deficiency are exposed to excess androgens prenatally and are born with virilized external genitalia. Most patients cannot synthesize sufficient aldosterone to maintain sodium balance and may develop potentially fatal "salt wasting" crises if not treated. The disease is caused by mutations in the CYP21 gene encoding the steroid 21-hydroxylase enzyme. More than 90% of these mutations result from intergenic recombinations between CYP21 and the closely linked CYP21P pseudogene. Approximately 20% are gene deletions due to unequal crossing over during meiosis, whereas the remainder are gene conversions--transfers to CYP21 of deleterious mutations normally present in CYP21P. The degree to which each mutation compromises enzymatic activity is strongly correlated with the clinical severity of the disease in patients carrying it. Prenatal diagnosis by direct mutation detection permits prenatal treatment of affected females to minimize genital virilization. Neonatal screening by hormonal methods identifies affected children before salt wasting crises develop, reducing mortality from this condition. Glucocorticoid and mineralocorticoid replacement are the mainstays of treatment, but more rational dosing and additional therapies are being developed.
TL;DR: GAP activity can sharpen the termination of a signal upon removal of stimulus, attenuate a signal either as a feedback inhibitor or in response to a second input, promote regulatory association of other proteins, or redirect signaling within a G protein signaling network.
Abstract: ▪ Abstract GTPase-activating proteins (GAPs) regulate heterotrimeric G proteins by increasing the rates at which their α subunits hydrolyze bound GTP and thus return to the inactive state. G protein GAPs act allosterically on Gα subunits, in contrast to GAPs for the Ras-like monomeric GTP-binding proteins. Although they do not contribute directly to the chemistry of GTP hydrolysis, G protein GAPs can accelerate hydrolysis >2000-fold. G protein GAPs include both effector proteins (phospholipase C-β, p115RhoGEF) and a growing family of regulators of G protein signaling (RGS proteins) that are found throughout the animal and fungal kingdoms. GAP activity can sharpen the termination of a signal upon removal of stimulus, attenuate a signal either as a feedback inhibitor or in response to a second input, promote regulatory association of other proteins, or redirect signaling within a G protein signaling network. GAPs are regulated by various controls of their cellular concentrations, by complex interactions wit...
National Institutes of Health1, Indiana University – Purdue University Indianapolis2, George Washington University3, University of Cincinnati4, Emory University5, Case Western Reserve University6, University of Texas Southwestern Medical Center7, University of Miami8, Wayne State University9, University of Tennessee Health Science Center10, Stanford University11, University of New Mexico12, Yale University13
TL;DR: ELBW infants are at significant risk of neurologic abnormalities, developmental delays, and functional delays at 18 to 22 months' corrected age, and factors significantly associated with decreased morbidity included increased birth weight, female gender, higher maternal education, and white race.
Abstract: Objectives. The purposes of this study were to report the neurodevelopmental, neurosensory, and functional outcomes of 1151 extremely low birth weight (401–1000 g) survivors cared for in the 12 participating centers of the National Institute of Child Health and Human Development Neonatal Research Network, and to identify medical, social, and environmental factors associated with these outcomes. Study Design. A multicenter cohort study in which surviving extremely low birth weight infants born in 1993 and 1994 underwent neurodevelopmental, neurosensory, and functional assessment at 18 to 22 months9 corrected age. Data regarding pregnancy and neonatal outcome were collected prospectively. Socioeconomic status and a detailed interim medical history were obtained at the time of the assessment. Logistic regression models were used to identify maternal and neonatal risk factors for poor neurodevelopmental outcome. Results. Of the 1480 infants alive at 18 months of age, 1151 (78%) were evaluated. Study characteristics included a mean birth weight of 796 ± 135 g, mean gestation (best obstetric dates) 26 ± 2 weeks, and 47% male. Birth weight distributions of infants included 15 infants at 401 to 500 g; 94 at 501 to 600 g; 208 at 601 to 700 g; 237 at 701 to 800 g; 290 at 801 to 900 g; and 307 at 901 to 1000 g. Twenty-five percent of the children had an abnormal neurologic examination, 37% had a Bayley II Mental Developmental Index Conclusion. ELBW infants are at significant risk of neurologic abnormalities, developmental delays, and functional delays at 18 to 22 months9 corrected age.
TL;DR: A high intake of dietary fiber, particularly of the soluble type, above the level recommended by the ADA, improves glycemic control, decreases hyperinsulinemia, and lowers plasma lipid concentrations in patients with type 2 diabetes.
Abstract: Background The effect of increasing the intake of dietary fiber on glycemic control in patients with type 2 diabetes mellitus is controversial. Methods In a randomized, crossover study, we assigned 13 patients with type 2 diabetes mellitus to follow two diets, each for six weeks: a diet containing moderate amounts of fiber (total, 24 g; 8 g of soluble fiber and 16 g of insoluble fiber), as recommended by the American Diabetes Association (ADA), and a highfiber diet (total, 50 g; 25 g of soluble fiber and 25 g of insoluble fiber) containing foods not fortified with fiber (unfortified foods). Both diets, prepared in a research kitchen, had the same macronutrient and energy content. We compared the effects of the two diets on glycemic control and plasma lipid concentrations. Results Compliance with the diets was excellent. During the sixth week of the high-fiber diet, as compared with the sixth week of the ADA diet, mean daily preprandial plasma glucose concentrations were 13 mg per deciliter (0.7 mmol per liter) lower (95 percent confidence interval, 1 to 24 mg per deciliter [0.1 to 1.3 mmol per liter]; P=0.04) and mean daily urinary glucose excretion was 1.3 g lower (median difference, 0.23 g; 95 percent confidence interval, 0.03 to 1.83; P=0.008). The high-fiber diet also lowered the area under the curve for 24-hour plasma glucose and insulin concentrations, which were measured every two hours, by 10 percent (P=0.02) and 12 percent (P=0.05), respectively. The high-fiber diet reduced plasma total cholesterol concentrations by 6.7 percent (P=0.02), triglyceride concentrations by 10.2 percent (P=0.02), and very-low-density lipoprotein cholesterol concentrations by 12.5 percent (P=0.01). Conclusions A high intake of dietary fiber, particularly of the soluble type, above the level recommended by the ADA, improves glycemic control, decreases hyperinsulinemia, and lowers plasma lipid concentrations in patients with type 2 diabetes. (N Engl J
TL;DR: It is suggested that nucleo-cytoplasmic trafficking of HDACs is involved in the control of cellular differentiation, and a mechanism for transcriptional regulation through signal- and differentiation-dependent nuclear export of a chromatin-remodelling enzyme is highlighted.
Abstract: Members of the myocyte enhancer factor-2 (MEF2) family of transcription factors associate with myogenic basic helix-loop-helix transcription factors such as MyoD to activate skeletal myogenesis. MEF2 proteins also interact with the class II histone deacetylases HDAC4 and HDAC5, resulting in repression of MEF2-dependent genes. Execution of the muscle differentiation program requires release of MEF2 from repression by HDACs, which are expressed constitutively in myoblasts and myotubes. Here we show that HDAC5 shuttles from the nucleus to the cytoplasm when myoblasts are triggered to differentiate. Calcium/calmodulin-dependent protein kinase (CaMK) signalling, which stimulates myogenesis and prevents formation of MEF2-HDAC complexes, also induces nuclear export of HDAC4 and HDAC5 by phosphorylation of these transcriptional repressors. An HDAC5 mutant lacking two CaMK phosphorylation sites is resistant to CaMK-mediated nuclear export and acts as a dominant inhibitor of skeletal myogenesis, whereas a cytoplasmic HDAC5 mutant is unable to block efficiently the muscle differentiation program. Our results highlight a mechanism for transcriptional regulation through signal- and differentiation-dependent nuclear export of a chromatin-remodelling enzyme, and suggest that nucleo-cytoplasmic trafficking of HDACs is involved in the control of cellular differentiation.
TL;DR: While many details remain to be worked out, it is clear that the aqueous phase of the cytoplasm is crowded rather than dilute, and that the diffusion and partitioning of macromolecules and vesicles in cytopLasm is highly restricted by steric hindrance as well as by unexpected binding interactions.
Abstract: Classical biochemistry is founded on several assumptions valid in dilute aqueous solutions that are often extended without question to the interior milieu of intact cells. In the first section of this chapter, we present these assumptions and briefly examine the ways in which the cell interior may depart from the conditions of an ideal solution. In the second section, we summarize experimental evidence regarding the physical properties of the cell cytoplasm and their effect on the diffusion and binding of macromolecules and vesicles. While many details remain to be worked out, it is clear that the aqueous phase of the cytoplasm is crowded rather than dilute, and that the diffusion and partitioning of macromolecules and vesicles in cytoplasm is highly restricted by steric hindrance as well as by unexpected binding interactions. Furthermore, the enzymes of several metabolic pathways are now known to be organized into structural and functional units with specific localizations in the solid phase, and as much as half the cellular protein content may also be in the solid phase.
Emory University1, University of Mississippi2, University of Texas Southwestern Medical Center3, University of California, San Francisco4, The Royal Marsden NHS Foundation Trust5, University of Washington6, University of Iowa Hospitals and Clinics7, St. Joseph's Hospital and Medical Center8, Memorial Hospital of Rhode Island9, University of Michigan10, Western Pennsylvania Hospital11, NorthShore University HealthSystem12, Duke University13, University of Pennsylvania14, University of British Columbia15, Merck & Co.16
TL;DR: Overall PFS significantly improved with TMZ, with a median PFS of 12.4 weeks in the TMZ group and 8.32 months in the PCB group, and freedom from disease progression was associated with maintenance of HRQL, regardless of treatment received.
Abstract: A randomized, multicentre, open-label, phase II study compared temozolomide (TMZ), an oral second-generation alkylating agent, and procarbazine (PCB) in 225 patients with glioblastoma multiforme at first relapse. Primary objectives were to determine progression-free survival (PFS) at 6 months and safety for TMZ and PCB in adult patients who failed conventional treatment. Secondary objectives were to assess overall survival and health-related quality of life (HRQL). TMZ was given orally at 200 mg/m(2)/day or 150 mg/m(2)/day (prior chemotherapy) for 5 days, repeated every 28 days. PCB was given orally at 150 mg/m(2)/day or 125 mg/m(2)/day (prior chemotherapy) for 28 days, repeated every 56 days. HRQL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30 [+3]) and the Brain Cancer Module 20 (BCM20). The 6-month PFS rate for patients who received TMZ was 21%, which met the protocol objective. The 6-month PFS rate for those who received PCB was 8% (P = 0.008, for the comparison). Overall PFS significantly improved with TMZ, with a median PFS of 12.4 weeks in the TMZ group and 8.32 weeks in the PCB group (P = 0.0063). The 6-month overall survival rate for TMZ patients was 60% vs. 44% for PCB patients (P = 0.019). Freedom from disease progression was associated with maintenance of HRQL, regardless of treatment received. TMZ had an acceptable safety profile; most adverse events were mild or moderate in severity.
TL;DR: It is demonstrated that ligand binding facilitates cleavage at a novel site (S2), within the extracellular juxtamembrane region, which serves to release ectodomain repression of NICD production.
TL;DR: An enzyme system that regulates chromosome dynamics and controls histone phosphorylation that is conserved among diverse eukaryotes is revealed.
TL;DR: The high-resolution crystal structure of Smac/DIABLO complexed with the third BIR domain (BIR3) of XIAP is reported, revealing how Smac may relieve IAP inhibition of caspase-9 activity and identifies potential targets for drug screening.
Abstract: Apoptosis is an essential process in the development and homeostasis of all metazoans. The inhibitor-of-apoptosis (IAP) proteins suppress cell death by inhibiting the activity of caspases; this inhibition is performed by the zinc-binding BIR domains of the IAP proteins. The mitochondrial protein Smac/DIABLO promotes apoptosis by eliminating the inhibitory effect of IAPs through physical interactions. Amino-terminal sequences in Smac/DIABLO are required for this function, as mutation of the very first amino acid leads to loss of interaction with IAPs and concomitant loss of Smac/DIABLO function. Here we report the high-resolution crystal structure of Smac/DIABLO complexed with the third BIR domain (BIR3) of XIAP. Our results show that the N-terminal four residues (Ala-Val-Pro-Ile) in Smac/DIABLO recognize a surface groove on BIR3, with the first residue Ala binding a hydrophobic pocket and making five hydrogen bonds to neighbouring residues on BIR3. These observations provide a structural explanation for the roles of the Smac N terminus as well as the conserved N-terminal sequences in the Drosophila proteins Hid/Grim/Reaper. In conjunction with other observations, our results reveal how Smac may relieve IAP inhibition of caspase-9 activity. In addition to explaining a number of biological observations, our structural analysis identifies potential targets for drug screening.
TL;DR: It is shown that Smac/DIABLO promotes not only the proteolytic activation of procaspase-3 but also the enzymatic activity of mature caspases, both of which depend upon its ability to interact physically with IAPs.
Abstract: Apoptosis (programmed cell death), an essential process in the development and homeostasis of metazoans, is carried out by caspases. The mitochondrial protein Smac/DIABLO performs a critical function in apoptosis by eliminating the inhibitory effect of IAPs (inhibitor of apoptosis proteins) on caspases. Here we show that Smac/DIABLO promotes not only the proteolytic activation of procaspase-3 but also the enzymatic activity of mature caspase-3, both of which depend upon its ability to interact physically with IAPs. The crystal structure of Smac/DIABLO at 2.2 A resolution reveals that it homodimerizes through an extensive hydrophobic interface. Missense mutations inactivating this dimeric interface significantly compromise the function of Smac/DIABLO. As in the Drosophila proteins Reaper, Grim and Hid, the amino-terminal amino acids of Smac/DIABLO are indispensable for its function, and a seven-residue peptide derived from the amino terminus promotes procaspase-3 activation in vitro. These results establish an evolutionarily conserved structural and biochemical basis for the activation of apoptosis by Smac/DIABLO.
TL;DR: In this paper, the authors show that chronic hyperinsulinemia downregulates the mRNA for IRS-2, an essential component of the insulin-signaling pathway in liver, thereby producing insulin resistance.
TL;DR: In adults, the most common causes of cyanotic congenital heart disease are tetralogy of Fallot61 and Eisenmenger's syndrome.
Abstract: Cyanotic Conditions Patients with cyanotic congenital heart disease have arterial oxygen desaturation resulting from the shunting of systemic venous blood to the arterial circulation. The magnitude of shunting determines the severity of desaturation. Most children with cyanotic heart disease do not survive to adulthood without surgical intervention. In adults, the most common causes of cyanotic congenital heart disease are tetralogy of Fallot61 and Eisenmenger's syndrome. Tetralogy of Fallot Tetralogy of Fallot, the most common cyanotic congenital heart defect after infancy, is characterized by a large ventricular septal defect, an aorta that overrides the left and right ventricles, obstruction of the . . .
TL;DR: A role in behavior that is remarkably sensitive to alterations in BDNF activity is indicated and infusion with BDNF or NT4/5 can transiently reverse the eating behavior and obesity.
Abstract: Brain-derived neurotrophic factor (BDNF) was studied initially for its role in sensory neuron development. Ablation of this gene in mice leads to death shortly after birth, and abnormalities have been found in both the peripheral and central nervous systems. BDNF and its tyrosine kinase receptor, TrkB, are expressed in hypothalamic nuclei associated with satiety and locomotor activity. In heterozygous mice, BDNF gene expression is reduced and we find that all heterozygous mice exhibit abnormalities in eating behavior or locomotor activity. We also observe this phenotype in independently derived inbred and hybrid BDNF mutant strains. Infusion with BDNF or NT4/5 can transiently reverse the eating behavior and obesity. Thus, we identify a novel non-neurotrophic function for neurotrophins and indicate a role in behavior that is remarkably sensitive to alterations in BDNF activity.
TL;DR: Positional cloning work has revealed that Lps encodes the Toll-like receptor 4 (Tlr4), which functions as the transmembrane component of the LPS receptor complex, an unduplicated pathway for the detection of endotoxin.
TL;DR: It is shown that transcription of the gene encoding Nip3, a proapoptotic member of the Bcl-2 family of cell death factors, is strongly induced in response to hypoxia, indicating that Nip 3 may play a dedicated role in the pathological progression ofHypoxia-mediated apoptosis, as observed after ischemic injury.
Abstract: The ability to sense and respond to changes in oxygen availability is critical for many developmental, physiological, and pathological processes, including angiogenesis, control of blood pressure, and cerebral and myocardial ischemia. Hypoxia-inducible factor-1α (HIF-1α) is a basic-helix–loop–helix (bHLH)containing member of the PER–ARNT–SIM (PAS) family of transcription factors that plays a central role in the response to hypoxia. HIF-1α, and its relatives HIF-2α/endothelial PAS domain protein (EPAS) and HIF-3α, are induced in response to hypoxia and serve to coordinately activate the expression of target genes whose products facilitate cell survival under conditions of oxygen deprivation. When cells are exposed to chronic hypoxia, the protective response can fail, resulting in apoptosis. This study shows that transcription of the gene encoding Nip3, a proapoptotic member of the Bcl-2 family of cell death factors, is strongly induced in response to hypoxia. The Nip3 promoter contains a functional HIF-1-responsive element (HRE) and is potently activated by both hypoxia and forced expression of HIF-1α. Exposure of cultured cells to chronic hypoxia results in the accumulation of a protein recognized by antibodies raised against Nip3. This study demonstrates a direct link between HIF-1α and a proapoptotic member of the Bcl-2 family and offers a reasonable physiological function for members of the Bcl-2 subfamily, including Nip3 and its close relative Nix. These observations indicate that Nip3 may play a dedicated role in the pathological progression of hypoxia-mediated apoptosis, as observed after ischemic injury.