Showing papers by "Rockefeller University published in 1995"
TL;DR: Injection of wild-type mice twice daily with the mouse protein resulted in a sustained 12 percent weight loss, decreased food intake, and a reduction of body fat from 12.2 to 0.7 percent, suggesting that the OB protein serves an endocrine function to regulate body fat stores.
Abstract: The gene product of the ob locus is important in the regulation of body weight. The ob product was shown to be present as a 16-kilodalton protein in mouse and human plasma but was undetectable in plasma from C57BL/6J ob/ob mice. Plasma levels of this protein were increased in diabetic (db) mice, a mutant thought to be resistant to the effects of ob. Daily intraperitoneal injections of either mouse or human recombinant OB protein reduced the body weight of ob/ob mice by 30 percent after 2 weeks of treatment with no apparent toxicity but had no effect on db/db mice. The protein reduced food intake and increased energy expenditure in ob/ob mice. Injections of wild-type mice twice daily with the mouse protein resulted in a sustained 12 percent weight loss, decreased food intake, and a reduction of body fat from 12.2 to 0.7 percent. These data suggest that the OB protein serves an endocrine function to regulate body fat stores.
4,708 citations
TL;DR: Weight loss due to food restriction was associated with a decrease in plasma leptin in samples from mice and obese humans, suggesting differences in its secretion rate from fat.
Abstract: Leptin, the gene product of the obese gene, may play an important role in regulating body weight by signalling the size of the adipose tissue mass. Plasma leptin was found to be highly correlated with body mass index (BMI) in rodents and in 87 lean and obese humans. In humans, there was variability in plasma leptin at each BMI suggesting that there are differences in its secretion rate from fat. Weight loss due to food restriction was associated with a decrease in plasma leptin in samples from mice and obese humans.
3,763 citations
TL;DR: It is shown that gene activation by Stat1 and Stat3, which obligatorily require tyrosine phosphorylation to become active, also depends for maximal activation on one or more of the many serine kinases.
2,001 citations
TL;DR: Maintenance of a reduced or elevated body weight is associated with compensatory changes in energy expenditure, which oppose the maintenance of a body weight that is different from the usual weight, which may account for the poor long-term efficacy of treatments for obesity.
Abstract: Background No current treatment for obesity reliably sustains weight loss, perhaps because compensatory metabolic processes resist the maintenance of the altered body weight. We examined the effects of experimental perturbations of body weight on energy expenditure to determine whether they lead to metabolic changes and whether obese subjects and those who have never been obese respond similarly. Methods We repeatedly measured 24-hour total energy expenditure, resting and nonresting energy expenditure, and the thermic effect of feeding in 18 obese subjects and 23 subjects who had never been obese. The subjects were studied at their usual body weight and after losing 10 to 20 percent of their body weight by underfeeding or gaining 10 percent by overfeeding. Results Maintenance of a body weight at a level 10 percent or more below the initial weight was associated with a mean (±SD) reduction in total energy expenditure of 6±3 kcal per kilogram of fat-free mass per day in the subjects who had never been obese...
1,897 citations
TL;DR: Evidence suggests that the glucocorticoid- and stress-related cognitive impairments involving declarative memory are probably related to the changes they effect in the hippocampus, whereas the stress-induced catecholamine effects on emotionally laden memories are postulated to involve structures such as the amgydala.
1,811 citations
TL;DR: This presents the first test of the Ruelle principle on a many particle system far from equilibrium, and a specific prediction, obtained without the need to construct explicitly the SRB itself, is shown to be in agreement with a recent computer experiment on a strongly sheared fluid.
Abstract: Ruelle`s principle for turbulence leading to what is usually called the Sinai-Ruelle-Bowen (SRB) distribution is applied to the statistical mechanics of many particle systems in nonequilibrium stationary states. A specific prediction, obtained without the need to construct explicitly the SRB itself, is shown to be in agreement with a recent computer experiment on a strongly sheared fluid. This presents the first test of the principle on a many particle system far from equilibrium. A possible application to fluid mechanics is also discussed.
1,587 citations
TL;DR: Mice deficient in inducible nitric oxide synthase (iNOS) were generated to test the idea that iNOS defends the host against infectious agents and tumor cells at the risk of contributing to tissue damage and shock, and found there exist both iN OS-dependent and iNos-independent routes to LPS-induced hypotension and death.
1,487 citations
TL;DR: Data support the role of NF-kappa B as a vital transcription factor for both specific and nonspecific immune responses, but do not indicate a developmental role for the factor.
1,203 citations
TL;DR: 3D models of human nucleoside diphosphate kinase, mouse cellular retinoic acid binding protein I, and human eosinophil neurotoxin that were calculated by MODELLER, a program for comparative protein modeling by satisfaction of spatial restraints, have good stereochemistry and are at least as similar to the crystallographic structures as the closest template structures.
Abstract: We evaluate 3D models of human nucleoside diphosphate kinase, mouse cellular retinoic acid binding protein I, and human eosinophil neurotoxin that were calculated by MODELLER, a program for comparative protein modeling by satisfaction of spatial restraints. The models have good stereochemistry and are at least as similar to the crystallographic structures as the closest template structures. The largest errors occur in the regions that were not aligned correctly or where the template structures are not similar to the correct structure. These regions correspond predominantly to exposed loops, insertions of any length, and non-conserved side chains. When a template structure with more than 40% sequence identity to the target protein is available, the model is likely to have about 90% of the mainchain atoms modeled with an rms deviation from the X-ray structure of approximately 1 A, in large part because the templates are likely to be that similar to the X-ray structure of the target. This rms deviation is comparable to the overall differences between refined NMR and X-ray crystallography structures of the same protein.
1,128 citations
TL;DR: These factors are increasing in prevalence; this increase suggests that infections will continue to emerge and probably increase and emphasizes the urgent need for effective surveillance and control.
Abstract: “Emerging” infectious diseases can be defined as infections that have newly appeared in a population or have existed but are rapidly increasing in incidence or geographic range. Among recent examples are HIV/AIDS, hantavirus pulmonary syndrome, Lyme disease, and hemolytic uremic syndrome (a foodborne infection caused by certain strains of Escherichia coli). Specific factors precipitating disease emergence can be identified in virtually all cases. These include ecological, environmental, or demographic factors that place people at increased contact with a previously unfamiliar microbe or its natural host or promote dissemination. These factors are increasing in prevalence; this increase, together with the ongoing evolution of viral and microbial variants and selection for drug resistance, suggests that infections will continue to emerge and probably increase and emphasizes the urgent need for effective surveillance and control. Dr. David Satcher’s article and this overview inaugurate “Perspectives,” a regular section in this journal intended to present and develop unifying concepts and strategies for considering emerging infections and their underlying factors. The editors welcome, as contributions to the Perspectives section, overviews, syntheses, and case studies that shed light on how and why infections emerge, and how they may be anticipated and prevented. Infectious diseases emerging throughout history have included some of the most feared plagues of the past. New infections continue to emerge today, while many of the old plagues are with us still. These are global problems (William Foege, former CDC director now at the Carter Center, terms them “global infectious disease threats”). As demonstrated by influenza epidemics, under suitable circumstances, a new infection first appearing anywhere in the world could traverse entire continents within days or weeks.
1,040 citations
TL;DR: In this paper, the existence of the top quark was established using a data sample of collisions at the Fermilab National Ensemble (CDF) collected with the Collider Detector.
Abstract: We establish the existence of the top quark using a $67{\mathrm{pb}}^{\ensuremath{-}1}$ data sample of $\overline{p}p$ collisions at $\sqrt{s}\phantom{\rule{0ex}{0ex}}=\phantom{\rule{0ex}{0ex}}1.8\mathrm{TeV}$ collected with the Collider Detector at Fermilab (CDF). Employing techniques similar to those we previously published, we observe a signal consistent with $t\overline{t}$ decay to $\mathrm{WWb}\overline{b}$, but inconsistent with the background prediction by $4.8\ensuremath{\sigma}$. Additional evidence for the top quark is provided by a peak in the reconstructed mass distribution. We measure the top quark mass to be $176\ifmmode\pm\else\textpm\fi{}8(\mathrm{stat})\ifmmode\pm\else\textpm\fi{}10(\mathrm{syst})\mathrm{GeV}{/c}^{2}$, and the $t\overline{t}$ production cross section to be ${6.8}_{\ensuremath{-}2.4}^{+3.6}\mathrm{pb}$.
TL;DR: DEC-205 is a novel endocytic receptor that can be used by dendritic cells and thymic epithelial cells to direct captured antigens from the extracellular space to a specialized antigen-processing compartment.
Abstract: Dendritic cells and thymic epithelial cells perform important immunoregulatory functions by presenting antigens in the form of peptides bound to cell-surface major histocompatibility complex (MHC) molecules to T cells. Whereas B cells are known to present specific antigens efficiently through their surface immunoglobins, a comparable mechanism for the capture and efficient presentation of diverse antigens by dendritic cells and thymic epithelial cells has not previously been described. We show here that their antigen-presentation function is associated with the high-level expression of DEC-205, an integral membrane protein homologous to the macrophage mannose receptor and related receptors which are able to bind carbohydrates and mediate endocytosis. DEC-205 is rapidly taken up by means of coated pits and vesicles, and is delivered to a multivesicular endosomal compartment that resembles the MHC class II-containing vesicles implicated in antigen presentation. Rabbit antibodies that bind DEC-205 are presented to reactive T-cell hybridomas 100-fold more efficiently than rabbit antibodies that do not bind DEC-205. Thus DEC-205 is a novel endocytic receptor that can be used by dendritic cells and thymic epithelial cells to direct captured antigens from the extracellular space to a specialized antigen-processing compartment.
TL;DR: The number of applications where homology modeling has been proven useful is growing rapidly and an order of magnitude more sequences can be modeled by comparative modeling than there are experimentally determined protein structures.
TL;DR: The contextual sensitivity of human contrast thresholds and of superficial layer complex cells in monkey V1 was measured and it was shown that 42% of complex cells demonstrated facilitation for a second bar outside their classical receptive fields with a similar dependency on relative location and orientation.
TL;DR: In this paper, a chaotic hypothesis for reversible dissipative many-particle systems in nonequilibrium stationary states in general is proposed, which leads to the identification of a unique distribution μ describing the asymptotic properties of the system for initial data randomly chosen with respect to a uniform distribution on phase space.
Abstract: We propose, as a generalization of an idea of Ruelle's to describe turbulent fluid flow, a chaotic hypothesis for reversible dissipative many-particle systems in nonequilibrium stationary states in general. This implies an extension of the zeroth law of thermodynamics to nonequilibrium states and it leads to the identification of a unique distribution μ describing the asymptotic properties of the time evolution of the system for initial data randomly chosen with respect to a uniform distribution on phase space. For conservative systems in thermal equilibrium the chaotic hypothesis implies the ergodic hypothesis. We outline a procedure to obtain the distribution μ: it leads to a new unifying point of view for the phase space behavior of dissipative and conservative systems. The chaotic hypothesis is confirmed in a nontrivial, parameter-free, way by a recent computer experiment on the entropy production fluctuations in a shearing fluid far from equilibrium. Similar applications to other models are proposed, in particular to a model for the Kolmogorov-Obuchov theory for turbulent flow.
TL;DR: The crystal structure of the processivity factor required by eukaryotic DNA polymerase delta, proliferating cell nuclear antigen from S. cerevisiae, has been determined and the dimensions and electrostatic properties of the ring suggest that PCNA encircles duplex DNA, providing a DNA-bound platform for the attachment of the polymerase.
TL;DR: The results indicate that the reversible atrophy induced by 21 days of daily restraint stress requires corticosterone secretion and that excitatory mechanisms involving N-methyl-D-aspartate receptors play a major role in driving the atrophy.
TL;DR: The crystal structure of mammalian protein phosphatase-1, complexed with the toxin microcys-tin and determined at 2.1 Å resolution, reveals that it is a metalloenzyme unrelated in architecture to the tyrosine phosphatases.
Abstract: The crystal structure of mammalian protein phosphatase-1, complexed with the toxin microcystin and determined at 2.1 A resolution, reveals that it is a metalloenzyme unrelated in architecture to the tyrosine phosphatases. Two metal ions are positioned by a central beta-alpha-beta-alpha-beta scaffold at the active site, from which emanate three surface grooves that are potential binding sites for substrates and inhibitors. The carboxy terminus is positioned at the end of one of the grooves such that regulatory sequences following the domain might modulate function. The fold of the catalytic domain is expected to be closely preserved in protein phosphatases 2A and 2B (calcineurin).
TL;DR: It is reported that bone morphogenesis protein 4 (Bmp-4), a relative of activin that is expressed in the embryo at the time of ectodermal fate determination, is a potent epidermal inducer and neural inhibitor, the first reported in any vertebrate.
Abstract: DURING gastrulation in vertebrates, ectodermal cells choose between two fates, neural and epidermal. The nervous system forms in response to signals from the Spemann organizer1,2; ectoderm that does not receive these signals becomes epidermis. Unexpectedly, however, in Xenopus, neural tissue also forms when cell-cell communication within the ectoderm is disrupted by cell dissociation3,4 or by antagonists of the growth factor activin5-7. These observations suggest that epidermal specification depends on local signalling, by activin or a close relative, and that neural tissue forms when this communication is blocked6. Here we report that bone morphogenesis protein 4 (Bmp-4), a relative of activin that is expressed in the embryo at the time of ectodermal fate determination8,9, is a potent epidermal inducer and neural inhibitor, the first reported in any vertebrate. Activin can inhibit neuralization by inducing mesoderm, but does not induce epidermis. Moreover, the dominant-negative activin receptor, which stimulates neuralization when expressed in the embryo5,6, blocks Bmp-4 in our assay. Our findings demonstrate that epidermal fate can be induced, and thus provide further evidence that neural specification is under inhibitory control in vertebrates.
TL;DR: Given a set of empirical eigenfunctions, it is shown how to recover the modal coefficients for each gappy snapshot by a least-squares procedure that gives an unbiased estimate of the data that lie in the gaps and permits gaps to be filled in a reasonable manner.
Abstract: The problem of using the Karhunen–Loeve transform with partial data is addressed. Given a set of empirical eigenfunctions, we show how to recover the modal coefficients for each gappy snapshot by a least-squares procedure. This method gives an unbiased estimate of the data that lie in the gaps and permits gaps to be filled in a reasonable manner. In addition, a scheme is advanced for finding empirical eigenfunctions from gappy data. It is shown numerically that this procedure obtains spectra and eigenfunctions that are close to those obtained from unmarred data.
TL;DR: Data indicate that human telomerase is not restricted to immortal cells and suggest that the somatic expression of this enzyme may be more widespread than was previously inferred from the decline of human telomeres.
Abstract: Bone marrow and peripheral blood leukocytes from 19 leukemia patients were found to contain telomerase activity detectable by a PCR-based assay. Telomerase was also detectable in nonmalignant bone marrow and peripheral blood leukocytes from normal donors, including fractions enriched for granulocytes, T lymphocytes, and monocytes/B cells. Semiquantitative comparison revealed considerable overlap between telomerase activities in samples from normal subjects and leukemia patients, confounding evaluation of the role of telomerase in this disease. These data indicate that human telomerase is not restricted to immortal cells and suggest that the somatic expression of this enzyme may be more widespread than was previously inferred from the decline of human telomeres.
TL;DR: It is proposed that movement of NLS proteins across the nuclear pore complex is a stochastic process that operates via repeated association-dissociation reactions.
TL;DR: It is shown that inflammatory activation of human cells shifts the targeting of the pneumococcus to a new receptor, that for the G-protein-coupled platelet-activating factor (PAF) and this progression could be arrested in vitro and in vivo by PAF-receptor-specific antagonists, suggesting a possible approach to therapy.
Abstract: THE Gram-positive bacterium Streptococcus pneumoniae is a major cause of pneumonia, sepsis and meningitis1. Although the invasive disease is severe, some 40% of individuals harbour the pneumococcus in the nasopharynx asymptomatically2. Here we investigate the molecular elements of the encounter between host and pathogen that distinguish these different outcomes. We show that inflammatory activation of human cells shifts the targeting of the pneumococcus to a new receptor, that for the G-protein-coupled platelet-activating factor (PAF). Only virulent pneumococci engage the PAF receptor. Attachment of the bacterial phosphoryl-choline to the PAF receptor enhanced adherence, which was coupled to invasion of endothelial, epithelial and PAF-receptor-transfected cells. This progression could be arrested in vitro and in vivo by PAF-receptor-specific antagonists, suggesting a possible approach to therapy.
TL;DR: The results suggest that adult neurogenesis in the dentate gyrus of the rat is altered by afferent input, via NMDA receptors, and may be regulated naturally by endogenous excitatory amino acids.
Abstract: The effects of afferent input and N-methyl-D-aspartate (NMDA) receptor activation on neurogenesis were examined in an intact system, the rat dentate gyrus, where neurons are naturally born in the adult. In the adult dentate gyrus, activation of NMDA receptors rapidly decreased the number of cells synthesizing DNA, whereas blockade of NMDA receptors rapidly increased the number of cells in the S phase identified with 3H-thymidine. Acute treatment with NMDA receptor antagonists increased the birth of neurons and increased the overall density of neurons in the granule cell layer. Lesion of the entorhinal cortex, the main excitatory afferent population to the granule neurons, also increased the birth of cells in the dentate gyrus. These results suggest that adult neurogenesis in the dentate gyrus of the rat is altered by afferent input, via NMDA receptors, and may be regulated naturally by endogenous excitatory amino acids.
TL;DR: The hypothesis that Macrophage colony-stimulating factor and its effects on macrophage development and function play a key role in atherogenesis is supported.
Abstract: To develop a murine model system to test the role of monocyte-derived macrophage in atherosclerosis, the osteopetrotic (op) mutation in the macrophage colony-stimulating factor gene was bred onto the apolipoprotein E (apoE)-deficient background. The doubly mutant (op/apoE-deficient) mice fed a low-fat chow diet had significantly smaller proximal aortic lesions at an earlier stage of progression than their apoE-deficient control littermates. These lesions in the doubly mutant mice were composed of macrophage foam cells. The op/apoE-deficient mice also had decreased body weights, decreased blood monocyte differentials, and increased mean cholesterol levels of approximately 1300 mg/dl. Statistical analysis determined that atherosclerosis lesion area was significantly affected by the op genotype and gender. The confounding variables of body weight, plasma cholesterol, and monocyte differential, which were all affected by op genotype, had no significant additional effect on lesion area once they were adjusted for the effects of op genotype and gender. Unexpectedly, there was a significant inverse correlation between plasma cholesterol and lesion area, implying that each may be the result of a common effect of macrophage colony-stimulating factor levels. The data support the hypothesis that macrophage colony-stimulating factor and its effects on macrophage development and function play a key role in atherogenesis.
TL;DR: Immunofluorescent labeling shows that TRF specifically colocalizes with telomeric DNA in human interphase cells and is located at chromosome ends during metaphase, demonstrating that human telomeres form a specialized nucleoprotein complex.
Abstract: Telomeres are multifunctional elements that shield chromosome ends from degradation and end-to-end fusions, prevent activation of DNA damage checkpoints, and modulate the maintenance of telomeric DNA by telomerase. A major protein component of human telomeres has been identified and cloned. This factor, TRF, contains one Myb-type DNA-binding repeat and an amino-terminal acidic domain. Immunofluorescent labeling shows that TRF specifically colocalizes with telomeric DNA in human interphase cells and is located at chromosome ends during metaphase. The presence of TRF along the telomeric TTAGGG repeat array demonstrates that human telomeres form a specialized nucleoprotein complex.
TL;DR: This study recorded from thalamic and cortical neurons simultaneously and related their receptive fields to their connectivity, as measured by cross-correlation analysis, implying that the outline of the elongated, simple receptive field, and thus of cortical orientation selectivity, is laid down at the level of the first synapse from the thalami afferents.
Abstract: In cortical area 17 of the cat, simple receptive fields are arranged in elongated subregions that respond best to bright (on) or dark (off) oriented contours, whereas the receptive fields of their thalamic inputs have a concentric on and off organization. This dramatic transformation suggests that there are specific rules governing the connections made between thalamic and cortical neurons (see ref. 4). Here we report a study of these rules in which we recorded from thalamic (lateral geniculate nucleus; LGN) and cortical neurons simultaneously and related their receptive fields to their connectivity, as measured by cross-correlation analysis. The probability of finding a monosynaptic connection was high when a geniculate receptive field was superimposed anywhere over an elongated simple-cell subregion of the same signature (on or off). However, 'inappropriate' connections from geniculate cells of the opposite receptive field signature were extremely rare. Together, these findings imply that the outline of the elongated, simple receptive field, and thus of cortical orientation selectivity, is laid down at the level of the first synapse from the thalamic afferents.
Journal Article•
TL;DR: It is suggested that endocrine factors released during stress modulate leukocyte trafficking and result in the redistribution of leukocytes between the blood and other immune compartments, which may significantly affect the ability of the immune system to respond to potential or ongoing immune challenge.
Abstract: Immune cell trafficking is crucial to the performance of the surveillance as well as effector functions of the immune system Because immune cells travel between tissues through the bloodstream, the numbers and proportions of leukocytes in the circulation provide an important representation of the state of leukocyte distribution in the body The studies described here examine significant and selective changes in numbers and percentages of peripheral blood leukocyte subpopulations in the rat These changes were rapidly induced under conditions of mild acute stress Stress-induced increases in plasma corticosterone were accompanied by a significant decrease in numbers and percentages of lymphocytes, and by an increase in numbers and percentages of neutrophils flow cytometric analysis revealed that B cell, NK cell, and monocyte numbers showed a greater stress-induced decrease than did T cells All stress-induced changes were observed during the light (inactive) as well as the dark (active) period of the animal's diurnal cycle Importantly, the stress-induced changes in leukocyte numbers and percentages were rapidly reversed upon the cessation of stress Furthermore, the effects of stress were largely dependent on adrenal hormones, because the magnitude of the stress-induced changes was significantly reduced in adrenalectomized animals Moreover, administration of corticosterone to adrenalectomized animals resulted in a close replication of stress-induced changes observed in adrenal-intact animals These results suggest that endocrine factors released during stress modulate leukocyte trafficking and result in the redistribution of leukocytes between the blood and other immune compartments Such a redistribution may significantly affect the ability of the immune system to respond to potential or ongoing immune challenge
TL;DR: For MARCKS, and perhaps other proteins, phosphorylation of serines within its basic cluster reduces the electrostatic attraction, producing translocation of the protein from the membrane to the cytosol by a simple 'electrostatic switch' mechanism.
TL;DR: The reversal of several molecular markers of epidermal dysfunction was associated with a marked reduction in intraepidermal CD3+ and CD8+ T cells, suggesting a primary immunological basis for this widespread disorder.
Abstract: Psoriasis is a hyperproliferative and inflammatory skin disorder of unknown aetiology. A fusion protein composed of human interleukin-2 and fragments of diphtheria toxin (DAB389IL-2), which selectively blocks the growth of activated lymphocytes but not keratinocytes, was administered systemically to ten patients to gauge the contribution of activated T cells to the disease. Four patients showed striking clinical improvement and four moderate improvement, after two cycle of low dose IL-2-toxin. The reversal of several molecular markers of epidermal dysfunction was associated with a marked reduction in intraepidermal CD3+ and CD8+ T cells, suggesting a primary immunological basis for this widespread disorder.