Showing papers by "Yale University published in 1997"

Eigenfaces vs. Fisherfaces: recognition using class specific linear projection

Abstract: We develop a face recognition algorithm which is insensitive to large variation in lighting direction and facial expression. Taking a pattern classification approach, we consider each pixel in an image as a coordinate in a high-dimensional space. We take advantage of the observation that the images of a particular face, under varying illumination but fixed pose, lie in a 3D linear subspace of the high dimensional image space-if the face is a Lambertian surface without shadowing. However, since faces are not truly Lambertian surfaces and do indeed produce self-shadowing, images will deviate from this linear subspace. Rather than explicitly modeling this deviation, we linearly project the image into a subspace in a manner which discounts those regions of the face with large deviation. Our projection method is based on Fisher's linear discriminant and produces well separated classes in a low-dimensional subspace, even under severe variation in lighting and facial expressions. The eigenface technique, another method based on linearly projecting the image space to a low dimensional subspace, has similar computational requirements. Yet, extensive experimental results demonstrate that the proposed "Fisherface" method has error rates that are lower than those of the eigenface technique for tests on the Harvard and Yale face databases.

The Fusiform Face Area: A Module in Human Extrastriate Cortex Specialized for Face Perception

Abstract: Using functional magnetic resonance imaging (fMRI), we found an area in the fusiform gyrus in 12 of the 15 subjects tested that was significantly more active when the subjects viewed faces than when they viewed assorted common objects. This face activation was used to define a specific region of interest individually for each subject, within which several new tests of face specificity were run. In each of five subjects tested, the predefined candidate “face area” also responded significantly more strongly to passive viewing of (1) intact than scrambled two-tone faces, (2) full front-view face photos than front-view photos of houses, and (in a different set of five subjects) (3) three-quarter-view face photos (with hair concealed) than photos of human hands; it also responded more strongly during (4) a consecutive matching task performed on three-quarter-view faces versus hands. Our technique of running multiple tests applied to the same region defined functionally within individual subjects provides a solution to two common problems in functional imaging: (1) the requirement to correct for multiple statistical comparisons and (2) the inevitable ambiguity in the interpretation of any study in which only two or three conditions are compared. Our data allow us to reject alternative accounts of the function of the fusiform face area (area “FF”) that appeal to visual attention, subordinate-level classification, or general processing of any animate or human forms, demonstrating that this region is selectively involved in the perception of faces.

A human homologue of the Drosophila Toll protein signals activation of adaptive immunity

Abstract: . Like Drosophila Toll, human Toll is a type I transmembrane protein with an extracellular domain consisting of a leucine-rich repeat (LRR) domain, and a cytoplasmic domain homologous to the cytoplasmic domain of the human interleukin (IL)-1 receptor. Both Drosophila Toll and the IL-1 receptor are known to signal through the NF-kB pathway 5-7 . We show that a constitutively active mutant of human Toll transfected into human cell lines can induce the activation of NF-kB and the expression of NF-kB-controlled genes for the inflammatory cyto- kines IL-1, IL-6 and IL-8, as well as the expression of the co- stimulatory molecule B7.1, which is required for the activation of naive T cells. The Toll protein controls dorsal-ventral patterning in Drosophila embryos and activates the transcription factor Dorsal upon binding to its ligand Spatzle 8 . In adult Drosophila, the Toll/Dorsal signalling pathway participates in an anti-fungal immune response 2 . Signal- ling through Toll parallels the signalling pathway induced by the IL- 1 receptor (IL-1R) in mammalian cells: IL-1R signals through the NF-kB pathway, and Dorsal and its inhibitor Cactus are homo- logous to NF-kB and I-kB proteins, respectively 5,6 . Moreover, the cytoplasmic domain of Drosophila Toll is homologous to the cytoplasmic domain of IL-1R (ref. 9). Remarkably, the tobacco- virus-resistance gene that encodes N-protein is also similar to Toll in that it contains both a Toll signalling domain and an LRR domain 10 . It thus appears that the immune-response system mediated by Toll represents an ancient host defence mechanism 6 (Fig. 1). To inves- tigate the possibility that this pathway has been retained in the immune system of vertebrates, we used sequence and pattern searches 11 of the expressed-sequence tag (EST) database at the fragment was used to probe northern blots containing poly(A) + RNA from several organs. Most organs expressed two mRNA species: one of ,5 kilobases (kb) was predominant in most tissues except peripheral blood leukocytes (PBL), and corresponded to the length of the cDNA that we cloned. The lower band was ,4 kb long and this band was predominant in the PBL. The 4-kb band was not detectable in kidney, and liver did not contain any mRNA at all (Fig. 3). We also tested different mouse and human cell lines for expression of hToll mRNA by using PCR with reverse transcription (RT-PCR). We found mRNA for hToll in monocytes, macrophages, dendritic cells, g/d T cells, Th1 and Th2 a/b T cells, a small intestinal epithelial cell line, and a B-cell line (data not shown). The hToll gene is expressed most strongly in spleen and PBL (Fig. 3); its expression in other tissues may be due to the presence of macrophages and dendritic cells, in which it could act as an early-warning system for infection. Alternatively, hToll may be widely expressed because hToll signals through the conserved NF-kB pathway (see below) and NF- kB is a ubiquitous transcription factor. To characterize hToll functions and see whether it can induce transcription of immune response genes like dToll, we generated a dominant-positive mutant of hToll because the natural ligand of hToll is unknown. To produce a constitutively active mutant of hToll, we made use of genetic information from dToll: analysis of ventra- lizing mutants in Drosophila embryos had identified the function of the ectodomain C-flanking cysteine-rich region in dToll 16 as control- ling the activity of dToll in signal transduction. In three dominant

A novel anti-apoptosis gene, survivin , expressed in cancer and lymphoma

Abstract: Inhibitors of programmed cell death (apoptosis) aberrantly prolonging cell viability may contribute to cancer by facilitating the insurgence of mutations and by promoting resistance to therapy Despite the identification of several new apoptosis inhibitors related to bcl-2 or to the baculovirus IAP gene, it is not clear whether apoptosis inhibition plays a general role in neoplasia Here, we describe a new human gene encoding a structurally unique IAP apoptosis inhibitor, designated survivin Survivin contains a single baculovirus IAP repeat and lacks a carboxyl-terminal RING finger Present during fetal development, survivin is undetectable in terminally differentiated adult tissues However, survivin becomes prominently expressed in transformed cell lines and in all the most common human cancers of lung, colon, pancreas, prostate and breast, in vivo Survivin is also found in approximately 50% of high-grade non-Hodgkin's lymphomas (centroblastic, immunoblastic), but not in low-grade lymphomas (lymphocytic) Recombinant expression of survivin counteracts apoptosis of B lymphocyte precursors deprived of interleukin 3 (IL-3) These findings suggest that apoptosis inhibition may be a general feature of neoplasia and identify survivin as a potential new target for apoptosis-based therapy in cancer and lymphoma

Conductance of a Molecular Junction

Abstract: Molecules of benzene-1,4-dithiol were self-assembled onto the two facing gold electrodes of a mechanically controllable break junction to form a statically stable gold-sulfur-aryl-sulfur-gold system, allowing for direct observation of charge transport through the molecules. Current-voltage measurements at room temperature demonstrated a highly reproducible apparent gap at about 0.7 volt, and the conductance-voltage curve showed two steps in both bias directions. This study provides a quantative measure of the conductance of a junction containing a single molecule, which is a fundamental step in the emerging area of molecular-scale electronics.

Cloning and characterization of a mammalian proton-coupled metal-ion transporter

Abstract: Metal ions are essential cofactors for a wealth of biological processes, including oxidative phosphorylation, gene regulation and free-radical homeostasis. Failure to maintain appropriate levels of metal ions in humans is a feature of hereditary haemochromatosis, disorders of metal-ion deficiency, and certain neurodegenerative diseases. Despite their pivotal physiological roles, however, there is no molecular information on how metal ions are actively absorbed by mammalian cells. We have now identified a new metal-ion transporter in the rat, DCT1, which has an unusually broad substrate range that includes Fe2+, Zn2+, Mn2+, Co2+, Cd2+, Cu2+, Ni2+ and Pb2+. DCT1 mediates active transport that is proton-coupled and depends on the cell membrane potential. It is a 561-amino-acid protein with 12 putative membrane-spanning domains and is ubiquitously expressed, most notably in the proximal duodenum. DCT1 is upregulated by dietary iron deficiency, and may represent a key mediator of intestinal iron absorption. DCT1 is a member of the 'natural-resistance-associated macrophage protein' (Nramp) family and thus its properties provide insight into how these proteins confer resistance to pathogens.

The NEURON simulation environment

Abstract: The moment-to-moment processing of information by the nervous system involves the propagation and interaction of electrical and chemical signals that are distributed in space and time. Biologically realistic modeling is needed to test hypotheses about the mechanisms that govern these signals and how nervous system function emerges from the operation of these mechanisms. The NEURON simulation program provides a powerful and flexible environment for implementing such models of individual neurons and small networks of neurons. It is particularly useful when membrane potential is nonuniform and membrane currents are complex. We present the basic ideas that would help informed users make the most efficient use of NEURON.

A molecular and cellular theory of depression

Abstract: Recent studies have begun to characterize the actions of stress and antidepressant treatments beyond the neurotransmitter and receptor level. This work has demonstrated that long-term antidepressant treatments result in the sustained activation of the cyclic adenosine 3',5'-monophosphate system in specific brain regions, including the increased function and expression of the transcription factor cyclic adenosine monophosphate response element-binding protein. The activated cyclic adenosine 3',5'-monophosphate system leads to the regulation of specific target genes, including the increased expression of brain-derived neurotrophic factor in certain populations of neurons in the hippocampus and cerebral cortex. The importance of these changes is highlighted by the discovery that stress can decrease the expression of brain-derived neurotrophic factor and lead to atrophy of these same populations of stress-vulnerable hippocampal neurons. The possibility that the decreased size and impaired function of these neurons may be involved in depression is supported by recent clinical imaging studies, which demonstrate a decreased volume of certain brain structures. These findings constitute the framework for an updated molecular and cellular hypothesis of depression, which posits that stress-induced vulnerability and the therapeutic action of antidepressant treatments occur via intracellular mechanisms that decrease or increase, respectively, neurotrophic factors necessary for the survival and function of particular neurons. This hypothesis also explains how stress and other types of neuronal insult can lead to depression in vulnerable individuals and it outlines novel targets for the rational design of fundamentally new therapeutic agents.

Shaping Perceptions to Motivate Healthy Behavior: The Role of Message Framing

Abstract: Health-relevant communications can be framed in terms of the benefits (gains) or costs (losses) associated with a particular behavior, and the framing of such persuasive messages influences health decision making. Although to ask people to consider a health issue in terms of associated costs is considered an effective way to motivate behavior, empirical findings are inconsistent. In evaluating the effectiveness of framed health messages, investigators must appreciate the context in which health-related decisions are made. The influence of framed information on decision making is contingent on people, first, internalizing the advocated frame and, then, on the degree to which performing a health behavior is perceived as risky. The relative effectiveness of gain-framed or loss-framed appeals depends, in part, on whether a behavior serves an illness-detecting or a health-affirming function. Finally, the authors discuss the cognitive and affective processes that may mediate the influence of framed information on judgment and behavior.

Children's Yale-Brown Obsessive Compulsive Scale: Reliability and Validity

Abstract: Objective To evaluate the reliability and validity of a semistructured measure of obsessive-compulsive symptom severity in children and adolescents with obsessive-compulsive disorder (OCD). Method Sixty-five children with OCD (25 girls and 40 boys, aged 8 to 17 years) were assessed with the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS). Interrater agreement was assessed by four raters in a subsample (n = 24). Discriminant and convergent validity were assessed by comparing CY-BOCS scores to self-ratings of depression, anxiety, and obsessive-compulsive symptoms. Results Internal consistency was high, measuring .87 for the 10 items. The intraclass correlations for the CY-BOCS Total, Obsession, and Compulsion scores were .84, .91, and .68, suggesting good to excellent interrater agreement for subscale and total scores. The CY-BOCS Total score showed a significantly higher correlation with a self-report of obsessive-compulsive symptoms (r = .62 for the Leyton survey) compared with the Children's Depression Inventory (r = .34) and the Children's Manifest Anxiety Scale (r = .37) (p = .02 and .05, respectively). Conclusions The CY-BOCS yields reliable and valid subscale and total scores for obsessive-compulsive symptom severity in children and adolescents with OCD. Reliability and validity appear to be influenced by age of the child and the hazards associated with integrating data from parental and patient sources.

Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex

Abstract: Subanesthetic doses of ketamine, a noncompetitive NMDA receptor antagonist, impair prefrontal cortex (PFC) function in the rat and produce symptoms in humans similar to those observed in schizophrenia and dissociative states, including impaired performance of frontal lobe-sensitive tests. Several lines of evidence suggest that ketamine may impair PFC function in part by interacting with dopamine neurotransmission in this region. This study sought to determine the mechanism by which ketamine may disrupt dopaminergic neurotransmission in, and cognitive functions associated with, the PFC. A thorough dose-response study using microdialysis in conscious rats indicated that low doses of ketamine (10, 20, and 30 mg/kg) increase glutamate outflow in the PFC, suggesting that at these doses ketamine may increase glutamatergic neurotransmission in the PFC at non-NMDA glutamate receptors. An anesthetic dose of ketamine (200 mg/kg) decreased, and an intermediate dose of 50 mg/kg did not affect, glutamate levels. Ketamine, at 30 mg/kg, also increased the release of dopamine in the PFC. This increase was blocked by intra-PFC application of the AMPA/kainate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione CNQX. Furthermore, ketamine-induced activation of dopamine release and impairment of spatial delayed alternation in the rodent, a PFC-sensitive cognitive task, was ameliorated by systemic pretreatment with AMPA/kainate receptor antagonist LY293558. These findings suggest that ketamine may disrupt dopaminergic neurotransmission in the PFC as well as cognitive functions associated with this region, in part, by increasing the release of glutamate, thereby stimulating postsynaptic non-NMDA glutamate receptors.

Induction of th1 and th2 cd4+ t cell responses : the alternative approaches

Abstract: T helper lymphocytes can be divided into two distinct subsets of effector cells based on their functional capabilities and the profile of cytokines they produce. The Th1 subset of CD4+ T cells secretes cytokines usually associated with inflammation, such as IFN-gamma and TNF and induces cell-mediated immune responses. The Th2 subset produces cytokines such as IL-4 and IL-5 that help B cells to proliferate and differentiate and is associated with humoral-type immune responses. The selective differentiation of either subset is established during priming and can be significantly influenced by a variety of factors. One of these factors, the cytokine environment, has been put forward as the major variable influencing Th development and is already well reviewed by others. Instead, in the current review, we focus on some of the alternative approaches for skewing Th1/Th2 responses. Specifically, we discuss the effects on Th priming of (a) using altered peptide ligands as antigens, (b) varying the dose of antigen, and (c) altering costimulatory signals. The potential importance of each of these variables to influence immune responses to pathogens in vivo is discussed throughout.

Exploring the Implications of the Internet for Consumer Marketing

Abstract: Past commentaries on the potential impact of the Internet on consumer marketing have typically failed to acknowledge that consumer markets are heterogeneous and complex and that the Internet is but one possible distribution, transaction, and communication channel in a world dominated by conventional retailing channels This failure has led to excessively broad predictions regarding the effect of the Internet on the structure and performance of product and service markets The objective of this article is to provide a framework for understanding possible impacts of the Internet on marketing to consumers This is done by analyzing channel intermediary functions that can be performed on the Internet, suggesting classification schemes that clarify the potential impact of the Internet across different products and services, positioning the Internet against conventional retailing channels, and identifying similarities and differences that exist between them The article concludes with a series of questions designed to stimulate the development of theory and strategy in the context of Internet-based marketing

Recognition of unique carboxyl-terminal motifs by distinct PDZ domains

Abstract: The oriented peptide library technique was used to investigate the peptide-binding specificities of nine PDZ domains. Each PDZ domain selected peptides with hydrophobic residues at the carboxyl terminus. Individual PDZ domains selected unique optimal motifs defined primarily by the carboxyl terminal three to seven residues of the peptides. One family of PDZ domains, including those of the Discs Large protein, selected peptides with the consensus motif Glu-(Ser/Thr)-Xxx-(Val/Ile) (where Xxx represents any amino acid) at the carboxyl terminus. In contrast, another family of PDZ domains, including those of LIN-2, p55, and Tiam-1, selected peptides with hydrophobic or aromatic side chains at the carboxyl terminal three residues. On the basis of crystal structures of the PSD-95-3 PDZ domain, the specificities observed with the peptide library can be rationalized.

Adaptive control using multiple models

Abstract: Intelligent control may be viewed as the ability of a controller to operate in multiple environments by recognizing which environment is currently in existence and servicing it appropriately. An important prerequisite for an intelligent controller is the ability to adapt rapidly to any unknown but constant operating environment. This paper presents a general methodology for such adaptive control using multiple models, switching, and tuning. The approach was first introduced by Narendra et al. (1992) for improving the transient response of adaptive systems in a stable fashion. This paper proposes different switching and tuning schemes for adaptive control which combine fixed and adaptive models in novel ways. The principal mathematical results are the proofs of stability when these different schemes are used in the context of model reference control of an unknown linear time-invariant system. A variety of simulation results are presented to demonstrate the efficacy of the proposed methods.

Falls, Injuries Due to Falls, and the Risk of Admission to a Nursing Home

Abstract: Background Falls warrant investigation as a risk factor for nursing home admission because falls are common and are associated with functional disability and because they may be preventable. Methods We conducted a prospective study of a probability sample of 1103 people over 71 years of age who were living in the community. Data on demographic and medical characteristics, use of health care, and cognitive, functional, psychological, and social functioning were obtained at base line and one year later during assessments in the participants' homes. The primary outcome studied was the number of days from the initial assessment to a first long-term admission to a skilled-nursing facility during three years of follow-up. Patients were assigned to four categories during follow-up: those who had no falls, those who had one fall without serious injury, those who had two or more falls without serious injury, and those who had at least one fall causing serious injury. Results A total of 133 participants (12.1 perce...

Molecular and Cellular Basis of Addiction

Abstract: Drug addiction results from adaptations in specific brain neurons caused by repeated exposure to a drug of abuse. These adaptations combine to produce the complex behaviors that define an addicted state. Progress is being made in identifying such time-dependent, drug-induced adaptations and relating them to specific behavioral features of addiction. Current research needs to understand the types of adaptations that underlie the particularly long-lived aspects of addiction, such as drug craving and relapse, and to identify specific genes that contribute to individual differences in vulnerability to addiction. Understanding the molecular and cellular basis of addictive states will lead to major changes in how addiction is viewed and ultimately treated.

Coming to Terms With the Terms of Risk

Abstract: Terms such as risk, risk factors, and especially the term cause are inconsistently and imprecisely used, fostering scientific miscommunication and misleading research and policy. Clarifying such terms is the essential first step. We define risk and a risk factor (protective factor) and their potency, set out the conceptual basis of the methods by which risk factors are identified and potency demonstrated, and propose criteria for establishing the status of a risk factor as a fixed or variable marker or a causal risk factor. All definitions are based on the state of scientific knowledge (empirical documentation), rather than on hypotheses, speculations, or beliefs. We discuss common approaches and pitfalls and give a psychiatric research example. Imprecise reports can impede the search for understanding the cause and course of any disease and also may be a basis of inadequate clinical or policy decision-making. The issues in risk research are much too important to tolerate less than precise terminology or the less than rigorous research reporting that results from imprecise and inconsistent terminology.

Administration of Methylprednisolone for 24 or 48 Hours or Tirilazad Mesylate for 48 Hours in the Treatment of Acute Spinal Cord Injury Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial

Abstract: Objective. —To compare the efficacy of methylprednisolone administered for 24 hours with methyprednisolone administered for 48 hours or tirilazad mesylate administered for 48 hours in patients with acute spinal cord injury. Design. —Double-blind, randomized clinical trial. Setting. —Sixteen acute spinal cord injury centers in North America. Patients. —A total of 499 patients with acute spinal cord injury diagnosed in National Acute Spinal Cord Injury Study (NASCIS) centers within 8 hours of injury. Intervention. —All patients received an intravenous bolus of methylprednisolone (30 mg/kg) before randomization. Patients in the 24-hour regimen group (n=166) received a methylprednisolone infusion of 5.4 mg/kg per hour for 24 hours, those in the 48-hour regimen group (n=167) received a methylprednisolone infusion of 5.4 mg/kg per hour for 48 hours, and those in the tirilazad group (n=166) received a 2.5 mg/kg bolus infusion of tirilazad mesylate every 6 hours for 48 hours. Main Outcome Measures. —Motor function change between initial presentation and at 6 weeks and 6 months after injury, and change in Functional Independence Measure (FIM) assessed at 6 weeks and 6 months. Results. —Compared with patients treated with methylprednisolone for 24 hours, those treated with methylprednisolone for 48 hours showed improved motor recovery at 6 weeks (P=.09) and 6 months (P=.07) after injury. The effect of the 48-hour methylprednisolone regimen was significant at 6 weeks (P=.04) and 6 months (P=.01) among patients whose therapy was initiated 3 to 8 hours after injury. Patients who received the 48-hour regimen and who started treatment at 3 to 8 hours were more likely to improve 1 full neurologic grade (P=.03) at 6 months, to show more improvement in 6-month FIM (P=.08), and to have more severe sepsis and severe pneumonia than patients in the 24-hour methylprednisolone group and the tirilazad group, but other complications and mortality (P=.97) were similar. Patients treated with tirilazad for 48 hours showed motor recovery rates equivalent to patients who received methylprednisolone for 24 hours. Conclusions. —Patients with acute spinal cord injury who receive methylprednisolone within 3 hours of injury should be maintained on the treatment regimen for 24 hours. When methylprednisolone is initiated 3 to 8 hours after injury, patients should be maintained on steroid therapy for 48 hours.

Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene

Abstract: Excitatory amino acids induce both acute membrane depolarization and latent cellular toxicity, which often leads to apoptosis in many neurological disorders. Recent studies indicate that glutamate toxicity may involve the c-Jun amino-terminal kinase (JNK) group of mitogen-activated protein (MAP) kinases. One member of the JNK family, Jnk3, may be required for stress-induced neuronal apoptosis, as it is selectively expressed in the nervous system. Here we report that disruption of the gene encoding Jnk3 in mice caused the mice to be resistant to the excitotoxic glutamate-receptor agonist kainic acid: they showed a reduction in seizure activity and hippocampal neuron apoptosis was prevented. Although application of kainic acid imposed the same level of noxious stress, the phosphorylation of c-Jun and the transcriptional activity of the AP-1 transcription factor complex were markedly reduced in the mutant mice. These data indicate that the observed neuroprotection is due to the extinction of a Jnk3-mediated signalling pathway, which is an important component in the pathogenesis of glutamate neurotoxicity.

SLEEP AND AROUSAL: Thalamocortical Mechanisms

Abstract: Thalamocortical activity exhibits two distinct states: ( a) synchronized rhythmic activity in the form of delta, spindle, and other slow waves during EEGsynchronized sleep and (b) tonic activity during waking and rapid-eye-movement sleep. Spindle waves are generated largely through a cyclical interaction between thalamocortical and thalamic reticular neurons involving both the intrinsic membrane properties of these cells and their anatomical interconnections. Specific alterations in the interactions between these cells can result in the generation of paroxysmal events resembling absence seizures in children. The release of several different neurotransmitters from the brain stem, hypothalamus, basal forebrain, and cerebral cortex results in a depolarization of thalamocortical and thalamic reticular neurons and an enhanced excitability in many cortical pyramidal cells, thereby suppressing the generation of sleep rhythms and promoting a state that is conducive to sensory processing and cognition.

Nitric oxide production contributes to the angiogenic properties of vascular endothelial growth factor in human endothelial cells.

Abstract: Vascular endothelial growth factor (VEGF) is a regulator of vasculogenesis and angiogenesis. To investigate the role of nitric oxide (NO) in VEGF-induced proliferation and in vitro angiogenesis, human umbilical vein endothelial cells (HUVEC) were used. VEGF stimulated the growth of HUVEC in an NO-dependent manner. In addition, VEGF promoted the NO-dependent formation of network-like structures in HUVEC cultured in three dimensional (3D) collagen gels. Exposure of cells to VEGF led to a concentration-dependent increase in cGMP levels, an indicator of NO production, that was inhibited by nitro-L-arginine methyl ester. VEGF-stimulated NO production required activation of tyrosine kinases and increases in intracellular calcium, since tyrosine kinase inhibitors and calcium chelators attenuated VEGF-induced NO release. Moreover, two chemically distinct phosphoinositide 3 kinase (PI-3K) inhibitors attenuated NO release after VEGF stimulation. In addition, HUVEC incubated with VEGF for 24 h showed an increase in the amount of endothelial NO synthase (eNOS) protein and the release of NO. In summary, both short- and long-term exposure of human EC to VEGF stimulates the release of biologically active NO. While long-term exposure increases eNOS protein levels, short-term stimulation with VEGF promotes NO release through mechanisms involving tyrosine and PI-3K kinases, suggesting that NO mediates aspects of VEGF signaling required for EC proliferation and organization in vitro.

The evolution of female social relationships in nonhuman primates

Abstract: Considerable interspecific variation in female social relationships occurs in gregarious primates, par- ticularly with regard to agonism and cooperation be- tween females and to the quality of female relationships with males. This variation exists alongside variation in female philopatry and dispersal. Socioecological theories have tried to explain variation in female-female social relationships from an evolutionary perspective focused on ecological factors, notably predation and food dis- tribution. According to the current ''ecological model'', predation risk forces females of most diurnal primate species to live in groups; the strength of the contest component of competition for resources within and be- tween groups then largely determines social relationships between females. Social relationships among gregarious females are here characterized as Dispersal-Egalitarian, Resident-Nepotistic, Resident-Nepotistic-Tolerant, or Resident-Egalitarian. This ecological model has suc- cessfully explained diAerences in the occurrence of for- mal submission signals, decided dominance relation- ships, coalitions and female philopatry. Group size and female rank generally aAect female reproduction success as the model predicts, and studies of closely related species in diAerent ecological circumstances underscore the importance of the model. Some cases, however, can only be explained when we extend the model to incor- porate the eAects of infanticide risk and habitat satura- tion. We review evidence in support of the ecological model and test the power of alternative models that in- voke between-group competition, forced female phi- lopatry, demographic female recruitment, male inter- ventions into female aggression, and male harassment. Not one of these models can replace the ecological model, which already encompasses the between-group competition. Currently the best model, which explains several phenomena that the ecological model does not, is a ''socioecological model'' based on the combined im- portance of ecological factors, habitat saturation and infanticide avoidance. We note some points of similarity and divergence with other mammalian taxa; these re- main to be explored in detail.