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PubMed2002

Programmed death phenomena: from organelle to organism.

Programmed death phenomena appear to be inherent not only in living cells (apoptosis), but also in subcellular organelles (e.g., self-elimination of mitochondria, called mitoptosis), organs (organoptosis), and even whole organisms (phenoptosis). In all these cases, the "Samurai law of biology"--it is better to die than to be wrong--seems to be operative. The operation of this law helps complicated living systems avoid the risk of ruin when a system of lower hierarchic position makes a significant mistake. Thus, mitoptosis purifies a cell from damaged and hence unwanted mitochondria; apoptosis purifies a tissue from unwanted cells; and phenoptosis purifies a community from unwanted individuals. Defense against reactive oxygen species (ROS) is probably one of the primary evolutionary functions of programmed death mechanisms. So far, it seems that ROS play a key role in the mito-, apo-, organo-, and phenoptoses, which is consistent with Harman's theory of aging. Here a concept is described that tries to unite Weismann's hypothesis of aging as an adaptive programmed death mechanism and the generally accepted alternative point of view that considers aging as an inevitable result of accumulation in an organism of occasional injuries. It is suggested that injury accumulation is monitored by a system(s) actuating a phenoptotic death program when the number of injuries reaches some critical level. The system(s) in question are organized in such a way that the lethal case appears to be a result of phenoptosis long before the occasional injuries make impossible the functioning of the organism. It is stressed that for humans these cruel regulations look like an atavism that, if overcome, might dramatically prolong the human life span.

Aging↗
PubMed1990

Simulation of free radical reactions in biology and medicine: a new two-compartment kinetic model of intracellular lipid peroxidation.

To explore mechanisms of free radical reactions leading to intracellular lipid peroxidation in living systems, we developed a computational model of up to 109 simultaneous enzymatic and free radical reactions thought to be involved in the initiation, propagation, and termination of membrane lipid peroxidation. Rate constants for the various reactions were obtained from the published literature. The simulation model included a lipid membrane compartment and an aqueous cytosolic compartment, between which various chemical species were partitioned. Lipid peroxidation was initiated by the iron-catalyzed, superoxide-driven Fenton reaction. A "C" language computer program implemented numerical solution of the steady-state rate equations for concentrations of nine relevant free radicals. The rate equations were integrated by a modified Euler technique to describe the evolution with time of simulated concentrations of hydrogen peroxide, ferric and ferrous iron, unsaturated lipid, lipid hydroperoxides, superoxide anion, and biological antioxidants, including SOD and catalase. Initial results led to significant insights regarding mechanisms of membrane lipid peroxidation: 1. segregation and concentration of lipids within membrane compartments promotes chain propagation; 2. in the absence of antioxidants computed concentrations of lipid hydroperoxides increase linearly about 40 microM/min during oxidative stress; 3. lipid peroxidation is critically dependent upon oxygen concentration and the modeled dependence is similar to the experimental function; 4. lipid peroxidation is rapidly quenched by the presence of Vitamin E-like antioxidants, SOD, and catalase; 5. only small (1 to 50 microM) amounts of "free" iron are required for initiation of lipid peroxidation; 6. substantial lipid peroxidation occurs only when cellular defense mechanisms have been weakened or overcome by prolonged oxidative stress, hence understanding of the balance between free radical generation and antioxidant defense systems is critical to the understanding and control of free radical reactions in biology and medicine.

Antioxidants↗
PubMed2005

Triple layer control: phosphorylation, acetylation and ubiquitination of FOXO proteins.

FOXO proteins are transcriptional regulators that control cell cycle progression, DNA repair, defense against oxidative damage and apoptosis. These divergent functions of FOXO proteins are regulated by signal-induced, post-translational modifications. Phosphorylation of cytoplasmic FOXO at specific sites by JNK initiates translocation into the nucleus. Acetylation and deacetylation of nuclear FOXO affects the selection of transcriptional programs that are controlled by FOXO proteins. Activation of Akt by growth factors results in phosphorylation of nuclear FOXO at specific sites followed by additional phosphorylations mediated by other kinases. Akt-dependent phosphorylation reduces the DNA-binding activity of FOXO, interferes with binding to the co-activators p300/CBP, and inactivates the FOXO nuclear translocation signal. The Akt-phosphorylated FOXO is exported from the nucleus in a CRM1- and 14-3-3-dependent process. Cytoplasmic, Akt-phosphorylated FOXO interacts with the ubiquitin ligase Skp2 and is targeted for proteasomal degradation. The nuclear-cytoplasmic "FOXO shuttle" is driven by stress signals that result in nuclear import and FOXO transcriptional activity and growth signals that initiate nuclear export and proteasomal degradation of FOXO.

Acetylation↗
PubMed2006

A cyanobacterial LPS antagonist prevents endotoxin shock and blocks sustained TLR4 stimulation required for cytokine expression.

Toll-like receptors (TLRs) function as primary sensors that elicit coordinated innate immune defenses through recognition of microbial products and induction of immune and proinflammatory genes. Here we report the identification and biological characterization of a lipopolysaccharide (LPS)-like molecule extracted from the cyanobacterium Oscillatoria Planktothrix FP1 (cyanobacterial product [CyP]) that is not stimulatory per se but acts as a potent and selective antagonist of bacterial LPS. CyP binds to MD-2 and efficiently competes with LPS for binding to the TLR4-MD-2 receptor complex. The addition of CyP together with LPS completely inhibited both MyD88- and TRIF-dependent pathways and suppressed the whole LPS-induced gene transcription program in human dendritic cells (DCs). CyP protected mice from endotoxin shock in spite of a lower capacity to inhibit LPS stimulation of mouse DCs. Interestingly, the delayed addition of CyP to DCs responding to LPS strongly inhibited signaling and cytokine production by immediate down-regulation of inflammatory cytokine mRNAs while not affecting other aspects of DC maturation, such as expression of major histocompatibility complex molecules, costimulatory molecules, and CCR7. Collectively, these results indicate that CyP is a potent competitive inhibitor of LPS in vitro and in vivo and reveal the requirement of sustained TLR4 stimulation for induction of cytokine genes in human DCs.

Animals↗
PubMed2000

A survey of oysters Crassostrea virginica from Tampa Bay, Florida: associations of internal defense measurements with contaminant burdens.

Oysters from 16 sites in Tampa Bay, Florida, were collected during a 6-week period in winter 1993 and analyzed for both biological characteristics and tissue chemical concentrations. Using previous sediment contamination and toxicity data, oyster tissues from the selected sites were expected to exhibit a wide range in both quantity and type of chemicals. Chemical analysis showed tissue concentrations at some of these sites to be greater than national averages, as reported by the National Status and Trends Mussel Watch Program, for total PAH, total PCB, total chlordanes, DDT, Cu, Pb and Zn. Measures of oyster internal defense, including hemocyte density, rate of locomotion and superoxide generation, varied significantly among sites and were generally higher at sites with higher tissue concentrations of xenobiotic chemicals. Potential associations between oyster defense characteristics and accumulated chemical contaminants, either singly or in chemical classes, were explored using correlation analysis and a composited ranking procedure. Positive relationships were found for hemocyte characteristics with certain trace metal (Cu, Sn and Zn) and PAH analytes, whereas negative relationships were found with certain PCB and pesticide analytes. Heightened defenses in contaminated conditions may reflect a hemocyte process for sequestration and detoxification of environmental contaminants. Oysters from four of the 16 sites were additionally collected in June and September 1993 and site-related differences did not closely parallel those obtained in winter. Seasonal environmental factors may have altered contaminant-related differences among sites.

Animals↗
PubMed2006

Nuclear security and radiological preparedness for the olympic games, athens 2004: lessons learned for organizing major public events.

In light of the exceptional circumstances that arose from hosting the Olympic Games in Athens in 2004 and from recent terrorist events internationally, Greece attributes the highest priority to security issues. According to its statutory role, the Greek Atomic Energy Commission is responsible for emergency preparedness and response in case of nuclear and radiological events, and advises the Government on the measures and interventions necessary to protect the public. In this context, the Commission participated in the Nuclear, Radiological, Biological, and Chemical Threat National Emergency Plan, specially developed for the Olympic Games, and coordinated by the Olympic Games Security Division. The objective of this paper is to share the experience gained during the organization of the Olympic Games and to present the nuclear security program implemented prior to, during, and beyond the Games, in order to prevent, detect, assess, and respond to the threat of nuclear terrorism. This program adopted a multi-area coverage of nuclear security, including physical protection of nuclear and radiological facilities, prevention of smuggling of radioactive materials through borders, prevention of dispersion of these materials into the Olympic venues, enhancement of emergency preparedness and response to radiological events, upgrading of the technical infrastructure, establishment of new procedures for assessing the threat and responding to radiological incidents, and training personnel belonging to several organizations involved in the National Emergency Response Plan. Finally, the close cooperation of Greek Authorities with the International Atomic Energy Agency and the U.S. Department of Energy, under the coordination of the Greek Atomic Energy Commission, is also discussed.

Civil Defense↗
PubMed2004

Verotoxin (shiga toxin) sensitizes renal epithelial cells to increased heme toxicity: possible implications for the hemolytic uremic syndrome.

Escherichia coli-derived verotoxins (VT; Shiga toxins) are causally related to the pathogenesis of enteropathic hemolytic uremic syndrome (HUS). Profound hemolysis is a defining feature of the disease, but it is not known whether the acute intravascular release of heme proteins contributes to HUS pathology. This study examined the biologic effects of hemin and VT by means of tubular epithelial-derived ACHN cells. Hemin at concentrations >/=200 microM caused cell rounding, spike formation, and detachment that was morphologically distinct from verocytotoxicity. VT caused apoptosis at concentrations >100 pM, as demonstrated by nuclear segmentation and poly(ADP-ribose) polymerase cleavage, whereas hemin-mediated injury of ACHN cells grown in serum-containing medium lacked attributes of programmed cell death. Pretreatment of ACHN monolayers with sublethal concentrations (1 to 10 pM) of VT for 12 to 18 h led to superadditive hemin-mediated cytotoxicity. This effect was not limited to ACHN cells, but was similarly noted in microvascular endothelial cells. Heme catabolism is regulated by (inducible) heme oxygenase-1 (HO-1). VT abrogated HO-1 expression in ACHN cells. Stimulation of cells for 6 h with CdCl(2), which markedly increased HO-1 expression before the addition of VT, blunted subsequent hemin injury. In conclusion, VT augments hemin-induced toxicity in renal tubular epithelial cells that can be reversed by prior induction of HO-1. It is proposed that VT subverts the physiologic defense against heme proteins by interfering with the regulated expression of HO-1 and that this mechanism contributes to the renal pathology in patients with Escherichia coli-associated HUS.

Epithelial Cells↗
PubMed2001

Critical role for alpha/beta and gamma interferons in persistence of lymphocytic choriomeningitis virus by clonal exhaustion of cytotoxic T cells.

Under conditions of high antigenic load during infection with invasive lymphocytic choriomeningitis virus (LCMV) strains, virus can persist by selective clonal exhaustion of antigen-specific CD8(+) T cells. In this work we studied the down-regulation of the virus-specific CD8(+)-T-cell response during a persistent infection of adult mice, with particular emphasis on the contribution of the interferon response in promoting host defense. Studies were conducted by infecting mice deficient in receptors for type I (alpha/beta interferon [IFN-alpha/beta]), type II (IFN-gamma), and both type I and II IFNs with LCMV isolates that vary in their capacity to induce T-cell exhaustion. The main conclusions of this study are as follows. (i) IFNs play a critical role in LCMV infection by reducing viral loads in the initial stages of infection and thus modifying both the extent of CD8(+)-T-cell exhaustion and the course of infection. The importance of IFNs in this context varies with the biological properties of the LCMV strain. (ii) An inverse correlation exists between antigen persistence and responsiveness of virus-specific CD8(+) T cells. This results in distinct programs of activation or tolerance (functional unresponsiveness and/or physical elimination of antigen-specific cells) during acute and chronic virus infections, respectively. (iii) A successful immune response associated with definitive viral clearance requires an appropriate balance between cellular and humoral components of the immune system. We discuss the role of IFNs in influencing virus-specific T cells that determine the outcome of persistent infections.

Acute Disease↗
PubMed1997

Cytometric analysis of immunosenescence.

We have been studying the immune system of healthy centenarians for many years, and they provide the best example of successful aging. They are people who have escaped major age-related diseases and reached the extreme limit of human life in good clinical condition. In most cases, histories of centenarians reveal them to be free of cancer, dementia, diabetes, cardiovascular diseases, and cataracts. Moreover, in order to reach such an advanced age, they should be equipped with well preserved and efficient immuno- and defense mechanisms, and optimal combinations of an appropriate lifestyle and genetic background. Using this approach, several paradoxes emerged as far as the immune system of centenarians is concerned, regarding: i) humoral immunity (increase in plasma immunoglobulins and nonorgan-specific autoantibodies, decrease in B cell number and lack of organ-specific autoantibodies); ii) cellular immunity (well preserved number of "virgin" T cells, a relatively intact T cell repertoire despite a thymus involuting since puberty, increased number of cells with markers of NK activity); iii) decreased peripheral blood lymphocyte tendency to programmed cell death, associated with a well preserved mitochondria functionality and intracellular bcl-2 levels. An age-related increase in the levels of adhesion molecule present on lymphocyte plasma-membrane, accompanied by a complex reshaping of the cytokine network, must be added to this scenario. All our data fit the hypothesis that a complex, unpredicted remodeling of the immune system occurs with age. In the present review it is underlined how flow cytometry has been used to study most of the above mentioned aspects of immunosenescence, and to establish new age-related reference values.

Adult↗
PubMed2001

Numeric simulation of plant signaling networks.

Plants have evolved an intricate signaling apparatus that integrates relevant information and allows an optimal response to environmental conditions. For instance, the coordination of defense responses against pathogens involves sophisticated molecular detection and communication systems. Multiple protection strategies may be deployed differentially by the plant according to the nature of the invading organism. These responses are also influenced by the environment, metabolism, and developmental stage of the plant. Though the cellular signaling processes traditionally have been described as linear sequences of events, it is now evident that they may be represented more accurately as network-like structures. The emerging paradigm can be represented readily with the use of Boolean language. This digital (numeric) formalism allows an accurate qualitative description of the signal transduction processes, and a dynamic representation through computer simulation. Moreover, it provides the required power to process the increasing amount of information emerging from the fields of genomics and proteomics, and from the use of new technologies such as microarray analysis. In this review, we have used the Boolean language to represent and analyze part of the signaling network of disease resistance in Arabidopsis.

Algorithms↗
PubMed2006

The Arabidopsis protein kinase PTI1-2 is activated by convergent phosphatidic acid and oxidative stress signaling pathways downstream of PDK1 and OXI1.

Arabidopsis PDK1 activity is regulated by binding to the lipid phosphatidic acid (PA) resulting in activation of the oxidative stress-response protein kinase OXI1/AGC2-1. Thus there is an inferred link between lipid signaling and oxidative stress signaling modules. Among a panel of hormones and stresses tested, we found that, in addition to PA, the fungal elicitor xylanase activated PDK1, suggesting that PDK1 has a role in plant pathogen defense mechanisms. The downstream OXI1 was activated by additional stress factors, including PA, H(2)O(2), and partially by xylanase. We have isolated an interacting partner of OXI1, a Ser/Thr kinase (PTI1-2), which is downstream of OXI1. Its sequence closely resembles the tomato Pti kinase, which has been implicated in the hypersensitive response, a localized programmed cell death that occurs at the site of pathogen infection. PTI1-2 is activated by the same stresses/elicitors as OXI1 and additionally flagellin. We have used RNA interference to knock out the expression of PDK1 and OXI1 and to study the effects on PTI1-2 activity. We show that specific lipid signaling pathways converge on PTI1-2 via the PDK1-OXI1 axis, whereas H(2)O(2) and flagellin signals to OXI1-PTI1-2 via a PDK1-independent pathway. PTI1-2 represents a new downstream component that integrates diverse lipid and reactive oxygen stress signals and functions closely with OXI1.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed1986

Cumulative incidence rates for Hodgkin's disease and other hematologic malignancies, with special reference to age-related carcinogenesis.

The cumulative incidence rate throughout the life span was analyzed for 4,865 Hodgkin's disease cases, in comparison with 16,015 malignant lymphomas (ML), 1,694 acute lymphocytic leukemias (ALL), 3,967 acute myeloid leukemias (AML), 2,109 chronic myeloid leukemias (CML), and 4,752 chronic lymphoid leukemias (CLL) in US white reported in the SEER program during 1973-1981. A log-linear increase was observed in ML, AML, CML, and CLL throughout the life-span, but only in childhood in ALL. Hodgkin's disease showed a steep increase until age 20-24, and then the increase became much more gradual. The cumulative incidence rates for males and females were parallel for ML and leukemias, but diverged for Hodgkin's disease (the rate for females had a lower slope than that for males after age 20-24). This difference was mainly caused by a lower frequency in females of mixed cellularity and lymphocyte predominance subtypes. The incidence curve of Hodgkin's disease was consistent with the two-stage model of carcinogenesis; it is likely that the proliferation of progenitor cells peaks at a young age and that the death rate of so-called intermediate cells is a primary influence during the subclinical stage. The cytogenesis of Hodgkin's disease and the histologic variation with special reference to the T-zone histiocytes suggest that a strong host defense mechanism against neoplastic change is involved, rather than different etiologic influences.

Adolescent↗
PubMed1995

Mechanisms of lysis by cytotoxic T cells.

When a cytotoxic lymphocyte binds to an antigenic cell, there is a reorientation of the Golgi apparatus and a directed exocytosis of cytoplasmic granules toward the offending cell. In the model originally proposed by Henkart, these granules were hypothesized to contain lytic molecules that contribute to the demise of the target cell. Initially, perforin/cytolysin was believed to be the major player in the mechanism of lysis. Recent work, however, using a variety of biochemical, molecular biological, and genetic approaches, has provided convincing evidence that other granule-associated molecules contribute to the lytic pathway. Of particular note are the granzymes, whose proteolytic activity is intimately associated with the induction of DNA fragmentation and apoptosis. In this review we summarize these recent experiments and present an updated view of the granule-mediated killing mechanism. For some years the universality of the granule-killing mechanism has been challenged. Experiments reported in the last few years on the characteristics of target cell death, detailed studies with cytolytic T cell lines, and, ultimately, with lymphocytes from mice that have been genetically altered using homologous recombination, have proven the existence of a second pathway. We discuss whether the existence of this alternate, Fas antigen/Fas ligand, mechanism really deals a knock-out blow to the granule exocytosis followers. Most likely it represents an important immunoregulatory system rather than a defense against pathogenesis. The granule-mediated and Fas-dependent mechanisms of cytolysis represent, at first sight, completely different pathways. However, it is becoming increasingly apparent that once the kiss of death has been received, through either granules or Fas, the events within the target cell are remarkably similar. Considerable attention is now being focussed on a family of interleukin-1 beta-converting enzymes (ICEs) that become activated within the target cell after attack by a cytotoxic lymphocyte. These enzymes are particularly interesting as they have now been shown to be directly involved in developmentally controlled, programmed cell death.

Animals↗
PubMed1999

Exploring for a record of ancient Martian life.

The immediate task facing exopaleontology is to define a strategy to explore Mars for a fossil record during the decade-long exploration program that lies ahead. Consideration of the quality of paleontological information preserved under different geological conditions is important if we are to develop a strategy with broad applicability. The preservation of microbial fossils is strongly influenced by the physical, chemical, and biological factors of the environment which, acting together, determine the types of information that will be captured and retained in the rock record. In detrital sedimentary systems, preservation is favored by rapid burial in fine-grained, clay-rich sediments. In chemical sedimentary systems, preservation is enhanced by rapid entombment in fine-grained chemical precipitates. For long-term preservation, host rocks must be composed of stable minerals that are resistant to chemical weathering and that form an impermeable matrix and closed chemical system to protect biosignatures from alteration during subsequent diagenesis or metamorphism. In this context, host rocks composed of highly ordered, chemically stable mineral phases, like silica (e.g., cherts) or phosphate (e.g., phosphorites), are especially favored. Such lithologies tend to have very long crustal residence times and, along with carbonates and shales, are the most common host rocks for the Precambrian microfossil record on Earth. Although we make the defensible assumption that Mars was more like the Earth early in its history, clearly, the geological and historical differences between the two planets are many. Such differences must be carefully considered when adapting an Earth-based strategy to Mars.

Carbonates↗
PubMed2004

The novel yeast PAS kinase Rim 15 orchestrates G0-associated antioxidant defense mechanisms.

The highly conserved PKA and TOR proteins define key signaling pathways that control cell proliferation in response to growth factors and/or nutrients. In yeast, inactivation of PKA and/or TOR causes cells to arrest growth early G1 and induces a program that is characteristic of G0 cells. We have recently shown that the protein kinase Rim15 integrates both PKA- and TOR-mediated signals. In this work, we demonstrate that the Rim15-activated genomic expression program following glucose limitation at the diauxic shift is mediated by the three transcription factors Gis1, Msn2, and Msn4. The Rim15 regulon comprises several gene clusters implicated in the adaptation to respiratory growth, including classical oxidative stress genes such as SOD1 and SOD2, suggesting that the reduced life span of rim15delta cells may be due to their deficiency in oxidative damage prevention. Interestingly, we found that the primary amino acid sequence of Rim15 includes in its amino-terminal part a conserved PAS domain, known to act as a sensor for a variety of stimuli, We propose that Rim15 has evolved to integrate nutrient signals (transduced via TOR and PKA) and redox and/or oxidative stress signals to appropriately induce a transcriptional program that ensures survival in G0.

Amino Acid Sequence↗
PubMed2025

Distinct transcriptional and epigenomic programs define Hofbauer cells in term placenta.

Hofbauer cells (HBCs) are fetal macrophages located in the placenta that contribute to antimicrobial defense, angiogenesis, tissue remodeling, and metabolic processes within the chorionic villi. Although their roles in placental biology are increasingly recognized, the mechanisms that regulate HBC identity and function are not yet fully defined. This study aimed to define the core transcriptomic and epigenomic features of HBCs in term placentas and to examine their capacity for transcriptional responsiveness and phenotypic variation. Using chromatin accessibility profiling and bulk RNA-seq, we found that HBCs exhibit a unique gene expression and chromatin accessibility profile compared with other fetal and adult macrophages. We identified a coordinated transcriptional network involving nuclear receptors (NRs) NR4A1-3, the glucocorticoid receptor, and RFX family members (RFX1, RFX2, RFX5) that appears to shape HBC identity, particularly through pathways linked to lipid metabolism and angiogenesis. Although exploratory in nature, in vitro stimulation studies showed that HBCs exhibited increased transcriptional activity in response to combined IL-4 and rosiglitazone treatment, including induction of the lipid transporter CD36. Mass cytometry analysis revealed surface markers indicative of both immature and mature macrophage states. These results together indicate that HBCs are a distinct and diverse population of macrophages with a specialized, adaptable regulatory program in the human placenta.

Female↗
PubMed2005

Molecular pathology of aging and its implications for senescent coronary atherosclerosis.

PURPOSE OF REVIEW: This review highlights common mechanisms of organismal aging and inflammatory coronary atherosclerosis. RECENT FINDINGS: A substantial body of evidence now indicates that aging is largely due to molecular damage inflicted by reactive oxygen species, electrophiles, and other reactive endobiotic and xenobiotic metabolites. Our understanding of genetic pathways regulating longevity began 12 years ago with the discovery that a developmental-arrest program in the nematode Caenorhabditis elegans also has marked effects on adult lifespan. This pathway, closely related to the insulin and insulinlike growth factor-signaling pathways of mammals, modulates longevity and stress resistance in several model organisms. Insulin-like signaling also has an impact on redox signaling, antioxidant defenses, and metabolic generation of oxidative stress. Recently, additional signaling pathways--involving Sirtuins, AMP kinase, Jun N-terminal kinase 1, and other master regulatory proteins--have been implicated in longevity and stress-resistance mechanisms. The inflammatory process involves acute production of reactive oxygen species by specialized cells responding to infection, exposure to toxins or allergens, cell damage, hypoxia, ischemia/reperfusion, and other factors, initiating signaling through several of these pathways. Free radical chain reactions arise from lipid oxidation and generate oxidized low-density lipoprotein, a powerful inflammatory signal and potentiator of atherosclerosis. Oxidized low-density lipoprotein accumulates in atherosclerotic arteries, particularly in rupture-prone regions. Inflammation involving oxidative stress, by way of the production of reactive oxygen species, is a hallmark of coronary atherosclerosis. SUMMARY: Common pathways underlie both organismal aging and tissue-autonomous senescent pathologic processes, such as coronary atherosclerosis. The mechanisms discovered in model organisms may lead to pharmacotherapeutic interventions.

Aging↗
PubMed2004

Fatigue models for applied research in warfighting.

The U.S. Department of Defense (DOD) has long pursued applied research concerning fatigue in sustained and continuous military operations. In 1996, Hursh developed a simple homeostatic fatigue model and programmed the model into an actigraph to give a continuous indication of performance. Based on this initial work, the Army conducted a study of 1 wk of restricted sleep in 66 subjects with multiple measures of performance, termed the Sleep Dose-Response Study (SDR). This study provided numerical estimation of parameters for the Walter Reed Army Institute of Research Sleep Performance Model (SPM) and elucidated the relationships among several sleep-related performance measures. Concurrently, Hursh extended the original actigraph modeling structure and software expressions for use in other practical applications. The model became known as the Sleep, Activity, Fatigue, and Task Effectiveness (SAFTE) Model, and Hursh has applied it in the construction of a Fatigue Avoidance Scheduling Tool. This software is designed to help optimize the operational management of aviation ground and flight crews, but is not limited to that application. This paper describes the working fatigue model as it is being developed by the DOD laboratories, using the conceptual framework, vernacular, and notation of the SAFTE Model. At specific points where the SPM may differ from SAFTE, this is discussed. Extensions of the SAFTE Model to incorporate dynamic phase adjustment for both transmeridian relocation and shift work are described. The unexpected persistence of performance effects following chronic sleep restriction found in the SDR study necessitated some revisions of the SAFTE Model that are also described. The paper concludes with a discussion of several important modeling issues that remain to be addressed.

Aviation↗