Providing care for a frail older adult has been described as a stressful experience that may erode psychological well-being and physical health of caregivers. In this meta-analysis, the authors integrated findings from 84 articles on differences between caregivers and noncaregivers in perceived stress, depression, general subjective well-being, physical health, and self-efficacy. The largest differences were found with regard to depression (g = .58), stress (g = .55), self-efficacy (g = .54), and general subjective well-being (g = -.40). Differences in the levels of physical health in favor of noncaregivers were statistically significant, but small (g = .18). However, larger differences were found between dementia caregivers and noncaregivers than between heterogeneous samples of caregivers and noncaregivers. Differences were also influenced by the quality of the study, relationship of caregiver to the care recipient, gender, and mean age of caregivers.

Elimination of misfolded proteins from the endoplasmic reticulum (ER) by retro-translocation is an important physiological adaptation to ER stress. This process requires recognition of a substrate in the ER lumen and its subsequent movement through the membrane by the cytosolic p97 ATPase. Here we identify a p97-interacting membrane protein complex in the mammalian ER that links these two events. The central component of the complex, Derlin-1, is a homologue of Der1, a yeast protein whose inactivation prevents the elimination of misfolded luminal ER proteins. Derlin-1 associates with different substrates as they move through the membrane, and inactivation of Derlin-1 in C. elegans causes ER stress. Derlin-1 interacts with US11, a virally encoded ER protein that specifically targets MHC class I heavy chains for export from the ER, as well as with VIMP, a novel membrane protein that recruits the p97 ATPase and its cofactor.

A major cause of cell death caused by genotoxic stress is thought to be due to the depletion of NAD(+) from the nucleus and the cytoplasm. Here we show that NAD(+) levels in mitochondria remain at physiological levels following genotoxic stress and can maintain cell viability even when nuclear and cytoplasmic pools of NAD(+) are depleted. Rodents fasted for 48 hr show increased levels of the NAD(+) biosynthetic enzyme Nampt and a concomitant increase in mitochondrial NAD(+). Increased Nampt provides protection against cell death and requires an intact mitochondrial NAD(+) salvage pathway as well as the mitochondrial NAD(+)-dependent deacetylases SIRT3 and SIRT4. We discuss the relevance of these findings to understanding how nutrition modulates physiology and to the evolution of apoptosis.

Farmers and breeders have long known that often it is the simultaneous occurrence of several abiotic stresses, rather than a particular stress condition, that is most lethal to crops. Surprisingly, the co-occurrence of different stresses is rarely addressed by molecular biologists that study plant acclimation. Recent studies have revealed that the response of plants to a combination of two different abiotic stresses is unique and cannot be directly extrapolated from the response of plants to each of the different stresses applied individually. Tolerance to a combination of different stress conditions, particularly those that mimic the field environment, should be the focus of future research programs aimed at developing transgenic crops and plants with enhanced tolerance to naturally occurring environmental conditions.

Oxidative stress is induced by a wide range of environmental factors including UV stress, pathogen invasion (hypersensitive reaction), herbicide action and oxygen shortage. Oxygen deprivation stress in plant cells is distinguished by three physiologically different states: transient hypoxia, anoxia and reoxygenation. Generation of reactive oxygen species (ROS) is characteristic for hypoxia and especially for reoxygenation. Of the ROS, hydrogen peroxide (H(2)O(2)) and superoxide (O(2)(.-)) are both produced in a number of cellular reactions, including the iron-catalysed Fenton reaction, and by various enzymes such as lipoxygenases, peroxidases, NADPH oxidase and xanthine oxidase. The main cellular components susceptible to damage by free radicals are lipids (peroxidation of unsaturated fatty acids in membranes), proteins (denaturation), carbohydrates and nucleic acids. Consequences of hypoxia-induced oxidative stress depend on tissue and/or species (i.e. their tolerance to anoxia), on membrane properties, on endogenous antioxidant content and on the ability to induce the response in the antioxidant system. Effective utilization of energy resources (starch, sugars) and the switch to anaerobic metabolism and the preservation of the redox status of the cell are vital for survival. The formation of ROS is prevented by an antioxidant system: low molecular mass antioxidants (ascorbic acid, glutathione, tocopherols), enzymes regenerating the reduced forms of antioxidants, and ROS-interacting enzymes such as SOD, peroxidases and catalases. In plant tissues many phenolic compounds (in addition to tocopherols) are potential antioxidants: flavonoids, tannins and lignin precursors may work as ROS-scavenging compounds. Antioxidants act as a cooperative network, employing a series of redox reactions. Interactions between ascorbic acid and glutathione, and ascorbic acid and phenolic compounds are well known. Under oxygen deprivation stress some contradictory results on the antioxidant status have been obtained. Experiments on overexpression of antioxidant production do not always result in the enhancement of the antioxidative defence, and hence increased antioxidative capacity does not always correlate positively with the degree of protection. Here we present a consideration of factors which possibly affect the effectiveness of antioxidant protection under oxygen deprivation as well as under other environmental stresses. Such aspects as compartmentalization of ROS formation and antioxidant localization, synthesis and transport of antioxidants, the ability to induce the antioxidant defense and cooperation (and/or compensation) between different antioxidant systems are the determinants of the competence of the antioxidant system.

The heart responds to stress signals by hypertrophic growth, which is accompanied by activation of the MEF2 transcription factor and reprogramming of cardiac gene expression. We show here that class II histone deacetylases (HDACs), which repress MEF2 activity, are substrates for a stress-responsive kinase specific for conserved serines that regulate MEF2-HDAC interactions. Signal-resistant HDAC mutants lacking these phosphorylation sites are refractory to hypertrophic signaling and inhibit cardiomyocyte hypertrophy. Conversely, mutant mice lacking the class II HDAC, HDAC9, are sensitized to hypertrophic signals and exhibit stress-dependent cardiomegaly. Thus, class II HDACs act as signal-responsive suppressors of the transcriptional program governing cardiac hypertrophy and heart failure.

Photosynthetic plants are the principal solar energy converter sustaining life on Earth. Despite its fundamental importance, little is known about how plants sense and adapt to darkness in the daily light-dark cycle, or how they adapt to unpredictable environmental stresses that compromise photosynthesis and respiration and deplete energy supplies. Current models emphasize diverse stress perception and signalling mechanisms. Using a combination of cellular and systems screens, we show here that the evolutionarily conserved Arabidopsis thaliana protein kinases, KIN10 and KIN11 (also known as AKIN10/At3g01090 and AKIN11/At3g29160, respectively), control convergent reprogramming of transcription in response to seemingly unrelated darkness, sugar and stress conditions. Sensing and signalling deprivation of sugar and energy, KIN10 targets a remarkably broad array of genes that orchestrate transcription networks, promote catabolism and suppress anabolism. Specific bZIP transcription factors partially mediate primary KIN10 signalling. Transgenic KIN10 overexpression confers enhanced starvation tolerance and lifespan extension, and alters architecture and developmental transitions. Significantly, double kin10 kin11 deficiency abrogates the transcriptional switch in darkness and stress signalling, and impairs starch mobilization at night and growth. These studies uncover surprisingly pivotal roles of KIN10/11 in linking stress, sugar and developmental signals to globally regulate plant metabolism, energy balance, growth and survival. In contrast to the prevailing view that sucrose activates plant SnRK1s (Snf1-related protein kinases), our functional analyses of Arabidopsis KIN10/11 provide compelling evidence that SnRK1s are inactivated by sugars and share central roles with the orthologous yeast Snf1 and mammalian AMPK in energy signalling.

TIA-1 is an RNA binding protein that promotes the assembly of stress granules (SGs), discrete cytoplasmic inclusions into which stalled translation initiation complexes are dynamically recruited in cells subjected to environmental stress. The RNA recognition motifs of TIA-1 are linked to a glutamine-rich prion-related domain (PRD). Truncation mutants lacking the PRD domain do not induce spontaneous SGs and are not recruited to arsenite-induced SGs, whereas the PRD forms aggregates that are recruited to SGs in low-level-expressing cells but prevent SG assembly in high-level-expressing cells. The PRD of TIA-1 exhibits many characteristics of prions: concentration-dependent aggregation that is inhibited by the molecular chaperone heat shock protein (HSP)70; resistance to protease digestion; sequestration of HSP27, HSP40, and HSP70; and induction of HSP70, a feedback regulator of PRD disaggregation. Substitution of the PRD with the aggregation domain of a yeast prion, SUP35-NM, reconstitutes SG assembly, confirming that a prion domain can mediate the assembly of SGs. Mouse embryomic fibroblasts (MEFs) lacking TIA-1 exhibit impaired ability to form SGs, although they exhibit normal phosphorylation of eukaryotic initiation factor (eIF)2alpha in response to arsenite. Our results reveal that prion-like aggregation of TIA-1 regulates SG formation downstream of eIF2alpha phosphorylation in response to stress.

Drought and salinity are major abiotic stresses to crop production. Here, we show that overexpression of stress responsive gene SNAC1 (STRESS-RESPONSIVE NAC 1) significantly enhances drought resistance in transgenic rice (22-34% higher seed setting than control) in the field under severe drought stress conditions at the reproductive stage while showing no phenotypic changes or yield penalty. The transgenic rice also shows significantly improved drought resistance and salt tolerance at the vegetative stage. Compared with WT, the transgenic rice are more sensitive to abscisic acid and lose water more slowly by closing more stomatal pores, yet display no significant difference in the rate of photosynthesis. SNAC1 is induced predominantly in guard cells by drought and encodes a NAM, ATAF, and CUC (NAC) transcription factor with transactivation activity. DNA chip analysis revealed that a large number of stress-related genes were up-regulated in the SNAC1-overexpressing rice plants. Our data suggest that SNAC1 holds promising utility in improving drought and salinity tolerance in rice.

Unilateral neglect reflects a disturbance in the spatial distribution of directed attention. A review of unilateral neglect syndromes in monkeys and humans suggests that four cerebral regions provide an integrated network for the modulation of directed attention within extrapersonal space. Each component region has a unique functional role that reflects its profile of anatomical connectivity, and each gives rise to a different clinical type of unilateral neglect when damaged. A posterior parietal component provides an internal sensory map and perhaps also a mechanism for modifying the extent of synaptic space devoted to specific portions of the external world; a limbic component in the cingulate gyrus regulates the spatial distribution of motivational valence; a frontal component coordinates the motor programs for exploration, scanning, reaching, and fixating; and a reticular component provides the underlying level of arousal and vigilance. This hypothetical network requires at least three complementary and interacting representations of extrapersonal space: a sensory representation in posterior parietal cortex, a schema for distributing exploratory movements in frontal cortex, and a motivational map in the cingulate cortex. Lesions in only one component of this network yield partial unilateral neglect syndromes, while those that encompass all the components result in profound deficits that transcend the mass effect of the larger lesion. This network approach to the localization of complex functions offers an alternative to more extreme approaches, some of which stress an exclusive concentration of function within individual centers in the brain and others which advocate a more uniform (equipotential or holistic) distribution. In human beings, unilateral neglect syndromes are more frequent and severe after lesions in the right hemisphere. Also, right hemisphere mechanisms appear more effective in the execution of attentional tasks. Furthermore, the attentional functions of the right hemisphere span both hemispaces, while the left hemisphere seems to contain the neural apparatus mostly for contralateral attention. This evidence indicates that the right hemisphere of dextrals has a functional specialization for the distribution of directed attention within extrapersonal space.

Cells are continuously exposed to a variety of environmental stresses and have to decide 'to be or not to be' depending on the types and strength of stress. Among the many signaling pathways that respond to stress, mitogen-activated protein kinase (MAPK) family members are crucial for the maintenance of cells. Three subfamilies of MAPKs have been identified: extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38-MAPKs. It has been originally shown that ERKs are important for cell survival, whereas JNKs and p38-MAPKs were deemed stress responsive and thus involved in apoptosis. However, the regulation of apoptosis by MAPKs is more complex than initially thought and often controversial. In this review, we discuss MAPKs in apoptosis regulation with attention to mouse genetic models and critically point out the multiple roles of MAPKs.

Chronic obstructive pulmonary disease is a leading cause of death and disability, but has only recently been extensively explored from a cellular and molecular perspective. There is a chronic inflammation that leads to fixed narrowing of small airways and alveolar wall destruction (emphysema). This is characterised by increased numbers of alveolar macrophages, neutrophils and cytotoxic T-lymphocytes, and the release of multiple inflammatory mediators (lipids, chemokines, cytokines, growth factors). A high level of oxidative stress may amplify this inflammation. There is also increased elastolysis and evidence for involvement of several elastolytic enzymes, including serine proteases, cathepsins and matrix metalloproteinases. The inflammation and proteolysis in chronic obstructive pulmonary disease is an amplification of the normal inflammatory response to cigarette smoke. This inflammation, in marked contrast to asthma, appears to be resistant to corticosteroids, prompting a search for novel anti-inflammatory therapies that may prevent the relentless progression of the disease.

To withstand the high intracellular pressure, the cell wall of most bacteria is stabilized by a unique cross-linked biopolymer called murein or peptidoglycan. It is made of glycan strands [poly-(GlcNAc-MurNAc)], which are linked by short peptides to form a covalently closed net. Completely surrounding the cell, the murein represents a kind of bacterial exoskeleton known as the murein sacculus. Not only does the sacculus endow bacteria with mechanical stability, but in addition it maintains the specific shape of the cell. Enlargement and division of the murein sacculus is a prerequisite for growth of the bacterium. Two groups of enzymes, hydrolases and synthases, have to cooperate to allow the insertion of new subunits into the murein net. The action of these enzymes must be well coordinated to guarantee growth of the stress-bearing sacculus without risking bacteriolysis. Protein-protein interaction studies suggest that this is accomplished by the formation of a multienzyme complex, a murein-synthesizing machinery combining murein hydrolases and synthases. Enlargement of both the multilayered murein of gram-positive and the thin, single-layered murein of gram-negative bacteria seems to follow an inside-to-outside growth strategy. New material is hooked in a relaxed state underneath the stress-bearing sacculus before it becomes inserted upon cleavage of covalent bonds in the layer(s) under tension. A model is presented that postulates that maintenance of bacterial shape is achieved by the enzyme complex copying the preexisting murein sacculus that plays the role of a template.

The present research evaluated the psychometric properties of the credibility/expectancy questionnaire, a quick and easy-to-administer scale for measuring treatment expectancy and rationale credibility for use in clinical outcome studies. The results suggested that this questionnaire derives the two predicted factors (cognitively based credibility and relatively more affectively based expectancy) and that these factors are stable across different populations. Furthermore, the questionnaire demonstrated high internal consistency within each factor and good test-retest reliability. The expectancy factor predicted outcome on some measures, whereas the credibility factor was unrelated to outcome. The questionnaire is appended to the paper, yet the authors stress care when utilizing the scale. During the administration of the questionnaire, the participant sees two sections--one related to thinking and one related to feeling. However, the researcher needs to be aware that the 2 factors derived are not grouped into those questions. Instead credibility was found to be derived from the first three think questions and expectancy was derived from the fourth think question and the two feel questions.

When unfolded proteins accumulate in the endoplasmic reticulum (ER), transcription of glucose-regulated proteins (GRPs) representing ER-resident molecular chaperones is markedly induced via the unfolded protein response (UPR) pathway. In contrast to recent progress in the analysis of yeast UPR, both cis-acting elements and transactivators responsible for mammalian UPR have remained obscure. Here, we analyzed the promoter regions of human GRP78, GRP94, and calreticulin genes and identified a novel element designated the ER stress response element (ERSE). ERSE, with a consensus of CCAATN9CCACG, was shown to be necessary and sufficient for induction of these GRPs. Using yeast one-hybrid screening, we isolated a human cDNA encoding a basic leucine zipper (bZIP) protein, ATF6, as a putative ERSE-binding protein. When overexpressed in HeLa cells, ATF6 enhanced transcription of GRP genes in an ERSE-dependent manner, whereas CREB-RP, another bZIP protein closely related to ATF6, specifically inhibited GRP induction. Endogenous ATF6 constitutively expressed as a 90-kDa protein was converted to a 50-kDa protein in ER-stressed cells, which appeared to be important for the cellular response to ER stress. These results suggest that, as in yeast, bZIP proteins are involved in mammalian UPR, acting through newly defined ERSE.

The checkpoint kinases ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3 related) transduce genomic stress signals to halt cell cycle progression and promote DNA repair. We report the identification of an ATR-interacting protein (ATRIP) that is phosphorylated by ATR, regulates ATR expression, and is an essential component of the DNA damage checkpoint pathway. ATR and ATRIP both localize to intranuclear foci after DNA damage or inhibition of replication. Deletion of ATR mediated by the Cre recombinase caused the loss of ATR and ATRIP expression, loss of DNA damage checkpoint responses, and cell death. Therefore, ATR is essential for the viability of human somatic cells. Small interfering RNA directed against ATRIP caused the loss of both ATRIP and ATR expression and the loss of checkpoint responses to DNA damage. Thus, ATRIP and ATR are mutually dependent partners in cell cycle checkpoint signaling pathways.

In spite of the importance of jasmonates (JAs) as plant growth and stress regulators, the molecular components of their signaling pathway remain largely unknown. By means of a genetic screen that exploits the cross talk between ethylene (ET) and JAs, we describe the identification of several new loci involved in JA signaling and the characterization and positional cloning of one of them, JASMONATE-INSENSITIVE1 (JAI1/JIN1). JIN1 encodes AtMYC2, a nuclear-localized basic helix-loop-helix-leucine zipper transcription factor, whose expression is rapidly upregulated by JA, in a CORONATINE INSENSITIVE1-dependent manner. Gain-of-function experiments confirmed the relevance of AtMYC2 in the activation of JA signaling. AtMYC2 differentially regulates the expression of two groups of JA-induced genes. The first group includes genes involved in defense responses against pathogens and is repressed by AtMYC2. Consistently, jin1 mutants show increased resistance to necrotrophic pathogens. The second group, integrated by genes involved in JA-mediated systemic responses to wounding, is activated by AtMYC2. Conversely, Ethylene-Response-Factor1 (ERF1) positively regulates the expression of the first group of genes and represses the second. These results highlight the existence of two branches in the JA signaling pathway, antagonistically regulated by AtMYC2 and ERF1, that are coincident with the alternative responses activated by JA and ET to two different sets of stresses, namely pathogen attack and wounding.

BACKGROUND

Extinction of conditioned fear is thought to form a new safety memory that is expressed in the context in which the extinction learning took place. Rodent studies implicate the ventromedial prefrontal cortex (vmPFC) and hippocampus in extinction recall and its modulation by context, respectively. The aim of the present study is to investigate the mediating anatomy of extinction recall in healthy humans.

METHODS

We used event-related functional magnetic resonance imaging (fMRI) and a 2-day fear conditioning and extinction protocol with skin conductance response as the index of conditioned responses.

RESULTS

During extinction recall, we found significant activations in vmPFC and hippocampus in response to the extinguished versus an unextinguished stimulus. Activation in these brain regions was positively correlated with the magnitude of extinction memory. Functional connectivity analysis revealed significant positive correlation between vmPFC and hippocampal activation during extinction recall.

CONCLUSIONS

These results support the involvement of the human hippocampus as well as vmPFC in the recall of extinction memory. Furthermore, this provides a paradigm for future investigations of fronto-temporal function during extinction recall in psychiatric disorders such as posttraumatic stress disorder.

The p62/SQSTM1 (sequestosome 1) protein, which acts as a cargo receptor for autophagic degradation of ubiquitinated targets, is up-regulated by various stressors. Induction of the p62 gene by oxidative stress is mediated by NF-E2-related factor 2 (NRF2) and, at the same time, p62 protein contributes to the activation of NRF2, but hitherto the mechanisms involved were not known. Herein, we have mapped an antioxidant response element (ARE) in the p62 promoter that is responsible for its induction by oxidative stress via NRF2. Chromatin immunoprecipitation and gel mobility-shift assays verified that NRF2 binds to this cis-element in vivo and in vitro. Also, p62 docks directly onto the Kelch-repeat domain of Kelch-like ECH-associated protein 1 (KEAP1), via a motif designated the KEAP1 interacting region (KIR), thereby blocking binding between KEAP1 and NRF2 that leads to ubiquitylation and degradation of the transcription factor. The KIR motif in p62 is located immediately C-terminal to the LC3-interacting region (LIR) and resembles the ETGE motif utilized by NRF2 for its interaction with KEAP1. KIR is required for p62 to stabilize NRF2, and inhibition of KEAP1 by p62 occurs from a cytoplasmic location within the cell. The LIR and KIR motifs cannot be engaged simultaneously by LC3 and KEAP1, but because p62 is polymeric the interaction between KEAP1 and p62 leads to accumulation of KEAP1 in p62 bodies, which is followed by autophagic degradation of KEAP1. Our data explain how p62 contributes to activation of NRF2 target genes in response to oxidative stress through creating a positive feedback loop.

Growing evidence indicates that chronic and acute overproduction of reactive oxygen species (ROS) under pathophysiologic conditions is integral in the development of cardiovascular diseases (CVD). These ROS can be released from nicotinamide adenine dinucleotide (phosphate) oxidase, xanthine oxidase, lipoxygenase, mitochondria, or the uncoupling of nitric oxide synthase in vascular cells. ROS mediate various signaling pathways that underlie vascular inflammation in atherogenesis: from the initiation of fatty streak development through lesion progress to ultimate plaque rupture. Various animal models of oxidative stress support the notion that ROS have a causal role in atherosclerosis and other cardiovascular diseases. Human investigations also support the oxidative stress hypothesis of atherosclerosis. Oxidative stress is the unifying mechanism for many CVD risk factors, which additionally supports its central role in CVD. Despite the demonstrated role of antioxidants in cellular and animal studies, the ineffectiveness of antioxidants in reducing cardiovascular death and morbidity in clinical trials has led many investigators to question the importance of oxidative stress in human atherosclerosis. Others have argued that the prime factor for the mixed outcomes from using antioxidants to prevent CVD may be the lack of specific and sensitive biomarkers by which to assess the oxidative stress phenotypes underlying CVD. A better understanding of the complexity of cellular redox reactions, development of a new class of antioxidants targeted to specific subcellular locales, and the phenotype-genotype linkage analysis for oxidative stress will likely be avenues for future research in this area as we move toward the broader use of pharmacological and regenerative therapies in the treatment and prevention of CVD.

BACKGROUND

The efficient sequestration of hemoglobin by the red blood cell membrane and the presence of multiple hemoglobin clearance mechanisms suggest a critical need to prevent the buildup of this molecule in the plasma. A growing list of clinical manifestations attributed to hemoglobin release in a variety of acquired and iatrogenic hemolytic disorders suggests that hemolysis and hemoglobinemia should be considered as a novel mechanism of human disease.

METHODS

Pertinent scientific literature databases and references were searched through October 2004 using terms that encompassed various aspects of hemolysis, hemoglobin preparations, clinical symptoms associated with plasma hemoglobin, nitric oxide in hemolysis, anemia, pulmonary hypertension, paroxysmal nocturnal hemoglobinuria, and sickle-cell disease.

RESULTS

Hemoglobin is released into the plasma from the erythrocyte during intravascular hemolysis in hereditary, acquired, and iatrogenic hemolytic conditions. When the capacity of protective hemoglobin-scavenging mechanisms has been saturated, levels of cell-free hemoglobin increase in the plasma, resulting in the consumption of nitric oxide and clinical sequelae. Nitric oxide plays a major role in vascular homeostasis and has been shown to be a critical regulator of basal and stress-mediated smooth muscle relaxation and vasomotor tone, endothelial adhesion molecule expression, and platelet activation and aggregation. Thus, clinical consequences of excessive cell-free plasma hemoglobin levels during intravascular hemolysis or the administration of hemoglobin preparations include dystonias involving the gastrointestinal, cardiovascular, pulmonary, and urogenital systems, as well as clotting disorders. Many of the clinical sequelae of intravascular hemolysis in a prototypic hemolytic disease, paroxysmal nocturnal hemoglobinuria, are readily explained by hemoglobin-mediated nitric oxide scavenging.

CONCLUSIONS

A growing body of evidence supports the existence of a novel mechanism of human disease, namely, hemolysis-associated smooth muscle dystonia, vasculopathy, and endothelial dysfunction.

Stress is a part of every life to varying degrees, but individuals differ in their stress vulnerability. Stress is usefully viewed from a biological perspective; accordingly, it involves activation of neurobiological systems that preserve viability through change or allostasis. Although they are necessary for survival, frequent neurobiological stress responses increase the risk of physical and mental health problems, perhaps particularly when experienced during periods of rapid brain development. Recently, advances in noninvasive measurement techniques have resulted in a burgeoning of human developmental stress research. Here we review the anatomy and physiology of stress responding, discuss the relevant animal literature, and briefly outline what is currently known about the psychobiology of stress in human development, the critical role of social regulation of stress neurobiology, and the importance of individual differences as a lens through which to approach questions about stress experiences during development and child outcomes.

The extracellular space is an environment hostile to unmodified polypeptides. For this reason, many eukaryotic proteins destined for exposure to this environment through secretion or display at the cell surface require maturation steps within a specialized organelle, the endoplasmic reticulum (ER). A complex homeostatic mechanism, known as the unfolded protein response (UPR), has evolved to link the load of newly synthesized proteins with the capacity of the ER to mature them. It has become apparent that dysfunction of the UPR plays an important role in some human diseases, especially those involving tissues dedicated to extracellular protein synthesis. Diabetes mellitus is an example of such a disease, since the demands for constantly varying levels of insulin synthesis make pancreatic beta-cells dependent on efficient UPR signaling. Furthermore, recent discoveries in this field indicate that the importance of the UPR in diabetes is not restricted to the beta-cell but is also involved in peripheral insulin resistance. This review addresses aspects of the UPR currently understood to be involved in human disease, including their role in diabetes mellitus, atherosclerosis, and neoplasia.

The ataxia-telangiectasia mutated (ATM) protein kinase is activated by DNA double-strand breaks (DSBs) through the Mre11-Rad50-Nbs1 (MRN) DNA repair complex and orchestrates signaling cascades that initiate the DNA damage response. Cells lacking ATM are also hypersensitive to insults other than DSBs, particularly oxidative stress. We show that oxidation of ATM directly induces ATM activation in the absence of DNA DSBs and the MRN complex. The oxidized form of ATM is a disulfide-cross-linked dimer, and mutation of a critical cysteine residue involved in disulfide bond formation specifically blocked activation through the oxidation pathway. Identification of this pathway explains observations of ATM activation under conditions of oxidative stress and shows that ATM is an important sensor of reactive oxygen species in human cells.