Reticular dysgenesis-associated AK2 protects hematopoietic stem and progenitor cell development from oxidative stress.

Adenylate kinases (AKs) are phosphotransferases that regulate the cellular adenine nucleotide composition and play a critical role in the energy homeostasis of all tissues. The AK2 isoenzyme is expressed in the mitochondrial intermembrane space and is mutated in reticular dysgenesis (RD), a rare form of severe combined immunodeficiency (SCID) in humans. RD is characterized by a maturation arrest in the myeloid and lymphoid lineages, leading to early onset, recurrent, and overwhelming infections. To gain insight into the pathophysiology of RD, we studied the effects of AK2 deficiency using the zebrafish model and induced pluripotent stem cells (iPSCs) derived from fibroblasts of an RD patient. In zebrafish, Ak2 deficiency affected hematopoietic stem and progenitor cell (HSPC) development with increased oxidative stress and apoptosis. AK2-deficient iPSCs recapitulated the characteristic myeloid maturation arrest at the promyelocyte stage and demonstrated an increased AMP/ADP ratio, indicative of an energy-depleted adenine nucleotide profile. Antioxidant treatment rescued the hematopoietic phenotypes in vivo in ak2 mutant zebrafish and restored differentiation of AK2-deficient iPSCs into mature granulocytes. Our results link hematopoietic cell fate in AK2 deficiency to cellular energy depletion and increased oxidative stress. This points to the potential use of antioxidants as a supportive therapeutic modality for patients with RD.

The Aspergillus fumigatus septins play pleiotropic roles in septation, conidiation, and cell wall stress, but are dispensable for virulence.

Septins are a conserved family of GTPases that regulate important cellular processes such as cell wall integrity, and septation in fungi. The requirement of septins for virulence has been demonstrated in the human pathogenic yeasts Candida albicans and Cryptococcus neoformans, as well as the plant pathogen Magnaporthe oryzae. Aspergillus spp. contains five genes encoding for septins (aspA-E). While the importance of septins AspA, AspB, AspC, and AspE for growth and conidiation has been elucidated in the filamentous fungal model Aspergillus nidulans, nothing is known on the role of septins in growth and virulence in the human pathogen Aspergillus fumigatus. Here we deleted all five A. fumigatus septins, and generated certain double and triple septin deletion strains. Phenotypic analyses revealed that while all the septins are dispensable in normal growth conditions, AspA, AspB, AspC and AspE are required for regular septation. Furthermore, deletion of only the core septin genes significantly reduced conidiation. Concomitant with the absence of an electron-dense outer conidial wall, the ΔaspB strain was also sensitive to anti-cell wall agents. Infection with the ΔaspB strain in a Galleria mellonella model of invasive aspergillosis showed hypervirulence, but no virulence difference was noted when compared to the wild-type strain in a murine model of invasive aspergillosis. Although the deletion of aspB resulted in increased release of TNF-α from the macrophages, no significant inflammation differences in lung histology was noted between the ΔaspB strain and the wild-type strain. Taken together, these results point to the importance of septins in A. fumigatus growth, but not virulence in a murine model.

Oxidative stress in aging: advances in proteomic approaches

Aging is a gradual, complex process in which cells, tissues, organs, and the whole organism itself deteriorate in a progressive and irreversible manner that, in the majority of cases, implies pathological conditions that affect the individual"s Quality of Life (QOL). Although extensive research efforts in recent years have been made, the anticipation of aging and prophylactic or treatment strategies continue to experience major limitations. In this review, the focus is essentially on the compilation of the advances generated by cellular expression profile analysis through proteomics studies (two-dimensional [2D] electrophoresis and mass spectrometry [MS]), which are currently used as an integral approach to study the aging process. Additionally, the relevance of the oxidative stress factors is discussed. Emphasis is placed on postmitotic tissues, such as neuronal, muscular, and red blood cells, which appear to be those most frequently studied with respect to aging. Additionally, models for the study of aging are discussed in a number of organisms, such as Caenorhabditis elegans, senescence-accelerated probe-8 mice (SAMP8), naked mole-rat (Heterocephalus glaber), and the beagle canine. Proteomic studies in specific tissues and organisms have revealed the extensive involvement of reactive oxygen species (ROS) and oxidative stress in aging.

Childhood adversities as specific contributors to the co-occurrence of posttraumatic stress and alcohol use disorders.

There is much evidence that alcohol use disorders (AUD) often co-occur with posttraumatic stress disorders (PTSD), and that the comorbid condition is associated with a more severe clinical profile than that of PTSD without AUD. However, little is known about the role of childhood adversities as specific risk factors for the development of AUD in individuals presenting with PTSD. The aim of the study was to explore whether specific stressors from the spectrum of trauma and childhood adversities contribute to the development of AUD among subjects with PTSD. From a large community sample, of N=140 individuals with PTSD, N=24 (17.14%) received an additional diagnosis of AUD with an onset after the onset of PTSD. Those with comorbid PTSD/AUD and those with PTSD only were compared regarding type and features of their trauma, childhood adversities and psychiatric comorbidity. Compared to PTSD alone, PTSD/AUD was associated with higher levels of stress in terms of childhood adversities; in particular, sexual abuse below the age of 16, but also with having been brought up in a foster home. PTSD/AUD was also associated with an earlier age of adverse events. Treatment of AUD should include standardized assessments of trauma, especially of trauma experienced during childhood.

Posttraumatic stress avoidance symptoms as mediators in the development of alcohol use disorders after exposure to childhood sexual abuse in a Swiss community sample.

This study examined the role of posttraumatic stress disorder (PTSD) symptoms of re-experience, avoidance, and hyperarousal in the relationship between different types of trauma and alcohol use disorders (AUD). We used data from 731 trauma-exposed individuals who participated in the first wave of the PsyCoLaus-study. Trauma characteristics were assessed relatively to the occurrence of lifetime PTSD symptoms and AUD. The results suggest that lifetime and childhood sexual abuse as well as overall childhood trauma were directly linked to AUD and PTSD symptoms, in particular to avoidance symptoms. From single symptom clusters PTSD avoidance was found to specifically mediate the trauma-AUD pathway. Both childhood and sexual trauma strongly contribute to the comorbidity of PTSD and AUD and avoidance-type symptoms appear to play a central role in maintaining this association. Hence, the alleviation of avoidance symptoms might be an important target for therapeutic intervention among victims of sexual abuse before specific addiction treatment is initiated.

Quantifying insufficient coping behavior under chronic stress. A cross-cultural study of 1,303 students from Italy, Spain, and Argentina.

The question of how to quantify insufficient coping behavior under chronic stress is of major clinical relevance. In fact, chronic stress increasingly dominates modern work conditions and can affect nearly every system of the human body, as suggested by physical, cognitive, affective and behavioral symptoms. Since freshmen students experience constantly high levels of stress due to tight schedules and frequent examinations, we carried out a 3-center study of 1,303 students from Italy, Spain and Argentina in order to develop socioculturally independent means for quantifying coping behavior. The data analysis relied on 2 self-report questionnaires: the Coping Strategies Inventory (COPE) for the assessment of coping behavior and the Zurich Health Questionnaire which assesses consumption behavior and general health dimensions. A neural network approach was used to determine the structural properties inherent in the COPE instrument. Our analyses revealed 2 highly stable, socioculturally independent scales that reflected basic coping behavior in terms of the personality traits activity-passivity and defeatism-resilience. This replicated previous results based on Swiss and US-American data. The percentage of students exhibiting insufficient coping behavior was very similar across the study sites (11.5-18.0%). Given their stability and validity, the newly developed scales enable the quantification of basic coping behavior in a cost-efficient and reliable way, thus clearing the way for the early detection of subjects with insufficient coping skills under chronic stress who may be at risk of physical or mental health problems.

Exploring the path through which career adaptability increases job satisfaction and lowers work stress : the role of affect

The construct of career adaptability, or the ability to successfully manage one's career development and challenges, predicts several important outcomes; however, little is known about the mechanisms contributing to its positive effects. The present study investigated the impact of career adaptability on job satisfaction and work stress, as mediated by individuals' affective states. Using a representative sample of 1671 individuals employed in Switzerland we hypothesized that, over time, career adaptability amplifies job satisfaction and attenuates work stress, through higher positive affect and lower negative affect, respectively. The data resulted from the first three waves of a longitudinal project on professional paths conducted in Switzerland. For each wave, participants completed a survey. Results of the 3-wave cross-lagged longitudinal model show that employees with higher career adaptability at Time 1 indeed experienced at Time 3 higher job satisfaction and lower work stress than those with lower career adaptability. The effect of career adaptability on job satisfaction and work stress was accounted for by negative affect: Individuals higher on career adaptability experienced less negative affect, which led to lower levels of stress and higher levels of job satisfaction, beyond previous levels of job satisfaction and work stress. Overall results support the conception of career adaptability as a self-regulatory resource that may promote a virtuous cycle in which individuals' evaluations of their resources to cope with the environment (i.e., career adaptability) shape their affective states, which in turn influence the evaluations of their job.

The caspase-3-p120-RasGAP module generates a NF-κB repressor in response to cellular stress.

The nuclear factor κB (NF-κB) transcription factor is a master regulator of inflammation. Short-term NF-κB activation is generally beneficial. However, sustained NF-κB might be detrimental, directly causing apoptosis of cells or leading to a persistent damaging inflammatory response. NF-κB activity in stressed cells needs therefore to be controlled for homeostasis maintenance. In mildly stressed cells, caspase-3 cleaves p120 RasGAP, also known as RASA1, into an N-terminal fragment, which we call fragment N. We show here that this fragment is a potent NF-κB inhibitor. Fragment N decreases the transcriptional activity of NF-κB by promoting its export from the nucleus. Cells unable to generate fragment N displayed increased NF-κB activation upon stress. Knock-in mice expressing an uncleavable p120 RasGAP mutant showed exaggerated NF-κB activation when their epidermis was treated with anthralin, a drug used for the treatment of psoriasis. Our study provides biochemical and genetic evidence of the importance of the caspase-3-p120-RasGAP stress-sensing module in the control of stress-induced NF-κB activation.

Stress oxydant chez l'enfant prématuré : causes, biomarqueurs et possibilités thérapeutiques [Oxidative stress after preterm birth: Origins, biomarkers, and possible therapeutic approaches].

The survival of preterm babies has increased over the last few decades. However, disorders associated with preterm birth, known as oxygen radical diseases of neonatology, such as retinopathy, bronchopulmonary dysplasia, periventricular leukomalacia, and necrotizing enterocolitis are severe complications related to oxidative stress, which can be defined by an imbalance between oxidative reactive species production and antioxidant defenses. Oxidative stress causes lipid, protein, and DNA damage. Preterm infants have decreased antioxidant defenses in response to oxidative challenges, because the physiologic increase of antioxidant capacity occurs at the end of gestation in preparation for the transition to extrauterine life. Therefore, preterm infants are more sensitive to neonatal oxidative stress, notably when supplemental oxygen is being delivered. Furthermore, despite recent advances in the management of neonatal respiratory distress syndrome, controversies persist concerning the oxygenation saturation targets that should be used in caring for preterm babies. Identification of adequate biomarkers of oxidative stress in preterm infants such as 8-iso-prostaglandin F2α, and adduction of malondialdehyde to hemoglobin is important to promote specific therapeutic approaches. At present, no therapeutic strategy has been validated as prevention or treatment against oxidative stress. Breastfeeding should be considered as the main measure to improve the antioxidant status of preterm infants. In the last few years, melatonin has emerged as a protective molecule against oxidative stress, with antioxidant and free-radical scavenger roles, in experimental and preliminary human studies, giving hope that it can be used in preterm infants in the near future.

FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature.

Biomechanical forces, such as fluid shear stress, govern multiple aspects of endothelial cell biology. In blood vessels, disturbed flow is associated with vascular diseases, such as atherosclerosis, and promotes endothelial cell proliferation and apoptosis. Here, we identified an important role for disturbed flow in lymphatic vessels, in which it cooperates with the transcription factor FOXC2 to ensure lifelong stability of the lymphatic vasculature. In cultured lymphatic endothelial cells, FOXC2 inactivation conferred abnormal shear stress sensing, promoting junction disassembly and entry into the cell cycle. Loss of FOXC2-dependent quiescence was mediated by the Hippo pathway transcriptional coactivator TAZ and, ultimately, led to cell death. In murine models, inducible deletion of Foxc2 within the lymphatic vasculature led to cell-cell junction defects, regression of valves, and focal vascular lumen collapse, which triggered generalized lymphatic vascular dysfunction and lethality. Together, our work describes a fundamental mechanism by which FOXC2 and oscillatory shear stress maintain lymphatic endothelial cell quiescence through intercellular junction and cytoskeleton stabilization and provides an essential link between biomechanical forces and endothelial cell identity that is necessary for postnatal vessel homeostasis. As FOXC2 is mutated in lymphedema-distichiasis syndrome, our data also underscore the role of impaired mechanotransduction in the pathology of this hereditary human disease.

Embryonic gene expression of Coregonus palaea (whitefish) under pathogen stress as analyzed by high-throughput RNA-sequencing.

Most fishes produce free-living embryos that are exposed to environmental stressors immediately following fertilization, including pathogenic microorganisms. Initial immune protection of embryos involves the chorion, as a protective barrier, and maternally-allocated antimicrobial compounds. At later developmental stages, host-genetic effects influence susceptibility and tolerance, suggesting a direct interaction between embryo genes and pathogens. So far, only a few host genes could be identified that correlate with embryonic survival under pathogen stress in salmonids. Here, we utilized high-throughput RNA-sequencing in order to describe the transcriptional response of a non-model fish, the Alpine whitefish Coregonus palaea, to infection, both in terms of host genes that are likely manipulated by the pathogen, and those involved in an early putative immune response. Embryos were produced in vitro, raised individually, and exposed at the late-eyed stage to a virulent strain of the opportunistic fish pathogen Pseudomonas fluorescens. The pseudomonad increased embryonic mortality and affected gene expression substantially. For example, essential, upregulated metabolic pathways in embryos under pathogen stress included ion binding pathways, aminoacyl-tRNA-biosynthesis, and the production of arginine and proline, most probably mediated by the pathogen for its proliferation. Most prominently downregulated transcripts comprised the biosynthesis of unsaturated fatty acids, the citrate cycle, and various isoforms of b-cell transcription factors. These factors have been shown to play a significant role in host blood cell differentiation and renewal. With regard to specific immune functions, differentially expressed transcripts mapped to the complement cascade, MHC class I and II, TNF-alpha, and T-cell differentiation proteins. The results of this study reveal insights into how P. fluorescens impairs the development of whitefish embryos and set a foundation for future studies investigating host pathogen interactions in fish embryos.

The activity of the anti-apoptotic fragment generated by the caspase-3/p120 RasGAP stress-sensing module displays strict Akt isoform specificity.

The caspase-3/p120 RasGAP module acts as a stress sensor that promotes pro-survival or pro-death signaling depending on the intensity and the duration of the stressful stimuli. Partial cleavage of p120 RasGAP generates a fragment, called fragment N, which protects stressed cells by activating Akt signaling. Akt family members regulate many cellular processes including proliferation, inhibition of apoptosis and metabolism. These cellular processes are regulated by three distinct Akt isoforms: Akt1, Akt2 and Akt3. However, which of these isoforms are required for fragment N mediated protection have not been defined. In this study, we investigated the individual contribution of each isoform in fragment N-mediated cell protection against Fas ligand induced cell death. To this end, DLD1 and HCT116 isogenic cell lines lacking specific Akt isoforms were used. It was found that fragment N could activate Akt1 and Akt2 but that only the former could mediate the protective activity of the RasGAP-derived fragment. Even overexpression of Akt2 or Akt3 could not rescue the inability of fragment N to protect cells lacking Akt1. These results demonstrate a strict Akt isoform requirement for the anti-apoptotic activity of fragment N.

Etat de stress post-traumatique : quel type de psychothérapie proposer? : Revue cochrane pour le praticien

L'état de stress post-traumatique (ESPT) apparaît dans les mois qui suivent un ou plusieurs événements potentiellement traumatiques (EPT) (par exemple, guerre, violences, accidents, chirurgie invasive). Les symptômes comprennent des souvenirs intrusifs, des cauchemars, un évitement et des émotions négatives (par exemple, honte, culpabilité, perte d'espoir, sentiment d'étrangeté), ainsi qu'une hypervigilance. Sous-diagnostiqué et sous-traité, l'ESPT a un impact négatif sur la qualité de vie et le fonctionnement des patients. Sa prévalence en Suisse est de 0,7 % (plus élevée dans certaines populations, par exemple, 13 % chez les hommes requérants d'asile déboutés). L'approche psychothérapeutique est centrale dans la prise en charge, un traitement médicamenteux pouvant également être utile. Cette revue (systématique) cherche à actualiser les connaissances sur l'efficacité des psychothérapies pour le traitement de l'ESPT.