Career derailment: burnout and bullying at the executive level

Executive derailment refers to unexpected and unwanted changes in the trajectory of an executive career caused either by factors within the person or by organisational factors external to the person, or a combination of both, leading to loss of identity. This phenomenological study explored subjective experiences of four high functioning professionals who had experienced executive derailment. Semi-structured interviews were conducted and data were analysed using Interpretative Phenomenological Analysis (IPA). Results showed four superordinate themes that encapsulated a trajectory from severe loss of identity, integrity, and livelihood, to newly defined authenticity following derailment: (1) Self-doubt and blame; (2) targeted bullying; (3) psychological vulnerability and distress; and (4) Meaning-making and personal growth. The first three themes highlight varying levels of psychological distress and burnout and the vicarious impact on family life. The fourth theme involved a redefined self-integrity where forgiveness and psychological recovery could emerge and allow for a reconsideration of career pathways. The recognition that personal and professional growth can arise following executive derailment is a novel finding with important implications for coaches. A positive psychological and growth-oriented mindset may be helpful in harnessing change with executives following derailment

Characterization of Selected Surface Treatments for Concrete Pavement

For a concrete pavement, the permeation properties for the surface have a crucial influence on its durability. Current practices assess the resistance of the surface to abrasion and freeze/thaw cycles based primarily on the compression strength of the concrete. A prominent way to enhance the durability of concrete is by use of surface treatments to reduce water and chloride penetration. In other words, surface treatments partake in protecting concrete surfaces from the ingress of deleterious substances such as salt, organic impurities and dust. The objective of this thesis is to investigate the efficiency of organic and inorganic surface treatments regarding abrasion, freeze/thaw damage, water and chloride penetration. ASTM standards were modified to abbreviate the testing and assess the efficiency of different products. Based on the tests performed, organic surface treatments remarkably increased the resistance of concrete subjected to freeze/thaw cycles by reducing the water intake compared to the inorganic ones. Similar results were observed regarding the chloride penetration test leading to an improvement in durability. The abrasion resistance of a concrete surface can be improved using inorganic surface treatments based on lithium and silicon. A model was proposed to relate the abrasion efficiency as a function of load cycles of a treated surface to represent the longevity of a concrete pavement. Based on the abrasion coefficient and the texture wavelength which is a measurement of the quality of the surface of the pavement, it is shown that the life cycle under abrasion of a concrete pavement can be calibrated. As part of the laboratory testing program, the untreated concrete specimens were used as the control. Results from the abrasion and freeze/thaw testing of treated specimens indicated a lower level of cumulative damage, which confirmed the benefit of using such products relative to the extension of the service life of a concrete pavement surface. The results of modeling indicated an increase of 14% of the ultimate load application to failure for the treated specimens, which indicates an increase in longevity of the pavement

The wrong suspect?

Parkinson's disease may be caused by microtubule, rather than mitochondrial complex I, dysfunction

Disease-causing mutations in Parkin impair mitochondrial ubiquitination, aggregation, and HDAC6-dependent mitophagy

Parkin catalyzes mitochondrial ubiquitination, recruiting autophagic components that clear damaged mitochondria. Defects in this pathway are implicated in Parkinson's disease

Oxidative stress, Nrf2 and keratin up‐regulation associate with Mallory‐Denk body formation in mouse erythropoietic protoporphyria

Mallory‐Denk bodies (MDBs) are hepatocyte inclusions commonly seen in steatohepatitis. They are induced in mice by feeding 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine (DDC) for 12 weeks, which also causes porphyrin accumulation. Erythropoietic protoporphyria (EPP) is caused by mutations in ferrochelatase (fch), and a fraction of EPP patients develop liver disease that is phenocopied in Fech m1Pas mutant (fch/fch) mice, which have an inactivating fch mutation. fch/fch mice develop spontaneous MDBs, but the molecular factors involved in their formation and whether they relate to DDC‐induced MDBs are unknown. We tested the hypothesis that fch mutation creates a molecular milieu that mimics experimental drug‐induced MDBs. In 13‐ and 20‐week‐old fch/fch mice, serum alkaline phosphatase, alanine aminotransferase, and bile acids were increased. The 13‐week‐old fch/fch mice did not develop histologically evident MDBs but manifested biochemical alterations required for MDB formation, including increased transglutaminase‐2 and keratin overexpression, with a greater keratin 8 (K8)‐to‐keratin 18 (K18) ratio, which are critical for drug‐induced MDB formation. In 20‐week‐old fch/fch mice, spontaneous MDBs were readily detected histologically and biochemically. Short‐term (3‐week) DDC feeding markedly induced MDB formation in 20‐week‐old fch/fch mice. Under basal conditions, old fch/fch mice had significant alterations in mitochondrial oxidative‐stress markers, including increased protein oxidation, decreased proteasomal activity, reduced adenosine triphosphate content, and Nrf2 (redox sensitive transcription factor) up‐regulation. Nrf2 knockdown in HepG2 cells down‐regulated K8, but not K18. Conclusion : Fch/fch mice develop age‐associated spontaneous MDBs, with a marked propensity for rapid MDB formation upon exposure to DDC, and therefore provide a genetic model for MDB formation. Inclusion formation in the fch/fch mice involves oxidative stress which, together with Nrf2‐mediated increase in K8, promotes MDB formation. (H epatology 2012;56:322–331)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/92074/1/25664_ftp.pd

Distinct Mechanisms of Pathogenic DJ-1 Mutations in Mitochondrial Quality Control

The deglycase and chaperone protein DJ-1 is pivotal for cellular oxidative stress responses and mitochondrial quality control. Mutations in PARK7, encoding DJ-1, are associated with early-onset familial Parkinson’s disease and lead to pathological oxidative stress and/or disrupted protein degradation by the proteasome. The aim of this study was to gain insights into the pathogenic mechanisms of selected DJ-1 missense mutations, by characterizing protein–protein interactions, core parameters of mitochondrial function, quality control regulation via autophagy, and cellular death following dopamine accumulation. We report that the DJ-1M26I mutant influences DJ-1 interactions with SUMO-1, in turn enhancing removal of mitochondria and conferring increased cellular susceptibility to dopamine toxicity. By contrast, the DJ-1D149A mutant does not influence mitophagy, but instead impairs Ca2+ dynamics and free radical homeostasis by disrupting DJ-1 interactions with a mitochondrial accessory protein known as DJ-1-binding protein (DJBP/EFCAB6). Thus, individual DJ-1 mutations have different effects on mitochondrial function and quality control, implying mutation-specific pathomechanisms converging on impaired mitochondrial homeostasis

Multiple sclerosis: Association of gelatinase B/matrix metalloproteinase-9 with risk and clinical course the disease

Background: Multiple sclerosis (MS) is an autoimmune disease characterized by inflammation and axonal degeneration of the central nervous system and a leading cause of disability in young adults. The matrix metalloproteinases in general and specially gelatinase B/metalloproteinase-9 (MMP-9) plays a role in the pathogenesis of multiple sclerosis. Objective: To investigate the presence of the MMP-9 1562 C/T polymorphism in a Portuguese population of MS patients and assess its impact in susceptibility and course of the disease. The relation of MMP-9 serum levels with the polymorphism and with clinical and therapeutic factors will also be assessed. Methods: Our study included 355 Caucasian individuals distributed as MS patients (n=169) and controls (n=186). Samples were genotyped for 1562 C/T polymorphism by PCR-RFLP analysis. MMP-9 concentration in serum was analyzed using a commercially available enzyme-linked immunosorbent assay. Results: A significant increase in T-allele frequency was found in female MS patients, but not in the total patient population. No association between the presence of the polymorphism and disease progression was found. MMP-9 serum concentrations were increased in patients, and although not influenced by the 1562 C/T polymorphism, were modified by INF-beta therapy. Conclusion: Although we did not find an association of this polymorphism with disease susceptibility or prognosis, MMP-9 appears to be a good therapeutic response marker for multiple sclerosis.Portuguese Foundation for Science and Technology (FCT) through SFRH/PROTEC/67690/2010info:eu-repo/semantics/publishedVersio

Chronic, low-dose rotenone reproduces Lewy neurites found in early stages of Parkinson's disease, reduces mitochondrial movement and slowly kills differentiated SH-SY5Y neural cells

<p>Abstract</p> <p>Background</p> <p>Parkinson's disease, the most common adult neurodegenerative movement disorder, demonstrates a brain-wide pathology that begins pre-clinically with alpha-synuclein aggregates ("Lewy neurites") in processes of gut enteric and vagal motor neurons. Rostral progression into substantia nigra with death of dopamine neurons produces the motor impairment phenotype that yields a clinical diagnosis. The vast majority of Parkinson's disease occurs sporadically, and current models of sporadic Parkinson's disease (sPD) can utilize directly infused or systemic neurotoxins.</p> <p>Results</p> <p>We developed a differentiation protocol for human SH-SY5Y neuroblastoma that yielded non-dividing dopaminergic neural cells with long processes that we then exposed to 50 nM rotenone, a complex I inhibitor used in Parkinson's disease models. After 21 days of rotenone, ~60% of cells died. Their processes retracted and accumulated ASYN-(+) and UB-(+) aggregates that blocked organelle transport. Mitochondrial movement velocities were reduced by 8 days of rotenone and continued to decline over time. No cytoplasmic inclusions resembling Lewy bodies were observed. Gene microarray analyses showed that the majority of genes were under-expressed. qPCR analyses of 11 mtDNA-encoded and 10 nDNA-encoded mitochondrial electron transport chain RNAs' relative expressions revealed small increases in mtDNA-encoded genes and lesser regulation of nDNA-encoded ETC genes.</p> <p>Conclusion</p> <p>Subacute rotenone treatment of differentiated SH-SY5Y neuroblastoma cells causes process retraction and partial death over several weeks, slowed mitochondrial movement in processes and appears to reproduce the Lewy neuritic changes of early Parkinson's disease pathology but does not cause Lewy body inclusions. The overall pattern of transcriptional regulation is gene under-expression with minimal regulation of ETC genes in spite of rotenone's being a complex I toxin. This rotenone-SH-SY5Y model in a differentiated human neural cell mimics changes of early Parkinson's disease and may be useful for screening therapeutics for neuroprotection in that disease stage.</p

PINK1 Is Necessary for Long Term Survival and Mitochondrial Function in Human Dopaminergic Neurons

Parkinson's disease (PD) is a common age-related neurodegenerative disease and it is critical to develop models which recapitulate the pathogenic process including the effect of the ageing process. Although the pathogenesis of sporadic PD is unknown, the identification of the mendelian genetic factor PINK1 has provided new mechanistic insights. In order to investigate the role of PINK1 in Parkinson's disease, we studied PINK1 loss of function in human and primary mouse neurons. Using RNAi, we created stable PINK1 knockdown in human dopaminergic neurons differentiated from foetal ventral mesencephalon stem cells, as well as in an immortalised human neuroblastoma cell line. We sought to validate our findings in primary neurons derived from a transgenic PINK1 knockout mouse. For the first time we demonstrate an age dependent neurodegenerative phenotype in human and mouse neurons. PINK1 deficiency leads to reduced long-term viability in human neurons, which die via the mitochondrial apoptosis pathway. Human neurons lacking PINK1 demonstrate features of marked oxidative stress with widespread mitochondrial dysfunction and abnormal mitochondrial morphology. We report that PINK1 plays a neuroprotective role in the mitochondria of mammalian neurons, especially against stress such as staurosporine. In addition we provide evidence that cellular compensatory mechanisms such as mitochondrial biogenesis and upregulation of lysosomal degradation pathways occur in PINK1 deficiency. The phenotypic effects of PINK1 loss-of-function described here in mammalian neurons provides mechanistic insight into the age-related degeneration of nigral dopaminergic neurons seen in PD