The microtubule-associated protein, tau, is the major subunit of neurofibrillary tangles associated with neurodegenerative conditions, such as Alzheimer's disease. In the cell, however, tau ...aggregation can be prevented by a class of proteins known as molecular chaperones. While numerous chaperones are known to interact with tau, though, little is known regarding the mechanisms by which these prevent tau aggregation. Here, we describe the effects of ATP-independent Hsp40 chaperones, DNAJA2 and DNAJB1, on tau amyloid-fiber formation and compare these to the small heat shock protein HSPB1. We find that the chaperones play complementary roles, with each preventing tau aggregation differently and interacting with distinct sets of tau species. Whereas HSPB1 only binds tau monomers, DNAJB1 and DNAJA2 recognize aggregation-prone conformers and even mature fibers. In addition, we find that both Hsp40s bind tau seeds and fibers via their C-terminal domain II (CTDII), with DNAJA2 being further capable of recognizing tau monomers by a second, distinct site in CTDI. These results lay out the mechanisms by which the diverse members of the Hsp40 family counteract the formation and propagation of toxic tau aggregates and highlight the fact that chaperones from different families/classes play distinct, yet complementary roles in preventing pathological protein aggregation.
Several neurological conditions, such as Alzheimer’s and Parkinson’s disease, are characterized by the build-up of protein clumps known as aggregates. In the case of Alzheimer’s disease, a key protein, called tau, aggregates to form fibers that are harmful to neuronal cells in the brain. One of the ways our cells can prevent this from occurring is through the action of proteins known as molecular chaperones, which can bind to tau proteins and prevent them from sticking together.
Tau can take on many forms. For example, a single tau protein on its own, known as a monomer, is unstructured. In patients with Alzheimer’s, these monomers join together into small clusters, known as seeds, that rapidly aggregate and accumulate into rigid, structured fibers. One chaperone, HSPB1, is known to bind to tau monomers and prevent them from being incorporated into fibers. Recently, another group of chaperones, called J-domain proteins, was also found to interact with tau. However, it was unclear how these chaperones prevent aggregation and whether they bind to tau in a similar manner as HSPB1.
To help answer this question, Irwin, Faust et al. studied the effect of two J-domain proteins, as well as the chaperone HSBP1, on tau aggregation. This revealed that, unlike HSBP1, the two J-domain proteins can bind to multiple forms of tau, including when it has already aggregated in to seeds and fibers. This suggests that these chaperones can stop the accumulation of fibers at several different stages of the aggregation process. Further experiments examining which sections of the J-domain proteins bind to tau, showed that both attach to fibers via the same region. However, the two J-domain proteins are not identical in their interaction with tau. While one of them uses a distinct region to bind to tau monomers, the other does not bind to single tau proteins at all.
These results demonstrate how different cellular chaperones can complement one another in order to inhibit harmful protein aggregation. Further studies will be needed to understand the full role of J-domain proteins in preventing tau from accumulating into fibers, as well as their potential as drug targets for developing new treatments.
Work engagement is defined as a positive, affective-motivational state of work-related well-being characterized by vigor, dedication and absorption. The Utrecht Work Engagement Scale (UWES) is the ...most frequently used measure of work engagement. The aim of this study was to analyze the psychometric properties of the Serbian versions of the UWES-17 and UWES-9. The sample consisted of 860 employees from a number of organizations and jobs across Serbia. Based on the UWES-17 findings, the data confirm both the three-factor and one-factor solutions by giving a slight advantage to the three-factor solution. As for the UWES-9, based on the PCFA and CFA, the one-factor solution was obtained as the preferred one. Taking into account the UWES-9 reliability and correlation patterns of its subscales with other well-being variables, both one- and three-factor solutions of the UWES-9 are suggested for future research. Serbian versions of both the UWES-17 and UWES-9 have satisfactory psychometric properties with high reliability, factorial structure in line with the theoretical model, and good predictive validity. The study contributes to enhanced understanding of work engagement by offering an insight from the Serbian cultural and economic context, significantly different from the UWES originating setting. There is still a need for exploring how employees from Serbia conceptualize work engagement, as well as for further, more stringent investigating of the cultural invariance of the UWES factorial structure.
Clinical manifestations of SARS-CoV-2 infection range from mild to critically severe. The aim of the study was to highlight the immunological events associated with the severity of SARS-CoV-2 ...infection, with an emphasis on cells of innate immunity. Thirty COVID-19 patients with mild/moderate symptoms and 27 patients with severe/critically severe symptoms were recruited from the Clinical Center of Kragujevac during April 2020. Flow cytometric analysis was performed to reveal phenotypic and functional alterations of peripheral blood cells and to correlate them with the severity of the disease. In severe cases, the number of T and B lymphocytes, dendritic cells, NK cells, and HLA-DR-expressing cells was drastically decreased. In the monocyte population proportion between certain subsets was disturbed and cells coexpressing markers of M1 and M2 monocytes were found in intermediate and non-classical subsets. In mild cases decline in lymphocyte number was less pronounced and innate immunity was preserved as indicated by an increased number of myeloid and activated dendritic cells, NK cells that expressed activation marker at the same level as in control and by low expression of M2 marker in monocyte population. In patients with severe disease, both innate and adoptive immunity are devastated, while in patients with mild symptoms decline in lymphocyte number is lesser, and the innate immunity is preserved.
The aim of the current study was to validate the Serbian adaptation of the Job Crafting Scale (JCS), applying both qualitative and quantitative approaches, within three studies totalling 832 ...employees from different industries. Job crafting is work behaviour aimed at modifying job tasks in order to enhance and maintain work motivation. In Study 1, we have tested the understanding of all items and their possible cultural embeddedness. In Study 2, we have tested the JCS factor structure, factors’ reliability and validity. In Study 3, we have tested the invariance of the proposed models (Study 2 and Study 3 models) and criterion validity by analysing the correlation between the JCS and work engagement. Qualitative analysis has revealed that the majority of items transferred the intended meaning. Special care should be taken in interpreting the decreasing hindering job demands dimension scores, since these items might point toward behaviours that were not perceived as positive. With its overall reliability, second-order four-factor model invariance and criterion validity, originally composed 21-item JCS could be considered to be a valid instrument for assessing job crafting in Serbia. The present study has also shown that the 12-item JCS-Serbian short version has satisfactory psychometric properties and that it could be considered as a valid local job crafting scale.
Previous research explored workplace climate as a factor of workplace bullying and coping with workplace bullying, but these concepts were not closely related to workplace bullying behaviors (WBBs). ...To examine whether the perceived exposure to bullying mediates the relationship between the climate of accepting WBBs and job satisfaction under the condition of different levels of WBBs coping self-efficacy beliefs, we performed moderated mediation analysis. The Negative Acts Questionnaire – Revised was given to 329 employees from Serbia for assessing perceived exposure to bullying. Leaving the original scale items, the instruction of the original Negative Acts Questionnaire – Revised was modified for assessing (1) the climate of accepting WBBs and (2) WBBs coping self-efficacy beliefs. There was a significant negative relationship between exposure to bullying and job satisfaction. WBB acceptance climate was positively related to exposure to workplace bullying and negatively related to job satisfaction. WBB acceptance climate had an indirect relationship with job satisfaction through bullying exposure, and the relationship between WBB acceptance and exposure to bullying was weaker among those who believed that they were more efficient in coping with workplace bullying. Workplace bullying could be sustained by WBB acceptance climate which threatens the job-related outcomes. WBBs coping self-efficacy beliefs have some buffering effects.
Breast cancer research is hampered by difficulties in obtaining and studying primary human breast tissue, and by the lack of in vivo preclinical models that reflect patient tumor biology accurately. ...To overcome these limitations, we propagated a cohort of human breast tumors grown in the epithelium-free mammary fat pad of severe combined immunodeficient (SCID)/Beige and nonobese diabetic (NOD)/SCID/IL-2γ-receptor null (NSG) mice under a series of transplant conditions. Both models yielded stably transplantable xenografts at comparably high rates (∼21% and ∼19%, respectively). Of the conditions tested, xenograft take rate was highest in the presence of a low-dose estradiol pellet. Overall, 32 stably transplantable xenograft lines were established, representing 25 unique patients. Most tumors yielding xenografts were "triple-negative" estrogen receptor (ER)-progesterone receptor (PR)-HER2+; n = 19. However, we established lines from 3 ER-PR-HER2+ tumors, one ER+PR-HER2-, one ER+PR+HER2-, and one "triple-positive" (ER+PR+HER2+) tumor. Serially passaged xenografts show biologic consistency with the tumor of origin, are phenotypically stable across multiple transplant generations at the histologic, transcriptomic, proteomic, and genomic levels, and show comparable treatment responses as those observed clinically. Xenografts representing 12 patients, including 2 ER+ lines, showed metastasis to the mouse lung. These models thus serve as a renewable, quality-controlled tissue resource for preclinical studies investigating treatment response and metastasis.
PurposeThe purpose of this paper is to examine the career shocks of Red Cross (RC) of Serbia staff and volunteers providing aid during the 2016 migrants’ influx. Specifically, the authors explore ...what the volatile environment in which RC staff and volunteers work can teach us about career shocks, and what makes a career shock for people whose everyday work entails stressful events.Design/methodology/approachThis study examined a number of anecdotes that reflect the career shock construct to a greater or lesser extent. These anecdotes were developed by RC staff and volunteers as part of a communications training storytelling exercise.FindingsThe authors analyzed these events from the perspective of recent developments in career shocks research and examined whether the anecdotes contained elements that would enable us to differentiate between career shocks and stressors. Those anecdotes found to be the most prototypical of career shocks, as opposed to stressors, were found to instigate in-depth reflection about the career, were identity related, and had a tangible career impact. Shocking events in the eyes of RC people entailed work demands that go beyond expectations, excessive media scrutiny, and conflicting values. The authors discuss how organizational values, fostering person–organization fit, providing organizational and collegial support, and deploying “weathered” staff, could comprise the “vaccine” that makes the organization immune to career shocks.Originality/valueBy taking a data before theory approach to the study of career shocks, this paper provides a novel perspective on the lived experiences of RC people, and how such experiences may be classified into career shocks or stressors.
Employability is one of the core concepts for the future career. Students' self-perceived employability is the concept that connects students' present context of education with their future ...professional engagement. Students' self-perceived employability is defined as the capacity to gain and keep employment in line with their future qualification level. Locus of control is a concept that explains where the person situates the causation of various life events. It is found that internal locus of control was related to different aspects of career success. Career ambition is regarded as a proxy for students' future career success. Both internal locus of control and ambition lead to proactive behaviors that are relevant for employability and consequently result in securing a sustainable job. The aim of this mixed-method study was to investigate the relations among locus of control, ambition and students' self-perceived employability. Firstly, we tested mediating role of career ambition in relation of internal locus of control and students' self-perceived employability, then we turned to qualitative analysis of students' career self-SWOT analyses in order to deepen and enrich quantitative findings. The sample consisted of 124 undergraduate psychology students that filled out Levenson's Internality subscale from IPC locus of control scale, Rothwell et al. (2008) Ambition subscale, and three items extracted from the Self-perceived employability subscale. Majority of the survey participants (
= 100) filled out personal career SWOT analysis. The mediation analysis showed that career ambition had a mediating role in the relation between the locus of control and employability. Students perceived personal capabilities and ambition as internal strengths and lack of ambition as a major internal weakness. As external opportunities students perceived various chances for developing professional skills, whereas as external threats they perceived limited opportunities in job market. In order to support university students to develop employability and future career success, university curricula should support developing future work skills that, in addition to functional competences and personal resources, entail career ambition, ways of utilizing external opportunities and dealing with job market threats.
This volume explores the significance of the physical materials and contexts of inscribed texts in Greek and Roman antiquity and their performative roles in ancient society from an anthropological ...and historical perspective (7th century B.C.E. to 4th century C.E.).
In breast cancer, a subset of tumor‐initiating cells (TIC) or “cancer stem cells” are thought to be responsible for tumor maintenance, treatment resistance, and disease recurrence. While current ...breast cancer stem cell markers (e.g., CD44high/CD24low/neg, ALDH positive) have allowed enrichment for such cells, they are not universally expressed and may actually identify distinct TIC subpopulations in the same tumor. Thus, additional markers of functional stem cells are needed. The STAT3 pathway is a critical regulator of the function of normal stem cells, and evidence is accumulating for its important role in breast cancer stem cells. However, due to the lack of a method for separating live cells based on their level of STAT3 activity, it remains unknown whether STAT3 functions in the cancer stem cells themselves, or in surrounding niche cells, or in both. To approach this question, we constructed a series of lentiviral fluorescent (enhanced green fluorescent protein, EGFP) reporters that enabled flow cytometric enrichment of cells differing in STAT3‐mediated transcriptional activity, as well as in vivo/in situ localization of STAT3 responsive cells. Using in vivo claudin‐low cell line xenograft models of human breast cancer, we found that STAT3 signaling reporter activity (EGFP+) is associated with a subpopulation of cancer cells enriched for mammosphere‐forming efficiency, as well as TIC function in limiting dilution transplantation assays compared to negative or unsorted populations. Our results support STAT3 signaling activity as another functional marker for human breast cancer stem cells thus making it an attractive therapeutic target for stem‐cell‐directed therapy in some breast cancer subtypes. Stem Cells 2014;32:2571–2582
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