The benefits accruing from diversity, equity and inclusion in the work place are many and noorganisation should ignore the same. With respect to diversity, it cannot be denied that diverse management ...teams perform better and equity in the work place helps in fostering a feeling ofaccomplishment among the employees. On the other hand, inclusion in the work place helps in promoting the self-care and bring about self-improvement among the employees by working on their pro-social behaviour. Above all the steps taken by an organization in this direction is sure to help it in creating a positive impression and in attracting the best talent. Thus, it goes without saying that HR Managers should dwell on analysing the benefits that could accrue from the above in ensuring acceptable HR practices which in turn would affect the overall effectiveness of the organisation.
This open access book considers how inclusive learning, wellbeing and active citizenship can be encouraged, taught, learnt, and supported in a digital world. The book poses and seeks to address three ...questions: How can governments and intergovernmental organisations support learning inclusion and active citizenship? How can the education sector and public/private enterprises support learning inclusion and active citizenship? How can professionals and communities work with vulnerable adults who are disadvantaged in a participatory, empowering manner? The Examples discussed in the book draw on the experiences of adult refugees and migrants, as well as people who may experience disadvantage and/or discrimination as a result of their social, economic, political, cultural, religious, physical, mental, age or gender-related status. One methodological pillar in this work is the development of skills in digital storytelling and digital stories creation for personal, community and professional purposes. Conceptually and of interest for researcher and policy makers at local, national and transnational levels, this book brings together a number of related concepts to generate innovative understanding and practices of applied relevance in the age of the pandemic and its aftermath.
Inclusions of TAR DNA-binding protein-43 (TDP-43), a nuclear protein that regulates transcription and RNA splicing, are the defining histopathological feature of frontotemporal lobar degeneration ...with ubiquitin-positive inclusions (FTLD-Us) and sporadic and familial forms of amyotrophic lateral sclerosis (ALS). In ALS and FTLD-U, aggregated, ubiquitinated, and N-terminally truncated TDP-43 can be isolated from brain tissue rich in neuronal and glial cytoplasmic inclusions. The loss of TDP-43 function resulting from inappropriate cleavage, translocation from the nucleus, or its sequestration into inclusions could play important roles in neurodegeneration. However, it is not known whether TDP-43 fragments directly mediate toxicity and, more specifically, whether their abnormal aggregation is a cause or consequence of pathogenesis. We report that the ectopic expression of a almost equal to25-kDa TDP-43 fragment corresponding to the C-terminal truncation product of caspase-cleaved TDP-43 leads to the formation of toxic, insoluble, and ubiquitin- and phospho-positive cytoplasmic inclusions within cells. The 25-kDa C-terminal fragment is more prone to phosphorylation at S409/S410 than full-length TDP-43, but phosphorylation at these sites is not required for inclusion formation or toxicity. Although this fragment shows no biological activity, its exogenous expression neither inhibits the function nor causes the sequestration of full-length nuclear TDP-43, suggesting that the 25-kDa fragment can induce cell death through a toxic gain-of-function. Finally, by generating a conformation-dependent antibody that detects C-terminal fragments, we show that this toxic cleavage product is specific for pathologic inclusions in human TDP-43 proteinopathies.
Algorithms designed to identify canonical yeast prions predict that around 250 human proteins, including several RNA-binding proteins associated with neurodegenerative disease, harbour a distinctive ...prion-like domain (PrLD) enriched in uncharged polar amino acids and glycine. PrLDs in RNA-binding proteins are essential for the assembly of ribonucleoprotein granules. However, the interplay between human PrLD function and disease is not understood. Here we define pathogenic mutations in PrLDs of heterogeneous nuclear ribonucleoproteins (hnRNPs) A2B1 and A1 in families with inherited degeneration affecting muscle, brain, motor neuron and bone, and in one case of familial amyotrophic lateral sclerosis. Wild-type hnRNPA2 (the most abundant isoform of hnRNPA2B1) and hnRNPA1 show an intrinsic tendency to assemble into self-seeding fibrils, which is exacerbated by the disease mutations. Indeed, the pathogenic mutations strengthen a 'steric zipper' motif in the PrLD, which accelerates the formation of self-seeding fibrils that cross-seed polymerization of wild-type hnRNP. Notably, the disease mutations promote excess incorporation of hnRNPA2 and hnRNPA1 into stress granules and drive the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology. Thus, dysregulated polymerization caused by a potent mutant steric zipper motif in a PrLD can initiate degenerative disease. Related proteins with PrLDs should therefore be considered candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone.
Synucleinopathies, which include multiple system atrophy (MSA), Parkinson's disease, Parkinson's disease with dementia and dementia with Lewy bodies (DLB), are human neurodegenerative diseases
. ...Existing treatments are at best symptomatic. These diseases are characterized by the presence of, and believed to be caused by the formation of, filamentous inclusions of α-synuclein in brain cells
. However, the structures of α-synuclein filaments from the human brain are unknown. Here, using cryo-electron microscopy, we show that α-synuclein inclusions from the brains of individuals with MSA are made of two types of filament, each of which consists of two different protofilaments. In each type of filament, non-proteinaceous molecules are present at the interface of the two protofilaments. Using two-dimensional class averaging, we show that α-synuclein filaments from the brains of individuals with MSA differ from those of individuals with DLB, which suggests that distinct conformers or strains characterize specific synucleinopathies. As is the case with tau assemblies
, the structures of α-synuclein filaments extracted from the brains of individuals with MSA differ from those formed in vitro using recombinant proteins, which has implications for understanding the mechanisms of aggregate propagation and neurodegeneration in the human brain. These findings have diagnostic and potential therapeutic relevance, especially because of the unmet clinical need to be able to image filamentous α-synuclein inclusions in the human brain.
Cytoplasmic inclusions containing α-synuclein (α-Syn) fibrils, referred to as Lewy bodies (LBs), are the signature neuropathological hallmarks of Parkinson's disease (PD). Although α-Syn fibrils can ...be generated from recombinant α-Syn protein in vitro, the production of fibrillar α-Syn inclusions similar to authentic LBs in cultured cells has not been achieved. We show here that intracellular α-Syn aggregation can be triggered by the introduction of exogenously produced recombinant α-Syn fibrils into cultured cells engineered to overexpress α-Syn. Unlike unassembled α-Syn, these α-Syn fibrils "seeded" recruitment of endogenous soluble α-Syn protein and their conversion into insoluble, hyperphosphorylated, and ubiquitinated pathological species. Thus, this cell model recapitulates key features of LBs in human PD brains. Also, these findings support the concept that intracellular α-Syn aggregation is normally limited by the number of active nucleation sites present in the cytoplasm and that small quantities of α-Syn fibrils can alter this balance by acting as seeds for aggregation.
Inclusion body myositis (IBM) is often viewed as an enigmatic disease with uncertain pathogenic mechanisms and confusion around diagnosis, classification and prospects for treatment. Its clinical ...features (finger flexor and quadriceps weakness) and pathological features (invasion of myofibres by cytotoxic T cells) are unique among muscle diseases. Although IBM T cell autoimmunity has long been recognized, enormous attention has been focused for decades on several biomarkers of myofibre protein aggregates, which are present in <1% of myofibres in patients with IBM. This focus has given rise, together with the relative treatment refractoriness of IBM, to a competing view that IBM is not an autoimmune disease. Findings from the past decade that implicate autoimmunity in IBM include the identification of a circulating autoantibody (anti-cN1A); the absence of any statistically significant genetic risk factor other than the common autoimmune disease 8.1 MHC haplotype in whole-genome sequencing studies; the presence of a marked cytotoxic T cell signature in gene expression studies; and the identification in muscle and blood of large populations of clonal highly differentiated cytotoxic CD8
T cells that are resistant to many immunotherapies. Mounting evidence that IBM is an autoimmune T cell-mediated disease provides hope that future therapies directed towards depleting these cells could be effective.
Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease that is characterized by eosinophilic hyaline intranuclear inclusions in neuronal and somatic cells. The wide ...range of clinical manifestations in NIID makes ante-mortem diagnosis difficult
, but skin biopsy enables its ante-mortem diagnosis
. The average onset age is 59.7 years among approximately 140 NIID cases consisting of mostly sporadic and several familial cases. By linkage mapping of a large NIID family with several affected members (Family 1), we identified a 58.1 Mb linked region at 1p22.1-q21.3 with a maximum logarithm of the odds score of 4.21. By long-read sequencing, we identified a GGC repeat expansion in the 5' region of NOTCH2NLC (Notch 2 N-terminal like C) in all affected family members. Furthermore, we found similar expansions in 8 unrelated families with NIID and 40 sporadic NIID cases. We observed abnormal anti-sense transcripts in fibroblasts specifically from patients but not unaffected individuals. This work shows that repeat expansion in human-specific NOTCH2NLC, a gene that evolved by segmental duplication, causes a human disease.
Demands for cleanliness of high chromium steel have been increasing. In steel refining process, aluminum is usually added in molten steel as a deoxidizing agent. As a result, such inclusions as ...alumina (Al2O3) and spinel (MgO∙Al2O3) are formed, which cause fatigue failures and surface defects. Therefore, it is important to understand the conditions of the inclusions which form in high chromium steel, and to reduce their harmful effects on steel qualities. In this work, to begin with, thermodynamic conditions of MgO and MgO∙Al2O3 formation in Fe-17mass%Cr molten steel at 1873 K were investigated. The results showed that MgO is more stable in high chromium steel than in plain steel. The boundary of the stable condition of MgO and MgO∙Al2O3 shifts toward higher Al and lower Mg contents in high Cr steel. This cause is judged to be the effect of thermodynamic interaction between Cr and Mg. The interaction parameter of Cr on Mg was estimated to be 0.040 so that the boundary of stable condition of MgO and MgO∙Al2O3 can be explained. Moreover, phase stability diagram of Fe–Cr–Al–Ca–Mg–O system at 1873 K was developed to estimate the effect of chromium on the stable condition of MgO, MgO∙Al2O3 and CaO–MgO–Al2O3(l). Subsequently, the variations of inclusions which formed in Fe-17mass%Cr molten steel were also investigated at 1873 K. The variations of inclusions in molten Fe–Cr steel were reasonably explained by considering the stable conditions of MgO and MgO∙Al2O3 investigated in this work.
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