Although one may not always see it, social life often involves choices that make people act in ways that are mindful of others or not. We adopt an interdependence theoretical approach to the novel ...concept of social mindfulness, which we conceptualize in terms of other-regarding choices involving both skill (to see it, e.g., theory of mind, perspective taking) and will (to do it, e.g., empathic concern, prosocial orientation) to act mindfully toward another person's control over outcomes. We operationalized social mindfulness in a new social decision-making paradigm that focuses on leaving or limiting choice options for others that we tested across 7 studies. Studies 1a through 1c showed that people with other-oriented mindsets left interdependent others more choice than people with self-oriented and/or unspecified mindsets. Studies 2a and 2b revealed that people developed more favorable judgments of a socially mindful than of a socially unmindful person. Study 3 revealed that unknown others with trustworthy (vs. untrustworthy) faces were met with more social mindfulness. Study 4 revealed that social mindfulness could be traced in personality by being positively related to Honesty-Humility and Agreeableness (HEXACO Personality Inventory-Revised) as well as to Empathy (Interpersonal Reactivity Index) and a prosocial value orientation (SVO). Together, these studies contribute to explaining how social mindfulness can help people to navigate the social world by aiming to maximize other people's control over their situational outcomes.
Parkinson disease (PD), once considered as a prototype of a sporadic disease, is now known to be considerably affected by various genetic factors, which interact with environmental factors and the ...normal process of aging, leading to PD. Large studies determined that the hereditary component of PD is at least 27%, and in some populations, single genetic factors are responsible for more than 33% of PD patients. Interestingly, many of these genetic factors, such as LRRK2, GBA, SMPD1, SNCA, PARK2, PINK1, PARK7, SCARB2, and others, are involved in the autophagy-lysosome pathway (ALP). Some of these genes encode lysosomal enzymes, whereas others correspond to proteins that are involved in transport to the lysosome, mitophagy, or other autophagic-related functions. Is it possible that all these factors converge into a single pathway that causes PD? In this review, we will discuss these genetic findings and the role of the ALP in the pathogenesis of PD and will try to answer this question. We will suggest a novel hypothesis for the pathogenic mechanism of PD that involves the lysosome and the different autophagy pathways.
An expansion of the hexanucleotide GGGGCC repeat in the first intron of C9ORF72 gene was recently linked to amyotrophic lateral sclerosis. It is not known if the mutation results in a gain of ...function, a loss of function or if, perhaps both mechanisms are linked to pathogenesis. We generated a genetic model of ALS to explore the biological consequences of a null mutation of the Caenorhabditis elegans C9ORF72 orthologue, F18A1.6, also called alfa-1. alfa-1 mutants displayed age-dependent motility defects leading to paralysis and the specific degeneration of GABAergic motor neurons. alfa-1 mutants showed differential susceptibility to environmental stress where osmotic stress provoked neurodegeneration. Finally, we observed that the motor defects caused by loss of alfa-1 were additive with the toxicity caused by mutant TDP-43 proteins, but not by the mutant FUS proteins. These data suggest that a loss of alfa-1/C9ORF72 expression may contribute to motor neuron degeneration in a pathway associated with other known ALS genes.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder caused by progressive loss of motor neurons and there is currently no effective therapy. Cytoplasmic mislocalization and ...aggregation of TAR DNA-binding protein 43 kDa (TDP-43) within the CNS is a pathological hallmark in sporadic ALS and prion-like propagation of pathogenic TDP-43 is thought to be implicated in disease progression. However, cell-to-cell transmission of pathogenic TDP-43 in the human CNS has not been confirmed experimentally. Here we used induced pluripotent stem cells (iPSCs)-derived cerebral organoids as recipient CNS tissue model that are anatomically relevant human brain. We injected postmortem spinal cord protein extracts individually from three non-ALS or five sporadic ALS patients containing pathogenic TDP-43 into the cerebral organoids to validate the templated propagation and spreading of TDP-43 pathology in human CNS tissue. We first demonstrated that the administration of spinal cord extracts from an ALS patient induced the formation of TDP-43 pathology that progressively spread in a time-dependent manner in cerebral organoids, suggesting that pathogenic TDP-43 from ALS functioned as seeds and propagated cell-to-cell to form de novo TDP-43 pathology. We also reported that the administration of ALS patient-derived protein extracts caused astrocyte proliferation to form astrogliosis in cerebral organoids, reproducing the pathological feature seen in ALS. Moreover, we showed pathogenic TDP-43 induced cellular apoptosis and that TDP-43 pathology correlated with genomic damage due to DNA double-strand breaks. Thus, our results provide evidence that patient-derived pathogenic TDP-43 can mimic the prion-like propagation of TDP-43 pathology in human CNS tissue. Our findings indicate that our assays with human cerebral organoids that replicate ALS pathophysiology have a promising strategy for creating readouts that could be used in future drug discovery efforts against ALS.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Interest in Public Theology is growing across the African continent. However, there are some important critiques of Public Theology and public theologians in Africa and from Africa. This article ...outlines three important critiques of Public Theology within the variety of African contexts. Having done so, it seeks to engage in a process of critical reflection on the two constituent concepts related to an ‘African Public Theology’. First, it considers what we might mean when we speak of ‘Africa’ or ‘African?’ It does so by engaging relevant literature on the subjects of decolonisation and Africanisation as they relate to knowledge production and African theological reflection. Second, we ask, what do we mean when we speak of ‘Public Theology?’ Two broad approaches are presented and critically considered. First, we discuss a descriptive approach to Public Theology. Then we consider a more prescriptive understanding of Public Theology. In each instance we relate to both the critiques of Public Theologies in African contexts, and to the principles of decolonisation and Africanisation, as presented in relevant literature related to the debates and the context. The intention of this article is to take the three identified critiques of ‘African Public Theology’ seriously, and by means of critical conceptual engagement, to keep an important conversation on Public Theology in and from Africa alive.Contribution This article contributes towards contemporary debates on the relationship between faith and public life in South Africa. South Africa remains a deeply religious society. Religion plays an important role in the formation of moral values, social norms, and dominant practices in public life. Gaining a clearer understanding of what Public Theology is and how it is practiced, helps to further our critical academic understanding of the concept and its practice in contemporary life.
Hereditary spastic paraplegia (HSP) is a genetically and clinically heterogeneous disease characterized by spasticity and weakness of the lower limbs with or without additional neurological symptoms. ...Although more than 70 genes and genetic loci have been implicated in HSP, many families remain genetically undiagnosed, suggesting that other genetic causes of HSP are still to be identified. HSP can be inherited in an autosomal-dominant, autosomal-recessive, or X-linked manner. In the current study, we performed whole-exome sequencing to analyze a total of nine affected individuals in three families with autosomal-recessive HSP. Rare homozygous and compound-heterozygous nonsense, missense, frameshift, and splice-site mutations in CAPN1 were identified in all affected individuals, and sequencing in additional family members confirmed the segregation of these mutations with the disease (spastic paraplegia 76 SPG76). CAPN1 encodes calpain 1, a protease that is widely present in the CNS. Calpain 1 is involved in synaptic plasticity, synaptic restructuring, and axon maturation and maintenance. Three models of calpain 1 deficiency were further studied. In Caenorhabditis elegans, loss of calpain 1 function resulted in neuronal and axonal dysfunction and degeneration. Similarly, loss-of-function of the Drosophila melanogaster ortholog calpain B caused locomotor defects and axonal anomalies. Knockdown of calpain 1a, a CAPN1 ortholog in Danio rerio, resulted in abnormal branchiomotor neuron migration and disorganized acetylated-tubulin axonal networks in the brain. The identification of mutations in CAPN1 in HSP expands our understanding of the disease causes and potential mechanisms.
How do we know who we are? What sources can we draw upon in order to explain and understand the complex notions of identity and consciousness? This article revisits this debate and argues that ...African approaches the consciousness and identity cohere with Wentzel van Huyssteen’s post-foundational theology. Post-foundational theology offers a transverse rationality that operates between explanatory power and truth. The impetus for the research that informs this article emerged from a conversation with Prof. Van Huyssteen in 2000. The conversation set the author on a path of exploration which led to the discovery of the richness of African religious, philosophical and social resources on identity and consciousness. The outcome was an integrated approach to identity known as a ‘generous ontology’ that draws upon subjective, objective, inter-subjective and inter-objective sources of knowledge. The article concludes that an African approach to consciousness, as a post-foundational theological contribution, helps us to offer clear explanations and deeper truths in relation to our understanding of identity and consciousness.Intradisciplinary and or interdisciplinary implications This article presents a post-foundationalist argument for the inclusion of African theological notions of identity and consciousness in the debates of this field that take place at the intersections of faith and science. The outcome textures our explanations and deepens our understandings of transdisciplinary approaches to identity and consciousness.
Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental psychiatric disorder. Genome-wide association studies (GWAS) have identified several loci associated with ADHD. However, ...understanding the biological relevance of these genetic loci has proven to be difficult. Here, we conduct an ADHD transcriptome-wide association study (TWAS) consisting of 19,099 cases and 34,194 controls and identify 9 transcriptome-wide significant hits, of which 6 genes were not implicated in the original GWAS. We demonstrate that two of the previous GWAS hits can be largely explained by expression regulation. Probabilistic causal fine-mapping of TWAS signals prioritizes KAT2B with a posterior probability of 0.467 in the dorsolateral prefrontal cortex and TMEM161B with a posterior probability of 0.838 in the amygdala. Furthermore, pathway enrichment identifies dopaminergic and norepinephrine pathways, which are highly relevant for ADHD. Overall, our findings highlight the power of TWAS to identify and prioritize putatively causal genes.
The glucocorticoid receptor (GR) is a major drug target in inflammatory disease. However, chronic glucocorticoid (GC) treatment leads to disordered energy metabolism, including increased weight gain, ...adiposity, and hepatosteatosis - all programs modulated by the circadian clock. We demonstrated that while antiinflammatory GC actions were maintained irrespective of dosing time, the liver was significantly more GC sensitive during the day. Temporal segregation of GC action was underpinned by a physical interaction of GR with the circadian transcription factor REVERBa and co-binding with liver-specific hepatocyte nuclear transcription factors (HNFs) on chromatin. REVERBa promoted efficient GR recruitment to chromatin during the day, acting in part by maintaining histone acetylation, with REVERBa-dependent GC responses providing segregation of carbohydrate and lipid metabolism. Importantly, deletion of Reverba inverted circadian liver GC sensitivity and protected mice from hepatosteatosis induced by chronic GC administration. Our results reveal a mechanism by which the circadian clock acts through REVERBa in liver on elements bound by HNF4A/HNF6 to direct GR action on energy metabolism.
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