The integrity and organization of the human AIPL1 functional domains is critical for its role as a HSP90-dependent co-chaperone for rod PDE6

Biallelic mutations in the photoreceptor-expressed aryl hydrocarbon receptor interacting protein-like 1 (AIPL1) are associated with autosomal recessive Leber congenital amaurosis (LCA), the most severe form of inherited retinopathy in early childhood. AIPL1 functions as a photoreceptor-specific co-chaperone that interacts with the molecular chaperone HSP90 to facilitate the stable assembly of the retinal cyclic GMP (cGMP) phosphodiesterase (PDE6) holoenzyme. In this study, we characterized the functional deficits of AIPL1 variations, some of which induce aberrant pre-mRNA AIPL1 splicing leading to the production of al- ternative AIPL1 isoforms. We investigated the ability of the AIPL1 variants to mediate an interaction with HSP90 and modulate the rod cGMP PDE6 stability and activity. Our data revealed that both the FK506 binding protein (FKBP)-like domain and the tetra- tricopeptide repeat (TPR) domain of AIPL1 are required for interaction with HSP90. We further demonstrate that AIPL1 signifi- cantly modulates the catalytic activity of heterologously expressed rod PDE6. Although the N-terminal FKBP-like domain of AIPL1 binds the farnesylated PDE6a subunit through direct interaction with the farnesyl moiety, mutations compromising the integrity of the C-terminal TPR domain of AIPL1 also failed to modulate PDE6 activity efficiently. These AIPL1 variants moreover failed to promote the HSP90-dependent stabilization of the PDE6a subunit in the cytosol. In summary, we have successfully vali- dated the disease-causing status of the AIPL1 variations in vitro. Our findings provide insight into the mechanism underlying the co-chaperone role of AIPL1 and will be critical for ensuring an early and effective diagnosis of AIPL1 LCA patients

The Bi-Functional Organization of Human Basement Membranes

The current basement membrane (BM) model proposes a single-layered extracellular matrix (ECM) sheet that is predominantly composed of laminins, collagen IVs and proteoglycans. The present data show that BM proteins and their domains are asymmetrically organized providing human BMs with side-specific properties: A) isolated human BMs roll up in a side-specific pattern, with the epithelial side facing outward and the stromal side inward. The rolling is independent of the curvature of the tissue from which the BMs were isolated. B) The epithelial side of BMs is twice as stiff as the stromal side, and C) epithelial cells adhere to the epithelial side of BMs only. Side-selective cell adhesion was also confirmed for BMs from mice and from chick embryos. We propose that the bi-functional organization of BMs is an inherent property of BMs and helps build the basic tissue architecture of metazoans with alternating epithelial and connective tissue layers

Seven properties of self-organization in the human brain

The principle of self-organization has acquired a fundamental significance in the newly emerging field of computational philosophy. Self-organizing systems have been described in various domains in science and philosophy including physics, neuroscience, biology and medicine, ecology, and sociology. While system architecture and their general purpose may depend on domain-specific concepts and definitions, there are (at least) seven key properties of self-organization clearly identified in brain systems: 1) modular connectivity, 2) unsupervised learning, 3) adaptive ability, 4) functional resiliency, 5) functional plasticity, 6) from-local-to-global functional organization, and 7) dynamic system growth. These are defined here in the light of insight from neurobiology, cognitive neuroscience and Adaptive Resonance Theory (ART), and physics to show that self-organization achieves stability and functional plasticity while minimizing structural system complexity. A specific example informed by empirical research is discussed to illustrate how modularity, adaptive learning, and dynamic network growth enable stable yet plastic somatosensory representation for human grip force control. Implications for the design of “strong” artificial intelligence in robotics are brought forward

The nature of the animacy organization in human ventral temporal cortex

The principles underlying the animacy organization of the ventral temporal cortex (VTC) remain hotly debated, with recent evidence pointing to an animacy continuum rather than a dichotomy. What drives this continuum? According to the visual categorization hypothesis, the continuum reflects the degree to which animals contain animal-diagnostic features. By contrast, the agency hypothesis posits that the continuum reflects the degree to which animals are perceived as (social) agents. Here, we tested both hypotheses with a stimulus set in which visual categorizability and agency were dissociated based on representations in convolutional neural networks and behavioral experiments. Using fMRI, we found that visual categorizability and agency explained independent components of the animacy continuum in VTC. Modeled together, they fully explained the animacy continuum. Finally, clusters explained by visual categorizability were localized posterior to clusters explained by agency. These results show that multiple organizing principles, including agency, underlie the animacy continuum in VTC.Comment: 16 pages, 5 figures, code+data at - https://doi.org/10.17605/OSF.IO/VXWG9 Update - added supplementary results and edited abstrac

The Meaning of Concepts of Human Nature in Organizational Life in Business Ethics Context

The main goal of this paper is to exhibit the role of the concept of human nature for the ethical orientation of organizational life. Therefore, after presenting some definitions of the concepts of human nature, which depict the complexity of these phenomena, some models of the concepts of human nature are described. Furthermore, the setting of the concepts of human nature in the organizational life is discussed. Those concepts can be perceived as a deep-structure of the organizational life, having an impact not only on the individual behaviour of employees and managers (like sensibility for human emotions, pro-social engagement, communication style), but also affecting their moral competence and influencing whole organizational culture – image of the organization, preferred management strategies and the way of perceiving justice. Those elements play crucial role in ethical attitude of the organization because all those variables support the efficacy of ethical rules and most of them are part of ethical code and corporate ethical code. Therefore, it is necessary for an organization to consider implicit and explicit concepts of human nature on which the organizational culture is based and support those concepts, which enables the ethical conduct of the organization and being alert especially to the consequences of materialistic/egoistic and competitive concepts of human nature. The theses discussed in the paper are supported by some empirical research studies conducted in this field.The National Science Centre (UMO-2011/03/D/HS4/00849

Turning it inside out: The organization of human septin heterooligomers.

Septin family proteins are quite similar to each other both within and between eukaryotic species. Typically, multiple discrete septins co-assemble into linear heterooligomers (usually hexameric or octameric rods) with a variety of cellular functions. We know little about how incorporation of different septins confers different properties to such complexes. This issue is especially acute in human cells where 13 separate septin gene products (often produced in multiple forms arising from alternative start codons and differential splicing) are expressed in a tissue-specific manner. Based on sequence alignments and phylogenetic criteria, human septins fall into four distinct groups predictive of their interactions, that is, members of the same group appear to occupy the same position within oligomeric septin protomers, which are "palindromic" (have twofold rotational symmetry about a central homodimeric pair). Many such protomers are capable of end-to-end polymerization, generating filaments. Over a decade ago, a study using X-ray crystallography and single-particle electron microscopy deduced the arrangement within recombinant heterohexamers comprising representatives of three human septin groups-SEPT2, SEPT6, and SEPT7. This model greatly influenced subsequent studies of human and other septin complexes, including how incorporating a septin from a fourth group forms heterooctamers, as first observed in budding yeast. Two recent studies, including one in this issue of Cytoskeleton, provide clear evidence that, in fact, the organization of subunits within human septin heterohexamers and heterooctamers is inverted relative to the original model. These findings are discussed here in a broader context, including possible causes for the initial confusion

Parallels in the sequential organization of birdsong and human speech.

Human speech possesses a rich hierarchical structure that allows for meaning to be altered by words spaced far apart in time. Conversely, the sequential structure of nonhuman communication is thought to follow non-hierarchical Markovian dynamics operating over only short distances. Here, we show that human speech and birdsong share a similar sequential structure indicative of both hierarchical and Markovian organization. We analyze the sequential dynamics of song from multiple songbird species and speech from multiple languages by modeling the information content of signals as a function of the sequential distance between vocal elements. Across short sequence-distances, an exponential decay dominates the information in speech and birdsong, consistent with underlying Markovian processes. At longer sequence-distances, the decay in information follows a power law, consistent with underlying hierarchical processes. Thus, the sequential organization of acoustic elements in two learned vocal communication signals (speech and birdsong) shows functionally equivalent dynamics, governed by similar processes

HUMAN RESOURCES MANAGEMENT - A COMPLEX, DYNAMIC AND EVOLUTIONAL PROCESS

The human capital is the essential element of the value of an organization. Quality assessment of human resources management, identifying the “measurement units”, as well as ways of understanding and analysis of information related to this capital, will allow the organization to focus on what must be done in order to find, preserve, develop and build human capital which it holds. Value quantifications and quality assessment of the human resources management, provides the basis of the HR strategies directed towards success, which aim at developing the basic competencies of the organization. The assessment can be used to track the status of reaching the human resources objectives and, in general, to assess the quality and efficiency of human resources practices.assessment, quality, management, resources, human capital