Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein

Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD) is a dominant progressive disorder that maps to chromosome 9p21.1-p12. We investigated 13 families with IBMPFD linked to chromosome 9 using a candidate-gene approach. We found six missense mutations in the gene encoding valosin-containing protein (VCP, a member of the AAA-ATPase superfamily) exclusively in all 61 affected individuals. Haplotype analysis indicated that descent from two founders in two separate North American kindreds accounted for IBMPFD in approximately 50% of affected families. VCP is associated with a variety of cellular activities, including cell cycle control, membrane fusion and the ubiquitin-proteasome degradation pathway. Identification of VCP as causing IBMPFD has important implications for other inclusion-body diseases, including myopathies, dementias and Paget disease of bone (PDB), as it may define a new common pathological ubiquitin-based pathway.     

The Relevance of Systems Thinking in the Quest for Multifinal Social Enterprises

Human deprivation and suffering around the world are increasing despite the efforts of traditional aid-based approaches focused on alleviating poverty and improving the quality of life for marginalized communities. There is ample evidence that billions of dollars in aid money have been expended on development projects that are fundamentally unsustainable. On the other hand, social enterprises, which improve lives and livelihoods through practical market-based approaches, are growing in number. Systems Thinking can be especially helpful in navigating the complexity and chaos inherent in social ventures in developing communities. Lack of clarity in the roles, responsibilities, and returns for the various stakeholders epitomizes this chaos and is a major contributor to the failure of such projects. By employing Systems Thinking, entrepreneurs can establish accountability mechanisms, ensure equity for all stakeholders, and facilitate system sustainability. Though much research exists on both Systems Thinking and social enterprise, few sources discuss how Systems Thinking can be practically applied to conceptualize, build, and sustain social enterprises in an easy-to-understand manner. This paper synthesizes definitions of the tenets of Systems Thinking including interdependence, holism, multifinality, equifinality, differentiation, regulation, abstraction, and leverage points. The relevance of each of these tenets to social entrepreneurship is described, and further reinforced, with examples. A practical understanding of these tenets can empower entrepreneurs as they navigate chaotic environments in the quest for social enterprises that create win–win situations for all stakeholders.     

Role of experience and oscillations in transforming a rate code into a temporal code

In the vast majority of brain areas, the firing rates of neurons, averaged over several hundred milliseconds to several seconds, can be strongly modulated by, and provide accurate information about, properties of their inputs. This is referred to as the rate code. However, the biophysical laws of synaptic plasticity require precise timing of spikes over short timescales (<10 ms). Hence it is critical to understand the physiological mechanisms that can generate precise spike timing in vivo, and the relationship between such a temporal code and a rate code. Here we propose a mechanism by which a temporal code can be generated through an interaction between an asymmetric rate code and oscillatory inhibition. Consistent with the predictions of our model, the rate and temporal codes of hippocampal pyramidal neurons are highly correlated. Furthermore, the temporal code becomes more robust with experience. The resulting spike timing satisfies the temporal order constraints of hebbian learning. Thus, oscillations and receptive field asymmetry may have a critical role in temporal sequence learning.     

Systems,Design, and Entrepreneurial Thinking: Comparative Frameworks

The philosophies of design thinking, entrepreneurial thinking, and systems thinking have widespread application in diverse fields. However, due to the inherently abstract rhetoric and lack of commonly accepted frameworks, these philosophies are often considered buzzwords and fads. This article deconstructs the rhetoric and literature from leaders of these three philosophies and identifies their fundamental tenets. A conceptual framework that captures the differences and convergences between design thinking, entrepreneurial thinking, and systems thinking is presented. A series of four case studies derived from diverse settings like healthcare, agriculture, and social networks further illustrate these interconnections. The article argues that the emergent integration of these philosophies, as captured in the fundamental tenets, presents the most compelling opportunities for the practical application of these theoretical frameworks.