The question whether human beings have free will has been debated by philosophers and theologians for thousands of years. More recently, neuroscientists have applied novel concepts and tools in neuroscience to address this question. We submit that human beings do have free will and the physiological substrate for its exercise is contained within neural networks. We discuss the potential neurobiology of free will by exploring volitionally initiated motor activity and the behavioural-response to a stimulus-response paradigm. We also submit that the (...) exercise of free will can be affected in patients with the certain neurological disorders such as the behavioural variant of frontotemporal dementia. Clinicopathological correlation in patients with this disorder provides an opportunity to further elucidate the neural substrate for this fundamental human attribute. We also discuss the clinical correlates of the loss of free will in this population, which is a source of significant distress to patients, significant others and care givers. (shrink)

The growth factor progranulin (PGRN) regulates cell division, survival, and migration. PGRN is an extracellular glycoprotein bearing multiple copies of the cysteine‐rich granulin motif. With PGRN family members in plants and slime mold, it represents one of the most ancient of the extracellular regulatory proteins still extant in modern animals. PRGN has multiple biological roles. It contributes to the regulation of early embryogenesis, to adult tissue repair and inflammation. Elevated PGRN levels often occur in cancers, and PGRN immunotherapy inhibits the (...) growth of hepatic cancer xenografts in mice. Recent studies have demonstrated roles for PGRN in neurobiology. An autosomal dominant mutation in GRN, the gene for PGRN, leads to neuronal atrophy in the frontal and temporal lobes, resulting in the disease frontotemporal lobar dementia. In this review we will discuss current knowledge of the multifaceted biology of PGRN. (shrink)

The transactivation response‐DNA binding protein of 43 kDa (TDP‐43) is an aggregation‐prone nucleic acid‐binding protein linked to the etiology of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). These conditions feature the accumulation of insoluble TDP‐43 aggregates in the neuronal cytoplasm that lead to cell death. The dynamics between cytoplasmic and nuclear TDP‐43 are altered in the disease state where TDP‐43 mislocalizes to the cytoplasm, disrupting Nuclear Pore Complexes (NPCs), and ultimately forming large fibrils stabilized by the C‐terminal (...) prion‐like domain. Here, we review three emerging and poorly understood aspects of TDP‐43 biology linked to its aggregation. First, how post‐translational modifications in the proximity of TDP‐43 N‐terminal domain (NTD) promote aggregation. Second, how TDP‐43 engages FG‐nucleoporins in the NPC, disrupting the pore permeability and function. Third, how the importin α/β heterodimer prevents TDP‐43 aggregation, serving both as a nuclear import transporter and a cytoplasmic chaperone. (shrink)

In this essay, seek to provide a plausible alternative to Maclntyre’s bold and provocative conception of modernity. I contest his claim that modern social life is marked by (1) the absence of any shared paradigm of the good, tradition, and social morality; (2) rationally interminable normative conflict; (3) characteristically instrumental poweroriented social relations; and (4) the impossibility of genuine human achievement and virtue. I argue that modern conflict is rooted not in the absence of a shored paradigm of the good (...) or the moral; but rather in a structure of social irrationality built into the modern conception of the good or the achievement of individual recognition in and through socioeconomic activity. I argue that while this conception has affirmative dimensions and does permit genuine virtue, the way it is culturally interpreted and institutionally embodied in modern capitalist society reproduces destructive scarcities in human recognition and the degradation of ordinary persons’ capacity for virtue. Where Moclntyre argues for a restoration of the pre-modern (Aristotelian) conception of the moral to be realized in spheres of activity external to socio-economic life, I argue for on immanent critique of modern liberal individualism which would humanize the meaning, conditions, and results of lobar and livelihood. (shrink)