Long-Term Potentiation: One Kind or Many?

Do neurobiologists aim to discover natural kinds? I address this question in this chapter via a critical analysis of classification practices operative across the 43-year history of research on long-term potentiation (LTP). I argue that this 43-year history supports the idea that the structure of scientific practice surrounding LTP research has remained an obstacle to the discovery of natural kinds

Agency, qualia and life: connecting mind and body biologically

Many believe that a suitably programmed computer could act for its own goals and experience feelings. I challenge this view and argue that agency, mental causation and qualia are all founded in the unique, homeostatic nature of living matter. The theory was formulated for coherence with the concept of an agent, neuroscientific data and laws of physics. By this method, I infer that a successful action is homeostatic for its agent and can be caused by a feeling - which does not motivate as a force, but as a control signal. From brain research and the locality principle of physics, I surmise that qualia are a fundamental, biological form of energy generated in specialized neurons. Subjectivity is explained as thermodynamically necessary on the supposition that, by converting action potentials to feelings, the neural cells avert damage from the electrochemical pulses. In exchange for this entropic benefit, phenomenal energy is spent as and where it is produced - which precludes the objective observation of qualia

A Single Polar Residue and Distinct Membrane Topologies Impact the Function of the Infectious Bronchitis Coronavirus E Protein

The coronavirus E protein is a small membrane protein with a single predicted hydrophobic domain (HD), and has a poorly defined role in infection. The E protein is thought to promote virion assembly, which occurs in the Golgi region of infected cells. It has also been implicated in the release of infectious particles after budding. The E protein has ion channel activity in vitro, although a role for channel activity in infection has not been established. Furthermore, the membrane topology of the E protein is of considerable debate, and the protein may adopt more than one topology during infection. We previously showed that the HD of the infectious bronchitis virus (IBV) E protein is required for the efficient release of infectious virus, an activity that correlated with disruption of the secretory pathway. Here we report that a single residue within the hydrophobic domain, Thr16, is required for secretory pathway disruption. Substitutions of other residues for Thr16 were not tolerated. Mutations of Thr16 did not impact virus assembly as judged by virus-like particle production, suggesting that alteration of secretory pathway and assembly are independent activities. We also examined how the membrane topology of IBV E affected its function by generating mutant versions that adopted either a transmembrane or membrane hairpin topology. We found that a transmembrane topology was required for disrupting the secretory pathway, but was less efficient for virus-like particle production. The hairpin version of E was unable to disrupt the secretory pathway or produce particles. The findings reported here identify properties of the E protein that are important for its function, and provide insight into how the E protein may perform multiple roles during infection

Knowledge, science and death: the theory of brain-sign

In today’s paradigmatic climate, the possibility of knowledge, and therefore science, still depends upon our being conscious. However, no scientifically accepted account of consciousness exists. In recent years I have developed the theory of brain-sign which replaces consciousness as a wholly physical neural condition. The first tenet is that the brain is a causal organ, not a knowledge organ. The second is that brain-sign, used in inter-neural communication for uncertain or imprecise collective action, derives at each moment from the causal orientation of the brain. Signs are ubiquitous bio-physical entities. Thus there is no problematic dualism, consciousness and world. We now have two accounts of the brain phenomenon. The first (consciousness) is an inexplicable physical anomaly. The second (brain-sign) belongs in the physical universe, and fulfils a crucial neurobiological function. With brain-sign theory we even ‘discover’ that we do not know we are alive or will die

Interplay of Substrate Retention and Export Signals in Endoplasmic Reticulum Quality Control

BACKGROUND: Endoplasmic reticulum (ER) quality control mechanisms are part of a comprehensive system to manage cell stress. The flux of molecules is monitored to retain folding intermediates and target misfolded molecules to ER-associated degradation (ERAD) pathways. The mechanisms of sorting remain unclear. While some proteins are retained statically, the classical model substrate CPY* is found in COPII transport vesicles, suggesting a retrieval mechanism for retention. However, its management can be even more dynamic. If ERAD is saturated under stress, excess CPY* traffics to the vacuole for degradation. These observations suggest that misfolded proteins might display different signals for their management. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report the existence of a functional ER exit signal in the pro-domain of CPY*. Compromising its integrity causes ER retention through exclusion from COPII vesicles. The signal co-exists with other signals used for retention and degradation. Physiologically, the export signal is important for stress tolerance. Disabling it converts a benign protein into one that is intrinsically cytotoxic. CONCLUSIONS/SIGNIFICANCE: These data reveal the remarkable interplay between opposing signals embedded within ERAD substrate molecules and the mechanisms that decipher them. Our findings demonstrate the diversity of mechanisms deployed for protein quality control and maintenance of protein homeostasis

Abstraction in ecology : reductionism and holism as complementary heuristics

In addition to their core explanatory and predictive assumptions, scientific models include simplifying assumptions, which function as idealizations, approximations, and abstractions. There are methods to investigate whether simplifying assumptions bias the results of models, such as robustness analyses. However, the equally important issue - the focus of this paper - has received less attention, namely, what are the methodological and epistemic strengths and limitations associated with different simplifying assumptions. I concentrate on one type of simplifying assumption, the use of mega parameters as abstractions in ecological models. First, I argue that there are two kinds of mega parameters qua abstractions, sufficient parameters and aggregative parameters, which have gone unnoticed in the literature. The two are associated with different heuristics, holism and reductionism, which many view as incompatible. Second, I will provide a different analysis of abstractions and the associated heuristics than previous authors. Reductionism and holism and the accompanying abstractions have different methodological and epistemic functions, strengths, and limitations, and the heuristics should be viewed as providing complementary research perspectives of cognitively limited beings. This is then, third, used as a premise to argue for epistemic and methodological pluralism in theoretical ecology. Finally, the presented taxonomy of abstractions is used to comment on the current debate whether mechanistic accounts of explanation are compatible with the use of abstractions. This debate has suffered from an abstract discussion of abstractions. With a better taxonomy of abstractions the debate can be resolved.Peer reviewe

Stoichiometry of HLA Class II-Invariant Chain Oligomers

BACKGROUND: The HLA gene complex encodes three class II isotypes, DR, DQ, and DP. HLA class II molecules are peptide receptors that present antigens for recognition by T lymphocytes. In antigen presenting cells, the assembly of matched α and β subunits to heterodimers is chaperoned by invariant chain (Ii). Ii forms a homotrimer with three binding sites for class II heterodimers. The current model of class II and Ii structure states that three αβ heterodimers bind to an Ii trimer. METHODOLOGY/PRINCIPAL FINDINGS: [corrected] We have now analyzed the composition and size of the complexes of class II and Ii using epitope tagged class II subunits and density gradient experiments. We show here that class II-Ii oligomers consist of one class II heterodimer associated with one Ii trimer, such that the DR, DQ and DP isotypes are contained within separate complexes with Ii. CONCLUSION/SIGNIFICANCE: We propose a structural model of the class II-Ii oligomer and speculate that the pentameric class II-Ii complex is bent towards the cell membrane, inhibiting the binding of additional class II heterodimers to Ii

Process-Tracing as a Tool to Analyse Discretion

status: publishe