Correction: Stuckey et al. Why the Tsirelson Bound? Bub's Question and Fuchs' Desideratum. Entropy 2019, 21, 692.

The authors wish to make the following correction to this paper [...].

Beyond Causal Explanation: Einstein's Principle Not Reichenbach's.

Our account provides a local, realist and fully non-causal principle explanation for EPR correlations, contextuality, no-signalling, and the Tsirelson bound. Indeed, the account herein is fully consistent with the causal structure of Minkowski spacetime. We argue that retrocausal accounts of quantum mechanics are problematic precisely because they do not fully transcend the assumption that causal or constructive explanation must always be fundamental. Unlike retrocausal accounts, our principle explanation is a complete rejection of Reichenbach's Principle. Furthermore, we will argue that the basis for our principle account of quantum mechanics is the physical principle sought by quantum information theorists for their reconstructions of quantum mechanics. Finally, we explain why our account is both fully realist and psi-epistemic.

No Preferred Reference Frame at the Foundation of Quantum Mechanics.

Quantum information theorists have created axiomatic reconstructions of quantum mechanics (QM) that are very successful at identifying precisely what distinguishes quantum probability theory from classical and more general probability theories in terms of information-theoretic principles. Herein, we show how one such principle, Information Invariance and Continuity, at the foundation of those axiomatic reconstructions, maps to "no preferred reference frame" (NPRF, aka "the relativity principle") as it pertains to the invariant measurement of Planck's constant h for Stern-Gerlach (SG) spin measurements. This is in exact analogy to the relativity principle as it pertains to the invariant measurement of the speed of light c at the foundation of special relativity (SR). Essentially, quantum information theorists have extended Einstein's use of NPRF from the boost invariance of measurements of c to include the SO(3) invariance of measurements of h between different reference frames of mutually complementary spin measurements via the principle of Information Invariance and Continuity. Consequently, the "mystery" of the Bell states is understood to result from conservation per Information Invariance and Continuity between different reference frames of mutually complementary qubit measurements, and this maps to conservation per NPRF in spacetime. If one falsely conflates the relativity principle with the classical theory of SR, then it may seem impossible that the relativity principle resides at the foundation of non-relativisitic QM. In fact, there is nothing inherently classical or quantum about NPRF. Thus, the axiomatic reconstructions of QM have succeeded in producing a principle account of QM that reveals as much about Nature as the postulates of SR.

Re-Thinking the World with Neutral Monism:Removing the Boundaries Between Mind, Matter, and Spacetime.

Herein we are not interested in merely using dynamical systems theory, graph theory, information theory, etc., to model the relationship between brain dynamics and networks, and various states and degrees of conscious processes. We are interested in the question of how phenomenal conscious experience and fundamental physics are most deeply related. Any attempt to mathematically and formally model conscious experience and its relationship to physics must begin with some metaphysical assumption in mind about the nature of conscious experience, the nature of matter and the nature of the relationship between them. These days the most prominent metaphysical fixed points are strong emergence or some variant of panpsychism. In this paper we will detail another distinct metaphysical starting point known as neutral monism. In particular, we will focus on a variant of the neutral monism of William James and Bertrand Russell. Rather than starting with physics as fundamental, as both strong emergence and panpsychism do in their own way, our goal is to suggest how one might derive fundamental physics from neutral monism. Thus, starting with two axioms grounded in our characterization of neutral monism, we will sketch out a derivation of and explanation for some key features of relativity and quantum mechanics that suggest a unity between those two theories that is generally unappreciated. Our mode of explanation throughout will be of the principle as opposed to constructive variety in something like Einstein's sense of those terms. We will argue throughout that a bias towards property dualism and a bias toward reductive dynamical and constructive explanation lead to the hard problem and the explanatory gap in consciousness studies, and lead to serious unresolved problems in fundamental physics, such as the measurement problem and the mystery of entanglement in quantum mechanics and lack of progress in producing an empirically well-grounded theory of quantum gravity. We hope to show that given our take on neutral monism and all that follows from it, the aforementioned problems can be satisfactorily resolved leaving us with a far more intuitive and commonsense model of the relationship between conscious experience and physics.

Answering Mermin's challenge with conservation per no preferred reference frame.

In 1981, Mermin published a now famous paper titled, "Bringing home the atomic world: Quantum mysteries for anybody" that Feynman called, "One of the most beautiful papers in physics that I know." Therein, he presented the "Mermin device" that illustrates the conundrum of quantum entanglement per the Bell spin states for the "general reader." He then challenged the "physicist reader" to explain the way the device works "in terms meaningful to a general reader struggling with the dilemma raised by the device." Herein, we show how "conservation per no preferred reference frame (NPRF)" answers that challenge. In short, the explicit conservation that obtains for Alice and Bob's Stern-Gerlach spin measurement outcomes in the same reference frame holds only on average in different reference frames, not on a trial-by-trial basis. This conservation is SO(3) invariant in the relevant symmetry plane in real space per the SU(2) invariance of its corresponding Bell spin state in Hilbert space. Since NPRF is also responsible for the postulates of special relativity, and therefore its counterintuitive aspects of time dilation and length contraction, we see that the symmetry group relating non-relativistic quantum mechanics and special relativity via their "mysteries" is the restricted Lorentz group.

Why the Tsirelson Bound? Bub's Question and Fuchs' Desideratum.

To answer Wheeler's question "Why the quantum?" via quantum information theory according to Bub, one must explain both why the world is quantum rather than classical and why the world is quantum rather than superquantum, i.e., "Why the Tsirelson bound?" We show that the quantum correlations and quantum states corresponding to the Bell basis states, which uniquely produce the Tsirelson bound for the Clauser-Horne-Shimony-Holt (CHSH) quantity, can be derived from conservation per no preferred reference frame (NPRF). A reference frame in this context is defined by a measurement configuration, just as with the light postulate of special relativity. We therefore argue that the Tsirelson bound is ultimately based on NPRF just as the postulates of special relativity. This constraint-based/principle answer to Bub's question addresses Fuchs' desideratum that we "take the structure of quantum theory and change it from this very overt mathematical speak ... into something like [special relativity]." Thus, the answer to Bub's question per Fuchs' desideratum is, "the Tsirelson bound obtains due to conservation per NPRF".

The implications of neural reuse for the future of both cognitive neuroscience and folk psychology.

If neural reuse is true, then: (1) fully escaping phrenology will eventually require an even less brain-centric and mechanistic cognitive neuroscience that focuses on relations and interactions between brain, body, and environment at many different scales and levels across both space and time, and (2) although scientific psychology must be heavily revised, the autonomy and irreducibility of folk psychology are assured.

Complexity and extended phenomenological-cognitive systems.

The complex systems approach to cognitive science invites a new understanding of extended cognitive systems. According to this understanding, extended cognitive systems are heterogenous, composed of brain, body, and niche, non-linearly coupled to one another. This view of cognitive systems, as non-linearly coupled brain-body-niche systems, promises conceptual and methodological advances. In this article we focus on two of these. First, the fundamental interdependence among brain, body, and niche makes it possible to explain extended cognition without invoking representations or computation. Second, cognition and conscious experience can be understood as a single phenomenon, eliminating fruitless philosophical discussion of qualia and the so-called hard problem of consciousness. What we call "extended phenomenological-cognitive systems" are relational and dynamical entities, with interactions among heterogeneous parts at multiple spatial and temporal scales.

Hydronephrosis index: a new method to track patients with hydronephrosis quantitatively.

OBJECTIVES: To show that hydronephrosis (HN) can be tracked by the quantitative reproducible hydronephrosis index (HI) and that HI is useful for serial ultrasound (US) studies to determine whether HN is improving or deteriorating. METHODS: We found 60 hydronephrotic kidneys in 46 study patients. The other 32 kidneys were normal or absent. Serial US studies were performed more than 1 month apart over a 3-year period. Hydration was maximized with oral fluids. Cases ranged in age from 2 days to 13 years. We determined HI as follows: Operators outlined the perimeters of the kidney and dilated renal pelvis in the maximal longitudinal view. Respective areas were automatically calculated. We obtained HI by outlining the area of the kidney and separately outlining the area of the dilated renal pelvis within the kidney. We calculated HI percentage as 100 x (Total area of kidney minus area of dilated pelvis and calices)/(Total area). This percentage calculation represents the renal area determined reproducibly in a standardized fashion as if the calices were not there and is recorded as a dimensionless number. RESULTS: Hydronephrosis for 30 of 60 kidneys (50%) showed decreasing HN, and for 17 of 60 kidneys (28%) showed increasing HN. In 13 of 60 (22%) HN was unchanged. Statistical analysis showed that HI was determined with an objectivity of 99.8%. CONCLUSIONS: Hydronephrosis is the most common abnormality detected with ultrasonography. The quantitative method for HI provides a reproducible measure of HN. With longitudinal studies, the quantitative HI shows whether HN is improving or deteriorating.

Exploring the binding sites of the haloalkane dehalogenase DhlA from Xanthobacter autotrophicus GJ10.

The catalytic site of haloalkane dehalogenase DhlA is buried more than 10 A from the protein surface. While potential access channels to this site have been reported, the precise mechanism of substrate import and product export is still unconfirmed. We used computational methods to examine surface pockets and their putative roles in ligand access to and from the catalytic site. Computational solvent mapping moves small organic molecule as probes over the protein surface in order to identify energetically favorable sites, that is, regions that tend to bind a variety of molecules. The mapping of three DhlA structures identifies seven such regions, some of which have been previously suggested to be involved in the binding and the import/export of substrates or products. These sites are the active site, the putative entrance of the channel leading to the active site, two pockets that bind Br- ions, a pocket in the slot region, and two additional sites between the main domain and the cap of DhlA. We also performed mapping and free energy analysis of the DhlA structures using the substrate, 1,2-dichloroethane, and halide ions as probes. The findings were compared to crystallographic data and to results obtained by CAVER, a program developed for finding routes from protein clefts and cavities to the surface. Solvent mapping precisely reproduced all three Br- binding sites identified by protein crystallography and the openings to four channels found by CAVER. The analyses suggest that (i) the active site has the highest affinity for the substrate molecule, (ii) the substrate initially binds at the entrance of the main tunnel, (iii) the site Br2, close to the entrance, is likely to serve as an intermediate binding site in product export, (iv) the site Br3, induced in the structure at high concentrations of Br-, could be part of an auxiliary route for product release, and (v) three of the identified sites are likely to be entrances of water-access channels leading to the active site. For comparison, we also mapped haloalkane dehalogenases DhaA and LinB, both of which contain significantly larger and more solvent accessible binding sites than DhlA. The mapping of DhaA and LinB places the majority of probes in the active site, but most of the other six regions consistently identified in DhlA were not observed, suggesting that the more open active site eliminates the need for intermediate binding sites for the collision complex seen in DhlA.

Computational methods for functional site identification suggest a substrate access channel in transaldolase.

The homozygous deletion of Serine 171 results in the catalytic inactivation of the human transaldolase. Since Ser171 is in an outside loop, whereas the catalytic site is inside of the alpha/beta-barrel of the protein at least 15 A away, the loss of activity is difficult to explain. Two distinct computational methods are used to elucidate the potential origin of inactivation. Computational solvent mapping, which moves small organic molecules as probes around a protein surface and finds favorable binding positions, identifies the region around Ser171 as an important binding site. Three-dimensional cluster analysis, based both on a reference structure and multiple sequence alignment, shows that a patch of functionally important residues extends from Ser171 toward the catalytic site. Based on the findings of these two methods, we propose a novel ligand access path connecting these specific sites to the enzyme's active site. We also suggest that this mechanism may be aided by a significant conformational change involving the separation of two helices, alphaD and alphaG, in order to create an easy-access channel between the Ser171-related site and the active site. Further experimental procedures will be necessary to examine the biological feasibility of this proposed ligand shuttling path.

Temporal exposure of cryptic collagen epitopes within ischemic muscle during hindlimb reperfusion.

Chronic limb-threatening ischemia is a devastating disease with limited surgical options. However, inducing controlled angiogenesis and enhancing reperfusion holds therapeutic promise. To gain a better understanding of the mechanisms that contribute to limb reperfusion, we examined the temporal biochemical and structural changes occurring within the extracellular matrix of ischemic skeletal muscle. Both the latent and active forms of MMP-2 and -9 significantly increased during the active phase of limb reperfusion. Moreover, small but significant alterations in tissue inhibitors of metalloproteinase levels also occurred during a similar time course, consistent with a net increase in extracellular matrix remodeling. This temporal increase in MMP activity coincided with enhanced exposure of the unique HU177 cryptic collagen epitope. Although the HUIV26 cryptic collagen epitope has been implicated in angiogenesis, little is known concerning such epitopes within ischemic muscle tissue. Here, we provide the first evidence that a functionally distinct cryptic collagen epitope (HU177) is temporally exposed in ischemic muscle tissue during the active phase of reperfusion. Interestingly, the exposure of the HU177 epitope was greatly diminished in MMP-9 null mice, corresponding with significantly reduced limb reperfusion. Therefore, the regulated exposure of a unique cryptic collagen epitope within ischemic muscle suggests an important role for collagen remodeling during the active phase of ischemic limb reperfusion.

Arterial injuries from femoral artery cannulation with port access cardiac surgery.

Although minimally invasive (MI) cardiac surgery reduces blood loss, hospital stay, and recovery time, some MI approaches require femoral arterial cannulation, which introduces a heretofore unknown risk of femoral arterial injury. This study was performed to examine the risk of femoral arterial injury after Port Access MI cardiac surgery (PA-MICS) with femoral cannulation. Data were prospectively obtained on 739 consecutive patients who had PA-MICS with femoral cannulation between June 1996 and April 2000, identifying any patient with new (<30 days postoperative) arterial insufficiency from the cannulation site. Patient characteristics (gender, age, height, weight, body surface area, smoking, peripheral vascular disease, diabetes) and operative variables (cannula size, cross-clamp time) were examined with univariate and multivariate analysis to identify risk factors for arterial injury. Injuries were defined and classified by radiologic and intraoperative assessment, and follow-up was obtained by patient examination and from the medical records. Femoral arterial occlusion (FAC) occurred in 0.68% (5/739) of patients (4 women, 1 man; age range 26-74 years). The risk of femoral injury was higher in women: 1.31% vs 0.23% (p = 0.07). One patient had intraoperative limb ischemia from iliofemoral dissection and was treated by axillopopliteal bypass. Four patients presented postoperatively with claudication. Three of these had iliofemoral arterial occlusion or localized iliofemoral dissection and were treated with iliofemoral bypass, and 1 patient had localized femoral artery stenosis treated by angioplasty. With a mean follow-up of 17.8 months (range 13-26 months) limb salvage was achieved in all patients. Secondary or tertiary interventions were required in 40% (2/5), both in patients with iliofemoral occlusion, and 1 patient (20% of femoral injuries, 0.135% of overall series) has chronic graft occlusion and long-term claudication. The risk of arterial injury after femoral arterial cannulation and perfusion for Port Access surgery was low (0.68%). This risk is increased in women and is unpredictable. Initial vascular repair has a significant failure rate, and secondary interventions are often necessary. Although the femoral cannulation and perfusion technique is safe overall, the risk must be clearly recognized.

Improved mapping of protein binding sites.

Computational mapping methods place molecular probes--small molecules or functional groups--on a protein surface in order to identify the most favorable binding positions by calculating an interaction potential. Mapping is an important step in a number of flexible docking and drug design algorithms. We have developed improved algorithms for mapping protein surfaces using small organic molecules as molecular probes. The calculations reproduce the binding of eight organic solvents to lysozyme as observed by NMR, as well as the binding of four solvents to thermolysin, in good agreement with x-ray data. Application to protein tyrosine phosphatase 1B shows that the information provided by the mapping can be very useful for drug design. We also studied why the organic solvents bind in the active site of proteins, in spite of the availability of alternative pockets that can very tightly accommodate some of the probes. A possible explanation is that the binding in the relatively large active site retains a number of rotational states, and hence leads to smaller entropy loss than the binding elsewhere else. Indeed, the mapping reveals that the clusters of the ligand molecules in the protein's active site contain different rotational-translational conformers, which represent different local minima of the free energy surface. In order to study the transitions between different conformers, reaction path and molecular dynamics calculations were performed. Results show that most of the rotational states are separated by low free energy barriers at the experimental temperature, and hence the entropy of binding in the active site is expected to be high.

Identification of substrate binding sites in enzymes by computational solvent mapping.

Enzyme structures determined in organic solvents show that most organic molecules cluster in the active site, delineating the binding pocket. We have developed algorithms to perform solvent mapping computationally, rather than experimentally, by placing molecular probes (small molecules or functional groups) on a protein surface, and finding the regions with the most favorable binding free energy. The method then finds the consensus site that binds the highest number of different probes. The probe-protein interactions at this site are compared to the intermolecular interactions seen in the known complexes of the enzyme with various ligands (substrate analogs, products, and inhibitors). We have mapped thermolysin, for which experimental mapping results are also available, and six further enzymes that have no experimental mapping data, but whose binding sites are well characterized. With the exception of haloalkane dehalogenase, which binds very small substrates in a narrow channel, the consensus site found by the mapping is always a major subsite of the substrate-binding site. Furthermore, the probes at this location form hydrogen bonds and non-bonded interactions with the same residues that interact with the specific ligands of the enzyme. Thus, once the structure of an enzyme is known, computational solvent mapping can provide detailed and reliable information on its substrate-binding site. Calculations on ligand-bound and apo structures of enzymes show that the mapping results are not very sensitive to moderate variations in the protein coordinates.

Algorithms for computational solvent mapping of proteins.

Computational mapping methods place molecular probes (small molecules or functional groups) on a protein surface to identify the most favorable binding positions by calculating an interaction potential. We have developed a novel computational mapping program called CS-Map (computational solvent mapping of proteins), which differs from earlier mapping methods in three respects: (i) it initially moves the ligands on the protein surface toward regions with favorable electrostatics and desolvation, (ii) the final scoring potential accounts for desolvation, and (iii) the docked ligand positions are clustered, and the clusters are ranked on the basis of their average free energies. To understand the relative importance of these factors, we developed alternative algorithms that use the DOCK and GRAMM programs for the initial search. Because of the availability of experimental solvent mapping data, lysozyme and thermolysin are considered as test proteins. Both DOCK and GRAMM speed up the initial search, and the combined algorithms yield acceptable mapping results. However, the DOCK-based approaches place the consensus site farther from its experimentally determined position than CS-Map, primarily because of the lack of a solvation term in the initial search. The GRAMM-based program also finds the correct consensus site for thermolysin. We conclude that good sampling is the most important requirement for successful mapping, but accounting for desolvation and clustering of ligand positions also help to reduce the number of false positives.