A pragmatic argument against equal weighting

We present a minimal pragmatic restriction on the interpretation of the weights in the “Equal Weight View” regarding peer disagreement and show that the view cannot respect it. Based on this result we argue against the view. The restriction is the following one: if an agent, $$\hbox {i}$$ i, assigns an equal or higher weight to another agent, $$\hbox {j}$$ j,, he must be willing—in exchange for a positive and certain payment—to accept an offer to let a completely rational and sympathetic $$\hbox {j}$$ j choose for him whether to accept a bet with positive expected utility. If $$\hbox {i}$$ i assigns a lower weight to $$\hbox {j}$$ j than to himself, he must not be willing to pay any positive price for letting $$\hbox {j}$$ j choose for him. Respecting the constraint entails, we show, that the impact of disagreement on one’s degree of belief is not independent of what the disagreement is discovered to be

Safety, Absoluteness, and Computability

The semantic notion of dependent safety is a common generalization of the notion of absoluteness used in set theory and the notion of domain independence used in database theory for characterizing safe queries. This notion has been used in previous works to provide a unified theory of constructions and operations as they are used in different branches of mathematics and computer science, including set theory, computability theory, and database theory. In this paper we provide a complete syntactic characterization of general first-order dependent safety. We also show that this syntactic safety relation can be used for characterizing the set of strictly decidable relations on the natural numbers, as well as for characterizing rudimentary set theory and absoluteness of formulas within it

Characterization of tumor infiltrating Natural Killer cell subset

ABSTRAC

Human malarial disease: a consequence of inflammatory cytokine release

Malaria causes an acute systemic human disease that bears many similarities, both clinically and mechanistically, to those caused by bacteria, rickettsia, and viruses. Over the past few decades, a literature has emerged that argues for most of the pathology seen in all of these infectious diseases being explained by activation of the inflammatory system, with the balance between the pro and anti-inflammatory cytokines being tipped towards the onset of systemic inflammation. Although not often expressed in energy terms, there is, when reduced to biochemical essentials, wide agreement that infection with falciparum malaria is often fatal because mitochondria are unable to generate enough ATP to maintain normal cellular function. Most, however, would contend that this largely occurs because sequestered parasitized red cells prevent sufficient oxygen getting to where it is needed. This review considers the evidence that an equally or more important way ATP deficency arises in malaria, as well as these other infectious diseases, is an inability of mitochondria, through the effects of inflammatory cytokines on their function, to utilise available oxygen. This activity of these cytokines, plus their capacity to control the pathways through which oxygen supply to mitochondria are restricted (particularly through directing sequestration and driving anaemia), combine to make falciparum malaria primarily an inflammatory cytokine-driven disease

Biology of the Extracellular Proteasome

Proteasomes are traditionally considered intracellular complexes that play a critical role in maintaining proteostasis by degrading short-lived regulatory proteins and removing damaged proteins. Remarkably, in addition to these well-studied intracellular roles, accumulating data indicate that proteasomes are also present in extracellular body fluids. Not much is known about the origin, biological role, mode(s) of regulation or mechanisms of extracellular transport of these complexes. Nevertheless, emerging evidence indicates that the presence of proteasomes in the extracellular milieu is not a random phenomenon, but rather a regulated, coordinated physiological process. In this review, we provide an overview of the current understanding of extracellular proteasomes. To this end, we examine 143 proteomic datasets, leading us to the realization that 20S proteasome subunits are present in at least 25 different body fluids. Our analysis also indicates that while 19S subunits exist in some of those fluids, the dominant proteasome activator in these compartments is the PA28α/β complex. We also elaborate on the positive correlations that have been identified in plasma and extracellular vesicles, between 20S proteasome and activity levels to disease severity and treatment efficacy, suggesting the involvement of this understudied complex in pathophysiology. In addition, we address the considerations and practical experimental methods that should be taken when investigating extracellular proteasomes. Overall, we hope this review will stimulate new opportunities for investigation and thoughtful discussions on this exciting topic that will contribute to the maturation of the field

Diagnostic and Prognostic Value of Chest Radiographs for COVID-19 at Presentation

Introduction: Pulmonary opacities in COVID-19 increase throughout the illness and peak after ten days. The radiological literature mainly focuses on CT findings. The purpose of this study was to assess the diagnostic and prognostic value of chest radiographs (CXR) for coronavirus disease 2019 (COVID-19) at presentation.Methods: We retrospectively identified consecutive reverse transcription polymerase reaction-confirmed COVID-19 patients (n = 104, 75% men) and patients (n = 75, 51% men) with repeated negative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tests. Two radiologists blindly and independently reviewed the CXRs, documented findings, assigned radiographic assessment of lung edema (RALE) scores, and predicted the patients’ COVID-19 status. We calculated interobserver reliability. The score use for diagnosis and prognosis of COVID-19 was evaluated with the area under the receiver operating characteristic curve.Results: The overall RALE score failed to identify COVID-19 patients at presentation. However, the score was inversely correlated with a COVID-19 diagnosis within ≤2 days, and a positive correlation was found six days after symptom onset.Interobserver agreement with regard to separating normal from abnormal CXRs was moderate (k = 0.408) with low specificity (25% and 27%). Definite pleural effusion had almost perfect agreement (k = 0.833) and substantially reduced the odds of a COVID-19 diagnosis. Disease distribution and experts’ opinion on COVID-19 status had only fair interobserver agreement. The RALE score interobserver reliability was moderate to good (intraclass correlation coefficient = 0.745). A high RALE score predicted a poor outcome (intensive care unit hospitalization, intubation, or death) in COVID-19 patients; a score of ≥5 substantially increased the odds of having a poor outcome.Conclusion: Chest radiography was found not to be a valid diagnostic tool for COVID-19, as normal or near-normal CXRs are more likely early in the disease course. Pleural effusions at presentation suggest a diagnosis other than COVID-19. More extensive lung opacities at presentation are associated with poor outcome in COVID-19 patients. Thus, patients with more than minimal opacities should be monitored closely for clinical deterioration. This clinical application of CXR is its greatest strength in COVID-19 as it impacts patient care

CSNAP Is a Stoichiometric Subunit of the COP9 Signalosome

The highly conserved COP9 signalosome (CSN) complex is a key regulator of all cullin-RING-ubiquitin ligases (CRLs), the largest family of E3 ubiquitin ligases. Until now, it was accepted that the CSN is composed of eight canonical components. Here, we report the discovery of an additional integral and stoichiometric subunit that had thus far evaded detection, and we named it CSNAP (CSN acidic protein). We show that CSNAP binds CSN3, CSN5, and CSN6, and its incorporation into the CSN complex is mediated through the C-terminal region involving conserved aromatic residues. Moreover, depletion of this small protein leads to reduced proliferation and a flattened and enlarged morphology. Finally, on the basis of sequence and structural properties shared by both CSNAP and DSS1, a component of the related 19S lid proteasome complex, we propose that CSNAP, the ninth CSN subunit, is the missing paralogous subunit of DSS1

Placenta-Derived Mesenchymal-like Adherent Stromal Cells as an Effective Cell Therapy for Cocaine Addiction in a Rat Model

Recent research points to mesenchymal stem cells’ potential for treating neurological disorders, especially drug addiction. We examined the longitudinal effect of placenta-derived mesenchymal stromal-like cells (PLX-PAD) in a rat model for cocaine addiction. Sprague–Dawley male rats were trained to self-administer cocaine or saline daily until stable maintenance. Before the extinction phase, PLX-PAD cells were administered by intracerebroventricular or intranasal routes. Neurogenesis was evaluated, as was behavioral monitoring for craving. We labeled the PLX-PAD cells with gold nanoparticles and followed their longitudinal migration in the brain parallel to their infiltration of essential peripheral organs both by micro-CT and by inductively coupled plasma-optical emission spectrometry. Cell locations in the brain were confirmed by immunohistochemistry. We found that PLX-PAD cells attenuated cocaine-seeking behavior through their capacity to migrate to specific mesolimbic regions, homed on the parenchyma in the dentate gyrus of the hippocampus, and restored neurogenesis. We believe that intranasal cell therapy is a safe and effective approach to treating addiction and may offer a novel and efficient approach to rehabilitation

Allosteric regulation of the 20S proteasome by the Catalytic Core Regulators (CCRs) family

Abstract Controlled degradation of proteins is necessary for ensuring their abundance and sustaining a healthy and accurately functioning proteome. One of the degradation routes involves the uncapped 20S proteasome, which cleaves proteins with a partially unfolded region, including those that are damaged or contain intrinsically disordered regions. This degradation route is tightly controlled by a recently discovered family of proteins named Catalytic Core Regulators (CCRs). Here, we show that CCRs function through an allosteric mechanism, coupling the physical binding of the PSMB4 β-subunit with attenuation of the complex’s three proteolytic activities. In addition, by dissecting the structural properties that are required for CCR-like function, we could recapitulate this activity using a designed protein that is half the size of natural CCRs. These data uncover an allosteric path that does not involve the proteasome’s enzymatic subunits but rather propagates through the non-catalytic subunit PSMB4. This way of 20S proteasome-specific attenuation opens avenues for decoupling the 20S and 26S proteasome degradation pathways as well as for developing selective 20S proteasome inhibitors