Ageing is associated with a decline in autophagy and elevated reactive oxygen species (ROS), which can breach the capacity of antioxidant systems. Resulting oxidative stress can cause further cellular damage, including DNA breaks and protein misfolding. This poses a challenge for longevous organisms, including humans. In this review, we hypothesise that in the course of human evolution selective autophagy receptors (SARs) acquired the ability to sense and respond to localised oxidative stress. We posit that in the vicinity (...) of protein aggregates and dysfunctional mitochondria oxidation of key cysteine residues in SARs induces their oligomerisation which initiates autophagy. The degradation of damaged cellular components thus could reduce ROS production and restore redox homeostasis. This evolutionarily acquired function of SARs may represent one of the biological adaptations that contributed to longer lifespan. Inversely, loss of this mechanism can lead to age‐related diseases associated with impaired autophagy and oxidative stress. (shrink)

Mitochondrial function is key for maintaining cellular health, while mitochondrial failure is associated with various pathologies, including inherited metabolic disorders and age‐related diseases. In order to maintain mitochondrial quality, several pathways of mitochondrial quality control have evolved. These systems monitor mitochondrial integrity through antioxidants, DNA repair systems, and chaperones and proteases involved in the mitochondrial unfolded protein response. Additional regulation of mitochondrial function involves dynamic exchange of components through mitochondrial fusion and fission. Sustained stress induces a selective autophagy (...) – termed mitophagy – and ultimately leads to apoptosis. Together, these systems form a network that acts on the molecular, organellar, and cellular level. In this review, we highlight how these systems are regulated in an integrated context‐ and time‐dependent network of mitochondrial quality control that is implicated in healthy aging. (shrink)

Autophagy functions in both selective and non‐selective ways to maintain cellular homeostasis. Endoplasmic reticulum autophagy (ER‐phagy) is a subclass of autophagy responsible for the degradation of the endoplasmic reticulum through selective encapsulation into autophagosomes. ER‐phagy occurs both under physiological conditions and in response to stress cues, and plays a crucial role in maintaining the homeostatic control of the organelle. Although specific receptors that target parts of the ER membrane, as well as, internal proteins for (...) lysosomal degradation have been identified, the molecular regulation of ER‐phagy has been elusive. Recent work has uncovered novel regulators of ER‐phagy that involve post‐translational modifications of ER‐resident proteins and functional cross‐talk with other cellular processes. Herein, we discuss how morphology affects the function of the peripheral ER, and how ER‐phagy modulates the turnover of this organelle. We also address how ER‐phagy is regulated at the molecular level, considering implications relevant to human diseases. (shrink)

AbstractmiRNA‐mediated gene repression and ubiquitin‐dependent processes are among the oldest and most versatile mechanisms that control multiple molecular pathways, rather than just protein turnover. These systems were discovered decades ago and have become among the most studied. All systems within cells are interconnected, and these two are no exception: the plethora of studies have demonstrated that the activity of the miRNAs system depends on players of the ubiquitin‐centered universe of processes, and vice versa. This review focuses on recent progress that (...) highlights that very similar mechanisms of regulation of miRNAs by ubiquitin‐related processes are likely to be found in distantly related species, including animals, plants, and viruses. Most of them occur through the ubiquitination of Argonaute proteins, but some of the other miRNA system factors are also regulated. This suggests that their regulatory relationships are either ancient evolutionary acquisitions or have arisen independently in different kingdoms. (shrink)

Selective protein degradation maintains cellular homeostasis, but this process is disrupted in many diseases. Targeted protein degradation (TPD) approaches, built upon existing cellular mechanisms, are promising methods for therapeutically regulating protein levels. Here, we review the diverse palette of tools that are now available for doing so throughout the gene expression pathway and in specific cellular compartments. These include methods for directly removing targeted proteins via the ubiquitin proteasome system with proteolysis targeting chimeras (PROTACs) or dephosphorylation targeting chimeras (DEPTACs). (...) Similar effects can also be achieved through the lysosomal system with autophagy‐targeting chimeras (AUTACs), autophagosome tethering compounds (ATTECs), and lysosome targeting chimeras (LYTACs). Other methods act upstream to degrade RNAs (ribonuclease targeting chimeras; RIBOTACs) or transcription factors (transcription factor targeting chimeras; TRAFTACs), offering control throughout the gene expression process. We highlight the evolution and function of these methods and discuss their clinical implications in diverse disease contexts. (shrink)

Liquid‐liquid phase separation (LLPS) has recently emerged as a possible mechanism that enables ubiquitin‐binding shuttle proteins to facilitate the degradation of ubiquitinated substrates via distinct protein quality control (PQC) pathways. Shuttle protein LLPS is modulated by multivalent interactions among their various domains as well as heterotypic interactions with polyubiquitin chains. Here, the properties of three different shuttle proteins (hHR23B, p62, and UBQLN2) are closely examined, unifying principles for the molecular determinants of their LLPS are identified, and how LLPS is connected (...) to their functions is discussed. Evidence supporting LLPS of other shuttle proteins is also found. In this review, it is proposed that shuttle protein LLPS leads to spatiotemporal regulation of PQC activities by mediating the recruitment of PQC machinery (including proteasomes or autophagic components) to biomolecular condensates, assembly/disassembly of condensates, selective enrichment of client proteins, and extraction of ubiquitinated proteins from condensates in cells. (shrink)

Reasoning research suggests that people use more stringent criteria when they evaluate others' arguments than when they produce arguments themselves. To demonstrate this “selective laziness,” we used a choice blindness manipulation. In two experiments, participants had to produce a series of arguments in response to reasoning problems, and they were then asked to evaluate other people's arguments about the same problems. Unknown to the participants, in one of the trials, they were presented with their own argument as if it (...) was someone else's. Among those participants who accepted the manipulation and thus thought they were evaluating someone else's argument, more than half rejected the arguments that were in fact their own. Moreover, participants were more likely to reject their own arguments for invalid than for valid answers. This demonstrates that people are more critical of other people's arguments than of their own, without being overly critical: They are better able to tell valid from invalid arguments when the arguments are someone else's rather than their own. (shrink)

This article examines epistemic impacts of social media, merging Gibson’s affordance theory with the notion of selective permeability, which holds people encounter objective differences in a setting because of their distinct capacities, only here applying the idea to online spaces. I start by circumscribing my deployment of “affordances,” taking care not to totally divorce the term from Gibson’s intent, as often happens in information technologies research. I next detail ways that selective permeability characterizes online epistemic landscapes, focusing on (...) how factors (like culture) moderate normative standards for sharing information. This leads to a discussion about selective receptivity and blindness to information in the context of social media—a situation that amplifies political divides and renders antagonists mutually incomprehensible. This segues into my final topic: an exposition of how social media can make the offline world more selectively hostile to some. An additional proposition is that practical habits cultivated on networking apps can modulate what affordances are present in offline arenas, as opposed to just affecting which ones get noticed. Throughout, I suggest that selective permeability answers an increasingly recognized challenge: the difficulty of generalizing conclusions about one app to others and across cultures, ages, etc. Ultimately, my aim is not only to explicate how social media fragments common social knowledge but to defend selective permeability as an epistemic template for comprehending social media. (shrink)

The discovery, made in Oxford, that crude penicillin could cure systemic and life‐threatening bacterial infections was followed by attempts to purify penicillin, to determine its structure and then to produce it by total chemical synthesis. The β‐lactam structure of the molecule, first proposed in October 1943, was a source of controversy until 1945. However, no useful chemical synthesis was achieved and fermentation became the commercial source of the antibiotic.In 1953, one of the products of a Cephalosporium sp. from Sardinia was (...) shown to be a new and hydrophilic penicillin (penicillin N). This was contaminated with a substance having the same side‐chain but a characteristic absorption spectrum. The latter, cephalosporin C, showed antibacterial activity but was not inactivated by a penicillinase. The determination of its β‐lactam structure and isolation of its nucleus enabled pharmaceutical companies to produce many semisynthetic cephalosporins.A new tripeptide was later found to be an intermediate in the biosynthesis of both penicillin N and cephalosporin C, and this was followed by the complete elucidation of the biosynthetic pathways leading to these compounds and to benzylpenicillin. (shrink)

Following the proposal of a new kind of selective structural realism that uses as a basis the distinction between framework and interaction theories, this work discusses relevant applications in fundamental physics. An ontology for the different entities and properties of well-known theories is thus consistently built. The case of classical field theories—including general relativity as a classical theory of gravitation—is examined in detail, as well as the implications of the classification scheme for issues of realism in quantum mechanics. These (...) applications also shed light on the different range of applicability of the ontic and epistemic versions of structural realism. (shrink)

In this paper, we discuss the thesis of selective representing — the idea that the contents of the mental representations had by organisms are highly constrained by the biological niches within which the organisms evolved. While such a thesis has been defended by several authors elsewhere, our primary concern here is to take up the issue of the compatibility of selective representing and realism. In this paper we hope to show three things. First, that the notion of (...) class='Hi'>selective representing is fully consistent with the realist idea of a mind-independent world. Second, that not only are these two consistent, but that the latter provides the most powerful perspective from which to motivate and understand the differing perceptual and cog- nitive profiles themselves. And third, that the sense in which organism and environment may together constitute an integrated system of scientific interest poses no additional threat to the realist conception. (shrink)

It has recently been suggested that realist responses to historical cases featured in pessimistic meta-inductions are not as successful as previously thought. In response, selective realists have updated the basic divide et impera strategy specifically to take such cases into account and to argue that more modern realist accounts are immune to the historical challenge. Using a case study—that of the nineteenth-century zymotic theory of disease—I argue that these updated proposals fail and that even the most sophisticated recent realist (...) accounts remain vulnerable to the challenge from history. (shrink)

Scholars working in science and technology studies have recently argued that we could learn much about the nature of scientific knowledge by paying closer attention to scientific ignorance. Building on the work of Robert Proctor, this article shows how ignorance can stem from a wide range of selective research choices that incline researchers toward partial, limited understandings of complex phenomena. A recent report produced by the International Assessment of Agricultural Knowledge, Science, and Technology for Development serves as the article’s (...) central case study. After arguing that the forms of selective ignorance illustrated in cases like this one are both socially important and difficult to address, I suggest several strategies for responding to them in a socially responsible manner. (shrink)

Optimists about mind-uploading believe that we can survive uploading. Pessimists about mind-uploading, on the other hand, believe that we cannot survive uploading. An under-explored middle ground between the two is a selective form of optimism, which claims that we can survive some forms of uploading, such as gradual replacement uploading, but not others, such as scan-and-copy uploading. Is selective optimism about uploading a rational stance? In this paper I argue that the answer is yes. The paper has a (...) negative and a positive part. First, I defuse an objection against selective optimism from Wiley and Koene (2016). Wiley and Koene argue that gradual replacement uploading is metaphysically equivalent to scanand-copy uploading, and hence optimism about the former and pessimism about the latter is unfounded. I show that Wiley and Koene's case for the supposed metaphysical equivalence fails, since there is a significant metaphysical contrast between the two types of uploading involving immanent causation. In the second part of the paper, I present a positive case for selective optimism about gradual uploading building on this contrast in immanent causation. (shrink)

This article examines multicultural classrooms through the selective permeability model, which posits that individuals encounter different action possibilities or affordances in the same setting. The goal is to illuminate how educational environments may support some students while disadvantaging others, thereby causing situated cognitive harm. The article proceeds in several parts. First, it explores selective permeability in relation to what Gibson describes as “positive” and “negative” affordances, articulating how these polarities can change depending on a person’s cultural background. Second, (...) it integrates insights from cultural psychology, such as the influence of regional geography and city design on behavior-constraining cultural norms. These norms can productively funnel actions and learning. Yet when a student’s cultural norms clash with tacit classroom prescriptions, the situation can be analogous to arriving at a rink with rollerblades only to be placed on ice: the learner confronts action limiting negative affordances and undergoes situated cognitive harm. Third, the article presents qualitative and quantitative data that clarify how culture moderates what students find helpful or hindering. Notably, incongruent norms are not always detrimental; under certain circumstances, they can serve as a catalyst for growth. (shrink)

Liberty-restricting measures have been implemented for centuries to limit the spread of infectious diseases. This article considers if and when it may be ethically acceptable to impose selective liberty-restricting measures in order to reduce the negative impacts of a pandemic by preventing particularly vulnerable groups of the community from contracting the disease. We argue that the commonly accepted explanation—that liberty restrictions may be justified to prevent harm to others when this is the least restrictive option—fails to adequately accommodate the (...) complexity of the issue or the difficult choices that must be made, as illustrated by the COVID-19 pandemic. We introduce a dualist consequentialist approach, weighing utility at both a population and individual level, which may provide a better framework for considering the justification for liberty restrictions. While liberty-restricting measures may be justified on the basis of significant benefits to the population and small costs for overall utility to individuals, the question of whether it is acceptable to discriminate should be considered separately. This is because the consequentialist approach does not adequately account for the value of equality. This value may be protected through the application of an additional proportionality test. An algorithm for making decisions is proposed. Ultimately whether selective liberty-restricting measures are imposed will depend on a range of factors, including how widespread infection is in the community, the level of risk and harm a society is willing to accept, and the efficacy and cost of other mitigation options. (shrink)

Sluggish cognitive tempo is a cluster of attentional symptoms characterized by slow information processing and behavior, distractibility, mental confusion, absent-mindedness, and hypoactivity. The present study aimed to compare early and late selective attention in the information processing speed of adults with SCT to those with attention-deficit/hyperactivity disorder and adults without any attentional problems. The participants were screened using Barkley Adult ADHD Rating Scale-IV and divided into the following groups: SCT, ADHD, and controls. All participants completed the irrelevant distractor task (...) measuring early and late selective attention under load condition and distractor condition. The inefficiency index was calculated by subtracting the reaction time of no-distractor condition of correct trials from the reaction time of distractor condition to control the impact of accuracy. Upon analysis, the SCT group showed a lower efficiency compared to the ADHD group under high load, while the ADHD group showed lower efficiency under low load than high load. This meant that the ADHD group had increased efficiency of selective attention with higher load, while the SCT group had low efficiency of selective attention even under high loads. These results suggest that the symptoms of “slow” or “distracted” in SCT could be attributed to the reduced speed and efficiency of selective attention in early information processing and the problem can be pronounced in situations with distractors. The results of the study imply that the attention-deficit-like symptoms shown in those with SCT and ADHD can be distinguished in specific stage of information processing. (shrink)

Defective newborn children are to be considered human persons. Thus, primary duty in proxy consent is to act with the infant's best interest in mind. This duty may at times override the otherwise prima facie right to life, but only under restricted circumstances. Refinements of McCormick's “relational potential” criteria and of ordinary-extraordinary means analysis prove useful in such decisions. Utilitarian considerations of social consequences have impact but can be kept subsidiary. The importance for decision making of available child support services (...) is considered. Spina bifida is used throughout as an example of issues discussed. (shrink)

This article examines epistemic impacts of social media, merging Gibson’s affordance theory with the notion of selective permeability, which holds people encounter objective differences in a setting because of their distinct capacities, only here applying the idea to online spaces. I start by circumscribing my deployment of “affordances,” taking care not to totally divorce the term from Gibson’s intent, as often happens in information technologies research. I next detail ways that selective permeability characterizes online epistemic landscapes, focusing on (...) how factors (like culture) moderate normative standards for sharing information. This leads to a discussion about selective receptivity and blindness to information in the context of social media—a situation that amplifies political divides and renders antagonists mutually incomprehensible. This segues into my final topic: an exposition of how social media can make the offline world more selectively hostile to some. An additional proposition is that practical habits cultivated on networking apps can modulate what affordances are present in offline arenas, as opposed to just affecting which ones get noticed. Throughout, I suggest that selective permeability answers an increasingly recognized challenge: the difficulty of generalizing conclusions about one app to others and across cultures, ages, etc. Ultimately, my aim is not only to explicate how social media fragments common social knowledge but to defend selective permeability as an epistemic template for comprehending social media. (shrink)

In the early 2000s, the development of local food systems in advanced industrial countries has expanded beyond creation and support of farmers’ markets and community supported agriculture farms and projects to include targeted Buy Local Food campaigns. Non-governmental groups in many U.S. places and regions have launched such campaigns with the intent of motivating and directing consumers toward more local food purchasing in general. This article examines the current manifestations and possibilities for social justice concerns in Buy Local Food campaigns, (...) by considering them within the more general category of “selective patronage“ campaigns. Historical campaign examples, such as Buy Union, Buy American, and Buy Black campaigns, offer instructive comparisons to contemporary consumer campaigns promoting local food. Through examining the construction of threats, intended beneficiaries, products to be avoided, and those to be preferentially selected, the paper demonstrates how selective patronage campaigns have emphasized social justice needs and concerns for designated groups in ways that have been potentially exclusionary of other disadvantaged groups and thus undermining of social justice more broadly. As a contemporary instance of “selective patronage,“ Buy Local Food campaigns exhibit similar contradictory impulses, which are intensified by the conceptual and practical pitfalls in designating “local.“ The article concludes by considering how the challenges and prospects for commitments to social justice in local food consumer campaigns reinforce the importance of emerging initiatives centered on domestic fair trade. (shrink)

Rather than set out an overarching view or take a stand on the debunking of morality tout court, in what follows I’ll explore a divide and conquer strategy. First, I will briefly sketch a debunking argument that, instead of targeting all of morality or human moral nature, has a more narrow focus—namely, the intuitive moral authority of disgust. The argument concludes that as vivid and compelling as they can be while one is in their grip, feelings of disgust should be (...) granted no power to justify moral judgments. Importantly, the argument is grounded in empirical advances concerning the character of the emotion itself. Next, I will step back and consider the argument’s general form. I then point to arguments that others have made that seem to share this form and selective focus, and comment on what such arguments do and do not presuppose. Finally, I locate the selective strategy with respect to other approaches moral debunking. (shrink)

. Selective incapacitation reexamined: The national academy of sciences' report on criminal careers and “career criminals”. Criminal Justice Ethics: Vol. 7, No. 1, pp. 19-35.

We study the preservation of selective covering properties, including classic ones introduced by Menger, Hurewicz, Rothberger, Gerlits and Nagy, and others, under products with some major families of concentrated sets of reals.Our methods include the projection method introduced by the authors in an earlier work, as well as several new methods. Some special consequences of our main results are : Every product of a concentrated space with a Hurewicz S1S1 space satisfies S1S1. On the other hand, assuming the Continuum (...) Hypothesis, for each Sierpiński set S there is a Luzin set L such that L×SL×S can be mapped onto the real line by a Borel function. Assuming Semifilter Trichotomy, every concentrated space is productively Menger and productively Rothberger. Every scale set is productively Hurewicz, productively Menger, productively Scheepers, and productively Gerlits–Nagy. Assuming d=ℵ1d=ℵ1, every productively Lindelöf space is productively Hurewicz, productively Menger, and productively Scheepers.A notorious open problem asks whether the additivity of Rothberger's property may be strictly greater than addadd, the additivity of the ideal of Lebesgue-null sets of reals. We obtain a positive answer, modulo the consistency of Semifilter Trichotomy >ℵ1.Our results improve upon and unify a number of results, established earlier by many authors. (shrink)

Assume that military professionals should have the right to exercise selective conscientious objection (SCO). Implementing policies and programs to facilitate the right to SCO would be tricky. This essay offers suggestions for how to proceed.

Many studies have revealed the top-down modulation on unconscious processing. However, there is little research about how category-selective attention could modulate the unconscious processing. In the present study, using functional magnetic resonance imaging , the results showed that category-selective attention modulated unconscious face/tool processing in the middle occipital gyrus . Interestingly, MOG effects were of opposed direction for face and tool processes. During unconscious face processing, activation in MOG decreased under the face-selective attention compared with tool-selective (...) attention. This result was in line with the predictive coding theory. During unconscious tool processing, however, activation in MOG increased under the tool-selective attention compared with face-selective attention. The different effects might be ascribed to an interaction between top-down category-selective processes and bottom-up processes in the partial awareness level as proposed by Kouider, De Gardelle, Sackur, and Dupoux . Specifically, we suppose an “excessive activation” hypothesis. (shrink)

Case studies of science concerning the interpretation of specific theories and the nature of theory change over time are often presented as evidence for or against forms of selective realism: versions of scientific realism that advocate belief in connection with certain components of theories as opposed to their content as a whole. I consider the question of how probative case studies can be in this sphere, focusing on two prominent examples of selectivity: explanationist realism, which identifies realist commitment with (...) components of theories that are putatively required to explain their empirical success; and entity realism, which identifies realist commitment with certain putatively causally efficacious entities. I argue that while case studies are essential to debates about these positions, they are not compelling in the way that their intended use suggests. Regarding explanationism, concerns about the “neutrality” of historical evidence are ultimately indefeasible. Regarding entity realism, arguments for and against naturally dissolve into disputes about the reference of theoretical terms which are insulated from the details of cases. I conclude by suggesting that the morals of this discussion extend to other forms of selective realism, namely structural realism and semirealism. (shrink)