Increased amyloid beta (Aβ) production by sequential cleavage of the amyloid precursor protein (APP) by the β‐ and γ‐secretases contributes to the etiological basis of Alzheimer's disease (AD). This process requires APP and the secretases to be in the same subcellular compartments, such as the endosomes. Since all membrane organelles in the endomembrane system are kinetically and functionally linked, any defects in the trafficking and sorting machinery would be expected to change the functional properties of the whole system. The Golgi (...) is a primary organelle for protein trafficking, sorting and modifications, and Golgi defects have been reported in AD. Here we hypothesize that Golgi fragmentation in AD accelerates APP trafficking and Aβ production. Furthermore, Golgi defects may perturb the proper trafficking and processing of many essential neuronal proteins, resulting in compromised neuronal function. Therefore, molecular tools that can restore Golgi structure and function could prove useful as potential drugs for AD treatment. (shrink)

Kireet Joshi, b. 1931, Indian philosopher and educationist; contributed articles.

Political protests, debates on college campuses, and social media tirades make it seem like everyone is speaking their minds today. Surveys, however, reveal that many people increasingly feel like they're walking on eggshells when communicating in public. Speaking your mind can risk relationships and professional opportunities. It can alienate friends and anger colleagues. Isn't it smarter to just put your head down and keep quiet about controversial topics? In this book, Hrishikesh Joshi offers a novel defense of speaking your (...) mind. He explains that because we are social creatures, we never truly think alone. What we know depends on what our community knows. And by bringing our unique perspectives to bear upon public discourse, we enhance our collective ability to reach the truth on a variety of important matters. Speaking your mind is also important for your own sake. It is essential for developing your own thinking. And it's a core aspect of being intellectually courageous and independent. Joshi argues that such independence is a crucial part of a well-lived life. The book draws from Aristotle, John Stuart Mill, Friedrich Nietzsche, Bertrand Russell, and a range of contemporary thinkers to argue that it's OK to speak your mind. Key Features Shows that we have not just a right but a moral duty to publicly share what we know. Argues that discussing your unique ideas with others is essential for developing as a critical thinker. Explores the value of intellectual honesty and independence in the writings of John Stuart Mill and Friedrich Nietzsche and connects their thinking to contemporary problems. Argues that avoiding cultural blind spots today is important for the fate of future generations. (shrink)

This paper argues for the existence of a certain type of defeater for one’s belief that P—the presence of social incentives not to share evidence against P. Such pressure makes it relatively likely that there is unpossessed evidence that would provide defeaters for P because it makes it likely that the evidence we have is a lopsided subset. This offers, I suggest, a rational reconstruction of a core strand of argument in Mill’s On Liberty. A consequence of the argument is (...) that on morally and politically laden issues in particular, a high degree of doxastic openness might be appropriate. (shrink)

The American political landscape exhibits significant polarization. People’s political beliefs cluster around two main camps. However, many of the issues with respect to which these two camps disagree seem to be rationally orthogonal. This feature raises an epistemic challenge for the political partisan. If she is justified in consistently adopting the party line, it must be true that her side is reliable on the issues that are the subject of disagreements. It would then follow that the other side is anti-reliable (...) with respect to a host of orthogonal political issues. Yet, it is difficult to find a psychologically plausible explanation for why one side would get things reliably wrong with respect to a wide range of orthogonal issues. While this project’s empirical discussion focuses on the US context, the argument generalizes to any situation where political polarization exists on a sufficiently large number of orthogonal claims. (shrink)

According to many philosophers, the world should embrace open borders – that is, let people move around the globe and settle as they wish, with exceptions made only in very specific cases such as fugitives or terrorists. Defenders of open borders have adopted two major argumentative strategies. The first is to claim that immigration restrictions involve coercion, and then show that such coercion cannot be morally justified. The second is to argue that adopting worldwide open borders policies would make the (...) world a much better place, particularly by improving average well-being. This essay contends that both of these argumentative strategies fail. Some immigration restrictions are not only morally justified, but morally required. (shrink)

Are immigration restrictions compatible with liberalism? Recently, Freiman and Hidalgo have argued that immigration restrictions conflict with the core commitments of liberalism. A society with immigration restrictions in place may well be optimal in some desired respects, but it is not liberal, they argue. So if you care about liberalism more deeply than you care about immigration restrictions, you should give up on restrictionism. You can’t hold on to both. I argue here that many restrictions on contractual, economic, and associational (...) liberties seem to be justified by considerations other than liberty – thus the task for Freiman and Hidalgo is to tell us why such restrictions are justified but immigration restrictions are not. Moreover, even if this worry can be addressed, I argue, liberalism is not committed to its own demise in scenarios where there exist large enough numbers of would-be immigrants who accept and endorse illiberal norms in a way that is sufficiently resistant to change. Such a commitment requires thinking of border coercion as violating an absolute deontological constraint. This, I contend, is implausible. (shrink)

Following Anthony Downs’s classic economic analysis of democracy, it has been widely noted that most voters lack the incentive to be well-informed. Recent empirical work, however, suggests further that political partisans can display selectively lazy or biased reasoning. Unfortunately, political knowledge seems to exacerbate, rather than mitigate, these tendencies. In this paper, I build on these observations to construct a more general skeptical challenge which affects what I call creedal beliefs. Such beliefs share three features: (i) the costs to the (...) individual of being wrong are negligible, (ii) the beliefs are subject to social scrutiny, and (iii) the evidential landscape relevant to the beliefs is sufficiently complex so as to make easy verification difficult. Some philosophers and social scientists have recently argued that under such conditions, beliefs are likely to play a signaling, as opposed to a navigational role, and that our ability to hold beliefs in this way is adaptive. However, if this is right, I argue there is at least a partial debunker for such beliefs. Moreover, this offers, I suggest, one way to develop the skeptical challenge based on etiological explanation that John Stuart Mill presents in On Liberty when he claims that the same causes which lead someone to be a devout Christian in London would have made them a Confucian in Peking. Finally, I contend that this skeptical challenge is appropriately circumscribed so that it does not over-extend in an implausible way. (shrink)

The aged in India have conventionally enjoyed privileges within the framework of a social economy where the needs of the old remained a moral responsibility of family, kith and kin. However the present changing times have forced a shift in the approach to old age care. The old person finds him- or herself in a sticky situation, in between an insensitive state and the demands of globalization. The present paper situates this problem within the framework of globalization and systematically measures (...) the strategic response of the state to this daunting challenge, with respect to economic security and health care in particular. In the conclusion, the paper argues for a rejection of the conventional welfare approach and it advocates an integrated approach based on a coherent social development perspective within the valuation framework of social quality. (shrink)

Sitting on the fine line between pathogen ‘transmissibility’ and ‘severity’, the Behavioural Immune System (BIS) is responsible for activating behaviours that minimise infection risks and maximise fitness. To achieve self-preservation, the BIS also fuels social and political attitudes. We aim to explain societal changes that may be sparked by COVID-19 by highlighting links between human evolutionary history and our psychological faculties mediated by the BIS.

Minichromosome maintenance (Mcm) proteins are well‐known for their functions in DNA replication. However, their roles in chromosome segregation are yet to be reviewed in detail. Following the discovery in 1984, a group of Mcm proteins, known as the ARS‐nonspecific group consisting of Mcm13, Mcm16‐19, and Mcm21‐22, were characterized as bonafide kinetochore proteins and were shown to play significant roles in the kinetochore assembly and high‐fidelity chromosome segregation. This review focuses on the structure, function, and evolution of this group of Mcm (...) proteins. Our in silico analysis of the physical interactors of these proteins reveals that they share non‐overlapping functions despite being copurified in biochemically stable complexes. We have discussed the contrasting results reported in the literature and experimental strategies to address them. Taken together, this review focuses on the structure‐function of the ARS‐nonspecific Mcm proteins and their evolutionary flexibility to maintain genome stability in various organisms. (shrink)

In setting up a formal system to specify a grammar formalism, the conventional (mathematical) wisdom is to start with primitives (basic primitive structures) as simple as possible, and then introduce various operations for constructing more complex structures. An alternate approach is to start with complex (more complicated) primitives, which directly capture some crucial linguistic properties and then introduce some general operations for composing these complex structures. These two approaches provide different domains of locality, i.e., domains over which various types of (...) linguistic dependencies can be specified. The latter approach, characterized as complicate locally, simplify globally (CLSG), pushes non‐local dependencies to become local, i.e., they arise in the basic primitive structures to start with.The CLSG approach has led to some new insights into syntactic description, semantic composition, language generation, statistical processing, and psycholinguistic phenomena, all these with possible relevance to the cognitive architecture of language. In this paper, we will describe these results in an introductory manner making use of the framework of lexicalized tree‐adjoining grammar (LTAG), a key example of the CLSG approach, thereby describing the interplay between formal analysis on the one hand and linguistic and processing issues on the other hand. (shrink)

P¯an.ini’s grammar includes several types of metarules which determine how its operational rules apply. Among them are “traffic rules” which constrain how rules interact with each other in grammatical derivations. These are typically formulated as designating a rule or class of rules asiddha “not effected” (or asiddhavat “as if not effected”) with respect to another rule or class of rules. For economy, the rules so designated are grouped into several sections, whose headings collectively declare them to be asiddha(vat). The biggest (...) such section, under the famous heading 8.2.1 p ¯urvatr¯asiddham, extends from 8.2.1 through the end of the grammar (8.4.68), and is hence called the Trip¯ad¯ı ‘Three Sections’. (shrink)

The questions of how human beings produce and comprehend language continue to engage a variety of researchers and scholars, and it is becoming increasingly clear that only interdisciplinary approaches will yield productive answers. This complex issue of discourse processing is the subject of this volume, and the contributors address it from the varying perspectives of cognitive psychology linguistics, and computer science. The chapters provide a fascinating overview of emerging theories in the new discipline of cognitive science. A useful introductory chapter (...) by the editors explains the relationships of chapters to one another and outlines the long-term implications of the work they report. (shrink)

We describe a categorial system (PPTS) based on partial proof trees(PPTs) as the building blocks of the system. The PPTs are obtained byunfolding the arguments of the type that would be associated with a lexicalitem in a simple categorial grammar. The PPTs are the basic types in thesystem and a derivation proceeds by combining PPTs together. We describe theconstruction of the finite set of basic PPTs and the operations forcombining them. PPTS can be viewed as a categorial system incorporating someof (...) the key insights of lexicalized tree adjoining grammar, namely the notionof an extended domain of locality and the consequent factoring of recursionfrom the domain of dependencies. PPTS therefore inherits the linguistic andcomputational properties of that system, and so can be viewed as a middleground between a categorial grammar and a phrase structure grammar. We alsodiscuss the relationship between PPTS, natural deduction, and linear logicproof-nets, and argue that natural deduction rather than a proof-net systemis more appropriate for the construction of the PPTs. We also discuss howthe use of PPTs allows us to localize the management of resources, therebyfreeing us from this management as the PPTs are combined. (shrink)

This chapter argues that governments have a duty to take reasonably effective and humane steps to minimize the occurrence of unauthorized migration and stay. While the effects of unauthorized migration on a country’s citizens and institutions have been vigorously debated, the literature has largely ignored duties of fairness to would-be immigrants. It is argued here that failing to take reasonable steps to prevent unauthorized migration and stay is deeply unfair to would-be immigrants who are not in a position to bypass (...) visa regulations. Importantly, the argument here is orthogonal to the debate as to how much and what kinds of immigration ought to be allowed. (shrink)

Within the immigration debate, libertarians have typically come down in favor of open borders by defending two main ideas: i) individuals have a right to free movement; and ii) immigration restrictions are economically inefficient, so that lifting them can make everyone better off. This entry describes the rationale for open borders from a libertarian perspective (in part by analogy to the debate around minimum wage laws). Three main objections within the immigration literature are then discussed: i) the view that states (...) may restrict immigration to protect the interests (e.g. jobs) of their domestic needy; ii) the claim that restrictions are justified as a means of preserving culture; and iii) the influential argument that the right to freedom of association entails a right to exclude. These arguments are well-known, and I describe some of the compelling responses to be found in the recent literature. The essay then turns to more neglected critiques. The first concerns how liberal regimes should think about immigration from countries where the dominant norms are illiberal. The second examines the idea that political and economic institutions are sensitive to immigration policy, especially in the long run. Both of these critiques approach the topic from a non-ideal theory perspective, emphasizing the “public choice” dimensions of immigration policy. The entry closes by suggesting that this form of critique is especially important for open-borders libertarians to respond to given their general commitments to non-ideal, non-romantic theorizing in the context of government institutions and policy. (shrink)

According to G.A. Cohen, the principles of justice are insensitive to facts about human moral limitations. This assumption allows him to mount a powerful defense of socialism. Here, I present a dilemma for Cohen. On the one hand, if such socialism is to be realized through collective property ownership, then the information problem renders the ideal incoherent, not merely infeasible. On the other hand, if socialism is to incorporate private ownership of productive assets, then Cohen loses the resources to distinguish (...) his view from capitalism. For, if agents were ideally motivated, there would be no need for coercive taxation schemes and limitations on trade. Moreover, incorporating coercion drastically undermines Cohen’s original argument for socialism, which relies on an analogy to a camping trip among friends. (shrink)

This paper addresses the problem of Twitter sentiment analysis through a hybrid approach in which SentiWordNet (SWN)-based feature vector acts as input to the classification model Support Vector Machine. Our main focus is to handle lexical modifier negation during SWN score calculation for the improvement of classification performance. Thus, we present naive and novel shift approach in which negation acts as both sentiment-bearing word and modifier, and then we shift the score of words from SWN based on their contextual semantic, (...) inferred from neighbouring words. Additionally, we augment negation accounting procedure with a few heuristics for handling the cases in which negation presence does not necessarily mean negation. Experimental results show that the contextual-based SWN feature vector obtained through shift polarity approach alone led to an improved Twitter sentiment analysis system that outperforms the traditional reverse polarity approach by 2–6%. We validate the effectiveness of our hybrid approach considering negation on benchmark Twitter corpus from SemEval-2013 Task 2 competition. (shrink)

Consider a binary afterlife, wherein some people go to Heaven, others to Hell, and nobody goes to both. Would such a system be just? Theodore Sider argues: no. For, any possible criterion of determining where people go will involve treating very similar individuals very differently. Here, I argue that this point has deep and underappreciated implications for moral philosophy. The argument proceeds by analogy: many ethical theories make a sharp and practically significant distinction between persons and non-persons. Yet, just like (...) in the binary afterlife, this involves treating very similar individuals very differently. I propose two ways out. The first is to deny that such theories are strictly speaking true, but to claim that it is practically best if people adopt them. The second is to modify such theories so as to allow for continuous variation in the scope and strength of the moral obligations arising from personhood. (shrink)

Analytical study of the concept of creation and perception in Vedāntasiddhāntamuktāvalī, treatise on Hindu Advaita (non-dualistic) Vedanta philosophy by Prakāśānanda, 16th cent.

The author has sought to remove a confusion regarding the state of liberation, (which is the avowed goal of indian philosophy), Arising from a failure to distinguish between two states both called 'samadhi.' in one sense, 'samadhi' is a state of deep contemplation wherein the mind is made to concentrate on a particular object, To the exclusion of all other thoughts. Another state, Called 'nirvikalpa samadhi,' comes into being when the mind is perfectly silent, Yet watchful and sensitive, Without any (...) effort to concentrate. This state of liberation remains ever undisturbed by whatever one does on the psycho-Biological plane. (shrink)

Epistemic paternalism involves interfering with the inquiry of others, without their consent, for their own epistemic good. Recently, such paternalism has been discussed as a method of getting the broader public to have more accurate views on important policy relevant matters. In this paper, I discuss a novel problem for such paternalism—what I call epistemic spillovers. The problem arises because what matters for rational belief is one’s total evidence, and further, individual pieces of evidence can have complex interactions with one (...) another. Because of this, I argue that justified epistemic paternalism requires the would-be paternalist to be in an unusually strong epistemic position, one that most would-be paternalists are unlikely to meet. (shrink)

Ever since the global spread of the COVID-19 pandemic in 2020, East Asians across the globe have been ostracized, othered, pathologized, and subjected to numerous anti-Asian hate crimes. Despite contemporary China’s rapid modernization, the country is still perceived as an Oriental and primitive site. Taking these cues, the current article aims to investigate the Sinophobic attitudes in the wake of COVID-19 through a detailed analysis of sequential comics and cartoons by artists of East Asian descent, such as Laura Gao and (...) Lisa Wool-Rim Sjöblom. Drawing theoretical insights from Alexandre White’s “epidemic orientalism” and Priscilla Wald’s “medicalized nativism,” this essay investigates how these chosen comics function as counternarratives through first-person storytelling. In so doing, these comics, while reinstating the dignity of East Asians, also challenge and resist the naturalized methods of seeing that justify violence and dehumanization. The article further argues that Sinophobia and anti-Asian hate crimes are motivated as much by the origins of COVID-19 in China as by the political, economic, and technological variables that have shaped modern China. (shrink)

In philosophical work on the ethics of conversational exchange, much has been written regarding the speaker side—i.e., on the rights and duties we have as speakers. This paper explores the relatively neglected topic of the duties pertaining to the listeners’ side of the exchange. Following W.K. Clifford, we argue that it's fruitful to think of our epistemic resources as common property. Furthermore, listeners have a key role in maintaining and improving these resources, perhaps a more important role than speakers. We (...) develop this idea by drawing from Hugo Mercier and Dan Sperber's “interactionist” picture of reason, which suggests that reasoning is essentially dialogical and relies on the epistemic vigilance of listeners. The paper defends an imperfect, prima facie duty to listen, one that is sufficiently strong to place substantial demands on individuals, but not so overly demanding as to be implausible. (shrink)

Lipid droplets (LDs) are ubiquitous, neutral lipid storage organelles that act as hubs of metabolic processes. LDs are structurally unique with a hydrophobic core that mainly consists of neutral lipids, sterol esters, and triglycerides, enclosed within a phospholipid monolayer. Nascent LD formation begins with the accumulation of neutral lipids in the endoplasmic reticulum (ER) bilayer. The ER membrane proteins such as seipin, LDAF1, FIT, and MCTPs are reported to play an important role in the formation of nascent LDs. As the (...) LDs grow, they unmix from the highly charged ER membrane to form mature LDs. LD biogenesis is an exciting, emerging research area, and herein, we discuss the recent progress in our understanding of the formation of eukaryotic nascent LDs. We focus on the role of ER membrane shaping proteins such as reticulons and reticulon‐like proteins, membrane lipids, and cytoskeleton proteins such as septin in the formation of nascent LDs. (shrink)

In the past few decades, increased awareness of environmental pollution has led to the exploitation of microbial metabolic potential in the construction of several genetically engineered microorganisms (GEMs) for bioremediation purposes. At the same time, environmental concerns and regulatory constraints have limited the in situ application of GEMs, the ultimate objective behind their development. In order to address the anticipated risks due to the uncontrolled survival/dispersal of GEMs or recombinant plasmids into the environment, some attempts have been made to construct (...) systems that would contain the released organisms. This article discusses the designing of safer genetically engineered organisms for environmental release with specific emphasis on the use of bacterial plasmid addiction systems to limit their survival thus minimizing the anticipated risk. We also conceptualize a novel strategy to construct “Suicidal Genetically Engineered Microorganisms (SGEMs)” by exploring/combining the knowledge of different plasmid addiction systems (such as antisense RNA‐regulated plasmid addiction, proteic plasmid addiction etc.) and inducible degradative operons of bacteria. BioEssays 27:563–573, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Censorship involves, inter alia, adopting a certain type of epistemic policy. While much has been written on the harms and benefits of free expression, and the associated rights thereof, the epistemic preconditions of justified censorship are relatively underexplored. In this paper, I argue that examining intrapersonal norms of how we ought to treat evidence that might come to us over time can shed light on interpersonal norms of evidence generation and sharing that are relevant in the context of censorship. The (...) upshot is that justified censorship requires the censor to meet a very high epistemic burden regarding the target proposition(s)—importantly, one that exceeds knowledge. (shrink)

Knowing Our Limits. By Ballantyne Nathan.