Upconverting Carbon Nanodots from EDTA as Near-Infrared Activated Phototheranostic Agents

This work describes the synthesis of nitrogen-doped carbon nanodots (CNDs) synthesized from ethylene diamine tetra acetic acid (EDTA) as a precursor and their application as luminescent agents with a dual-mode theranostic role as near-infrared (NIR) triggered imaging and photodynamic therapy agents. Interestingly, these fluorescent CNDs are more rapidly and selectively internalized in tumor cells and exhibit no cytotoxicity until remotely activated with a NIR illumination source. These CNDs are excellent candidates for photo-theranostic purposes, i.e.: simultaneous imaging and therapy can be carried out on cancer cells using their luminescent properties and the in situ generation of reactive oxidative species (ROS) upon excitation in the NIR range. In the presence of CNDs NIR remote activation induces the in vitro killing of U251 MG cells. Through the use of flow imaging cytometry we have been able to successfully map and quantify the different type of cell deaths induced by the presence of intracellular superoxide anions (¿O2-) and hydrogen peroxide (H2O2) ROS species generated in situ upon NIR irradiation

Antioxidant activity of pineal methoxyindoles on hepatocyte plasmatic membrane

Antioxidant effect of several pineal derived molecules has been well documented. Here, the protective effects of 5-methoxytryptophol (5-MTOH) and 5-methoxyindol-3-acetic acid (5-MIAA) on hepatic cell membrane lipid peroxidation and cell membrane rigidity induced by FeCl3 plus ascorbic acid have been systemically investigated. The membrane fluidity was evaluated by fluorescence spectroscopy, malondialdehyde (MDA) and 4-hydroxyalkenals (4-HDA) concentrations and carbonyl groups of protein were measured as the parameters of lipid and protein damage, respectively. Results showed that oxidative stress increased membrane rigidity, MDA and 4-HDA concentra-tions as well as carbonyl content in a concentration-dependent manner. 5-MTOH, but not 5-MIAA, significantly attenuated these oxidative indecies. In absence of oxidative stress, none of these methoxyindoleamines modified the content of MDA, 4-HDA or carbonyl-ation. However 5-MIAA at its highest concentration slightly modified membrane fluidity. The results suggest that structural modification of C3 in the methoxyindoleamine, that is, the carboxyl group replaced by hydroxyl group in this site could improve the ability of 5-methoxyindoleamine derivatives to preserve membrane fluidity of cells which are under oxidative stress

Alternatives and responsibility: an asymmetrical approach

En este trabajo defiendo una visión asimétrica sobre la relación entre las posibilidades alternativas y la responsabilidad moral, según la cual se requiere tener posibilidades alternativas para ser culpable por lo que uno decide o hace, pero no para ser laudable por ello. Defiendo la no necesidad de alternativas para ser laudable a través de un examen de lo que yo llamo “ejemplos Lutero”. Mi defensa de la necesidad de alternativas para ser culpable procede en cambio mediante un análisis de los llamados “casos Frankfurt”. En ambos casos, mis argumentos se basan en la afirmación según la cual, en las adscripciones de responsabilidad moral, la cuestión principal no es si el agente podría haber hecho algo distinto, sino si debería haber hecho lo que hizo, de modo que la primera pregunta solo se vuelve apremiante cuando la respuesta a la segunda es negativa. Así, pues, en lo que se refiere a la responsabilidad moral, el concepto de obligación o deber moral es previo al de posibilidades alternativas.In this paper, I defend an asymmetrical view concerning the relationship between alternative possibilities and moral responsibility, according to which alternative possibilities are required for being blameworthy, but not praiseworthy, for what one decides or does. I defend the non-necessity of alternatives for praiseworthiness through an examination of what I call ‘Luther’ examples. My defence of the necessity of alternatives for blameworthiness proceeds instead through an analysis of so-called ‘Frankfurt’ examples. In both cases, my arguments rest on the contention that, in ascriptions of moral responsibility, the primary question is not whether the agent could have done otherwise, but whether she should have done what she did, so that the former question only becomes pressing when the answer to the latter is negative. Concerning moral responsibility, then, the concept of moral obligation or duty is prior to that of alternative possibilities

Long-lived T follicular helper cells retain plasticity and help sustain humoral immunity

CD4; +; memory T cells play an important role in protective immunity and are a key target in vaccine development. Many studies have focused on T central memory (T; cm; ) cells, whereas the existence and functional significance of long-lived T follicular helper (T; fh; ) cells are controversial. Here, we show that T; fh; cells are highly susceptible to NAD-induced cell death (NICD) during isolation from tissues, leading to their underrepresentation in prior studies. NICD blockade reveals the persistence of abundant T; fh; cells with high expression of hallmark T; fh; markers to at least 400 days after infection, by which time T; cm; cells are no longer found. Using single-cell RNA-seq, we demonstrate that long-lived T; fh; cells are transcriptionally distinct from T; cm; cells, maintain stemness and self-renewal gene expression, and, in contrast to T; cm; cells, are multipotent after recall. At the protein level, we show that folate receptor 4 (FR4) robustly discriminates long-lived T; fh; cells from T; cm; cells. Unexpectedly, long-lived T; fh; cells concurrently express a distinct glycolytic signature similar to trained immune cells, including elevated expression of mTOR-, HIF-1-, and cAMP-regulated genes. Late disruption of glycolysis/ICOS signaling leads to T; fh; cell depletion concomitant with decreased splenic plasma cells and circulating antibody titers, demonstrating both unique homeostatic regulation of T; fh; and their sustained function during the memory phase of the immune response. These results highlight the metabolic heterogeneity underlying distinct long-lived T cell subsets and establish T; fh; cells as an attractive target for the induction of durable adaptive immunity

Ribosomal Protein Mutations Induce Autophagy through S6 Kinase Inhibition of the Insulin Pathway

Mutations affecting the ribosome lead to several diseases known as ribosomopathies, with phenotypes that include growth defects, cytopenia, and bone marrow failure. Diamond-Blackfan anemia (DBA), for example, is a pure red cell aplasia linked to the mutation of ribosomal protein (RP) genes. Here we show the knock-down of the DBA-linked RPS19 gene induces the cellular self-digestion process of autophagy, a pathway critical for proper hematopoiesis. We also observe an increase of autophagy in cells derived from DBA patients, in CD34+ erythrocyte progenitor cells with RPS19 knock down, in the red blood cells of zebrafish embryos with RP-deficiency, and in cells from patients with Shwachman-Diamond syndrome (SDS). The loss of RPs in all these models results in a marked increase in S6 kinase phosphorylation that we find is triggered by an increase in reactive oxygen species (ROS). We show that this increase in S6 kinase phosphorylation inhibits the insulin pathway and AKT phosphorylation activity through a mechanism reminiscent of insulin resistance. While stimulating RP-deficient cells with insulin reduces autophagy, antioxidant treatment reduces S6 kinase phosphorylation, autophagy, and stabilization of the p53 tumor suppressor. Our data suggest that RP loss promotes the aberrant activation of both S6 kinase and p53 by increasing intracellular ROS levels. The deregulation of these signaling pathways is likely playing a major role in the pathophysiology of ribosomopathies

Russellian Monism and Mental Causation

© 2019 Wiley Periodicals, Inc.According to Russellian monism, consciousness is constituted at least partly by quiddities: intrinsic properties that categorically ground dispositional properties described by fundamental physics. If the theory is true, then consciousness and such dispositional properties are closely connected. But how closely? The contingency thesis says that the connection is contingent. For example, on this thesis the dispositional property associated with negative charge might have been categorically grounded by a quiddity that is distinct from the one that actually grounds it. Some argue that Russellian monism entails the contingency thesis and that this makes its consciousness‐constituting quiddities epiphenomenal—a disastrous outcome for a theory that is motivated partly by its prospects for integrating consciousness into physical causation. We consider two versions of that argument, a generic version and an intriguing version developed by Robert J. Howell, which he bases on Jaegwon Kim's well‐known “exclusion argument.” We argue that neither succeeds.Peer reviewe

Larvae act as a transient transmission hub for the prevalent bumblebee parasite Crithidia bombi

Disease transmission networks are key for understanding parasite epidemiology. Within the social insects, structured contact networks have been suggested to limit the spread of diseases to vulnerable members of their society, such as the queen or brood. However, even these complex social structures do not provide complete protection, as some diseases, which are transmitted by workers during brood care, can still infect the brood. Given the high rate of feeding interactions that occur in a social insect colony, larvae may act as disease transmission hubs. Here we use the bumblebee Bombus terrestris and its parasite Crithidia bombi to determine the role of brood in bumblebee disease transmission networks. Larvae that were artificially inoculated with C. bombi showed no signs of infection seven days after inoculation. However, larvae that received either an artificial inoculation or a contaminated feed from brood-caring workers were able to transmit the parasite to naive workers. These results suggest that the developing brood is a potential route of intracolonial disease transmission and should be included when considering social insect disease transmission networks

Free Will & Empirical Arguments for Epiphenomenalism

While philosophers have worried about mental causation for centuries, worries about the causal relevance of conscious phenomena are also increasingly featuring in neuroscientific literature. Neuroscientists have regarded the threat of epiphenomenalism as interesting primarily because they have supposed that it entails free will scepticism. However, the steps that get us from a premise about the causal irrelevance of conscious phenomena to a conclusion about free will are not entirely clear. In fact, if we examine popular philosophical accounts of free will, we find, for the most part, nothing to suggest that free will is inconsistent with the presence of unconscious neural precursors to choices. It is only if we adopt highly non-naturalistic assumptions about the mind (e.g. if we embrace Cartesian dualism and locate free choice in the non-physical realm) that it seems plausible to suppose that the neuroscientific data generates a threat to free will

Aristotle on Deliberation and Contingency

The author discusses Aristotle’s notion of deliberation and shows that it differs considerably from the model of deliberation as is common in contemporary discussions of free will and moral responsibility. As opposed to the contemporary model, Aristotle’s account does not require that the deliberator has any belief (or lack thereof) concerning the availability of possible courses of action. However, the action chosen by deliberation, before it is performed, is still contingent––i.e. such that it can both be and not be done––and up to us. Moreover, the action’s being up to us can be seen as grounded in our having rational capacities that are necessarily two-sided. This might suggest that the agent can do otherwise than she has decided by deliberation. The author argues that this is not the case: after deliberation, or after forming the relevant desire, the agent can actualize only one arm of her two-sided capacity, and hence, she cannot act differently than as decided by deliberation. If it makes sense to say that she can act differently, it is only because there may occur, in the interval between deliberation and action, some other desire which takes over a role of the decisive factor

Getting Acquainted with Kant

My question here concerns whether Kant claims that experience has nonconceptual content, or whether, on his view, experience is essentially conceptual. However there is a sense in which this debate concerning the content of intuition is ill-conceived. Part of this has to do with the terms in which the debate is set, and part to do with confusion over the connection between Kant’s own views and contemporary concerns in epistemology and the philosophy of mind. However, I think much of the substance of the debate concerning Kant’s views on the content of experience can be salvaged by reframing it in terms of a debate about the dependence relations, if any, that exist between different cognitive capacities. Below, in Section 2, I clarify the notion of ‘content’ I take to be at stake in the interpretive debate. Section 3 presents reasons for thinking that intuition cannot have content in the relevant sense. I then argue, in Section 4, that the debate be reframed in terms of dependence. We should distinguish between Intellectualism, according to which all objective representation (understood in a particular way) depends on acts of synthesis by the intellect, and Sensibilism, according to which at least some forms of objective representation are independent of any such acts (or the capacity for such acts). Finally, in Section 5, I further elucidate the cognitive role of intuition. I articulate a challenge which Kant understands alethic modal considerations to present for achieving cognition, and argue that a version of Sensibilism that construes intuition as a form of acquaintance is better positioned to answer this challenge than Intellectualism