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Extracellular vesicles (EVs), crucial mediators of cell‐to‐cell communication, hold significant diagnostic potential due to their ability to concentrate protein biomarkers in bodily fluids. However, challenges in isolating EVs from biological specimens hinder their widespread use. The preferred strategy involves direct analysis, integrating isolation and analysis solutions, with immunoaffinity methods currently dominating. Yet, the heterogeneous nature of EVs poses challenges, as proposed markers may not be as universally present as thought, raising concerns about biomarker screening reliability. This issue extends to EV‐mimics, where conventional methods may lack applicability. Addressing these challenges, the study reports on Membrane Sensing Peptides (MSP) as pan‐vesicular affinity ligands for both EVs and their non‐canonical analogs, streamlining capture and phenotyping through Single Molecule Array (SiMoA). MSP ligands enable direct analysis of circulating EVs, eliminating the need for prior isolation. Demonstrating clinical translation, MSP technology detects an EV‐associated epitope signature in serum and plasma, distinguishing myocardial infarction from stable angina. Additionally, MSP allow analysis of tetraspanin‐lacking Red Blood Cell‐derived EVs, overcoming limitations associated with antibody‐based methods. Overall, the work underlines the value of MSP as complementary tools to antibodies, advancing EV analysis for clinical diagnostics and beyond, and marking the first‐ever peptide‐based application in SiMoA technology. [ABSTRACT FROM AUTHOR]

According to Arti Dhand, it can be argued that all Indian ethics have been primarily virtue ethics. Many have indeed jumped on the virtue bandwagon, providing prima facie interpretations of Hindu, Jain, and Buddhist canons in virtue terms. Others have expressed firm skepticism, claiming that virtues are not proven to be grounded in the nature of things and that, ultimately, the appeal to virtue might just well be a mere façon de parler. In this paper, we aim to advance the discussion of Indian virtue ethics. Our intent is not to provide a catch‐all interpretation of the different Indian schools. Our goal is, more modestly, to offer a theory of virtues in Indian philosophies, as a framework for theorists and interpreters who see these diverse traditions as amenable to systematic virtue analysis. Our theory grounds virtues in the reality of genuine moral dispositions and in a system of beliefs where morality is understood as transformative in nature. [ABSTRACT FROM AUTHOR]

Objective: Disease‐modifying therapies are available for amyloidosis but are ineffective if end‐organ damage is severe. As small fiber neuropathy is an early and common feature of amyloidosis, we assessed detection and typing yield of skin biopsy for amyloid in patients with confirmed systemic amyloidosis and neuropathic symptoms. Methods: In this case–control study, patients with transthyretin and light chain amyloidosis (ATTRv, ATTRwt, and AL) were consecutively recruited. They were sex and age‐matched to three control groups (1) non‐neuropathic controls (NNC), (2) monoclonal gammopathy of undetermined significance (MGUS), and (3) other neuropathic disease controls (ONC). Patients underwent a double 3 mm skin biopsy in proximal and distal leg. Amyloid index and burden, protein typing by immuno‐electron microscopy, intraepidermal nerve fiber density, electroneuromyography, and clinical characteristics were analyzed. Results: We studied 15 subjects with confirmed systemic amyloidosis, 20 NNC, 18 MGUS, and 20 ONC. Amyloid was detected in 100% of patients with amyloidosis (87% in ankle and 73% in thigh). It was not detected in any of the control groups. A small fiber neuropathy was encountered in 100% of amyloidosis patients, in 80% of MGUS, and in 78% of ONC. Amyloid burden was higher in ATTRv, followed by AL and ATTRwt. The ultrastructural examination allowed the identification of the precursor protein by immunotyping in most of the cases. Interpretation: Skin biopsy is a minimally invasive test with optimal sensitivity for amyloid. It allows amyloid typing by electron microscope to identify the precursor protein. The diagnostic work up of systemic amyloidosis should include a skin biopsy. [ABSTRACT FROM AUTHOR]

The recent identification of multiple dominant mutations in the gene encoding β-catenin in both humans and mice has enabled exploration of the molecular and cellular basis of β-catenin function in cognitive impairment. In humans, β-catenin mutations that cause a spectrum of neurodevelopmental disorders have been identified. We identified de novo β-catenin mutations in patients with intellectual disability, carefully characterized their phenotypes, and were able to define a recognizable intellectual disability syndrome. In parallel, characterization of a chemically mutagenized mouse line that displays features similar to those of human patients with β-catenin mutations enabled us to investigate the consequences of β-catenin dysfunction through development and into adulthood. The mouse mutant, designated batface (Bfc), carries a Thr653Lys substitution in the C-terminal armadillo repeat of β-catenin and displayed a reduced affinity for membrane-associated cadherins. In association with this decreased cadherin interaction, we found that the mutation results in decreased intrahemispheric connections, with deficits in dendritic branching, long-term potentiation, and cognitive function. Our study provides in vivo evidence that dominant mutations in β-catenin underlie losses in its adhesion-related functions, which leads to severe consequences, including intellectual disability, childhood hypotonia, progressive spasticity of lower limbs, and abnormal craniofacial features in adults., Introduction β-Catenin (CTNNB1) is a highly conserved protein that implements key cellular functions by interacting with cell-adhesion proteins, signaling molecules, and transcription factors (1). The characteristic structural feature of the [...]

Causal Dispositionalism provides an account of causation based on an ontology of causal powers, properties with causal essence. According to the account, causation can be analysed in terms of the interaction of powers and its subsequent production of their effect. Recently, Baltimore, J. A. (2022. "Dispositionalism, Causation, and the Interaction Gap." Erkenntnis 87: 677–92) has raised a challenge against two competing approaches, the compositional view (CV) and the mutual manifestation view (MMV), to explain what makes powers interactive – the interaction gap. In this paper, we raise the challenge of explaining what makes powers productive – the production gap. While Baltimore's verdict is tentatively favouring (MMV), we find both approaches wanting. Our conclusion is that Causal Dispositionalists should take Baltimore's and our critique seriously. Powers cannot cause their effects just by bearing the name "causal". To deserve their names, more metaphysical details are needed. [ABSTRACT FROM AUTHOR]

Hepatic lipid homeostasis depends on intracellular pathways that respire fatty acid in peroxisomes and mitochondria, and on systemic pathways that secrete fatty acid into the bloodstream, either free or condensed in very-low-density lipoprotein (VLDL) triglycerides. These systemic and intracellular pathways are interdependent, but it is unclear whether and how they integrate into a single cellular circuit. Here, we report that mouse liver wrappER, a distinct endoplasmic reticulum (ER) compartment with apparent fatty acid- and VLDL-secretion functions, connects peroxisomes and mitochondria. Correlative light electron microscopy, quantitative serial section electron tomography and three-dimensional organelle reconstruction analysis show that the number of peroxisome-wrappER-mitochondria complexes changes throughout fasting-to-feeding transitions and doubles when VLDL synthesis stops following acute genetic ablation of Mttp in the liver. Quantitative proteomic analysis of peroxisome-wrappER-mitochondria complex-enriched fractions indicates that the loss of Mttp upregulates global fatty acid ß-oxidation, thereby integrating the dynamics of this three-organelle association into hepatic fatty acid flux responses. Therefore, liver lipid homeostasis occurs through the convergence of systemic and intracellular fatty acid-elimination pathways in the peroxisome-wrappER-mitochondria complex. [ABSTRACT FROM AUTHOR]

This paper aims to provide an analysis of the legislative framework that regulates the inclusion of clauses on good governance in tax matters, in the agreements concluded between the European Union, with its Member States, and third countries. We provide a representation of the regulatory pathway from a set of standards on tax good governance according to the principles of transparency, exchange of information and fair tax competition towards a common EU external strategy for effective taxation. Agreements that the European Union has either in place or negotiating with countries and regions around the world are an excellent tool in fighting unfair trade practices and promoting international standards on good governance in the tax area, and set the basis for a fair competition in the economy of developing countries: a strong tax administration and institutions responsible for fighting illicit financial flows in developing countries can contribute to erase poverty and inequalities while promoting good governance and state-building. [ABSTRACT FROM AUTHOR]

Brentano's (1874 : 88–89) suggestion that intentionality is the mark of the mental is typically spelled out in terms of the thesis that all and only mental states are intentional. An influential objection is that intentionality is not necessary for mentality (McGinn 1982 ; Dretske 1995 ; Deonna and Teroni 2012 ; Bordini 2017). What about the idea that only mental states are intentional? In his 2008 paper published in Analysis, Nes shows that on a popular characterization of intentionality, notably defended by Crane (2014 [1998] , 2001), some non-mental states come out as intentional. Crane (2008) replies that the concept of representation solves the problem. In this paper, I argue that no representational account of intentionality meets Nes's challenge. After distinguishing between two notions of representation, I contend that there are two versions of Crane's representational account, but neither of them is able to solve the problem posed by Nes. [ABSTRACT FROM AUTHOR]

Disorders of lysosomal physiology have increasingly been found to underlie the pathology of a rapidly growing cast of neurodevelopmental disorders and sporadic diseases of aging. One cardinal aspect of lysosomal (dys)function is lysosomal acidification in which defects trigger lysosomal stress signaling and defects in proteolytic capacity. We have developed a genetically encoded ratiometric probe to measure lysosomal pH coupled with a purification tag to efficiently purify lysosomes for both proteomic and in vitro evaluation of their function. Using our probe, we showed that lysosomal pH is remarkably stable over a period of days in a variety of cell types. Additionally, this probe can be used to determine that lysosomal stress signaling via TFEB is uncoupled from gross changes in lysosomal pH. Finally, we demonstrated that while overexpression of ARL8B GTPase causes striking alkalinization of peripheral lysosomes in HEK293 T cells, peripheral lysosomes per se are no less acidic than juxtanuclear lysosomes in our cell lines. Abbreviations: ARL8B: ADP ribosylation factor like GTPase 8B; ATP: adenosine triphosphate; ATP5F1B/ATPB: ATP synthase F1 subunit beta; ATP6V1A: ATPase H+ transporting V1 subunit A; Baf: bafilomycin A1; BLOC-1: biogenesis of lysosome-related organelles complex 1; BSA: bovine serum albumin; Cos7: African green monkey kidney fibroblast-like cell line; CQ: chloroquine; CTSB: cathepsin B; CYCS: cytochrome c, somatic; DAPI: 4′,6-diamidino −2- phenylindole; DIC: differential interference contrast; DIV: days in vitro; DMEM: Dulbecco′s modified Eagle′s medium;‎ E8: embryonic day 8; EEA1: early endosome antigen 1; EGTA: ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid; ER: endoplasmic reticulum; FBS: fetal bovine serum; FITC: fluorescein isothiocyanate; GABARAPL2: GABA type A receptor associated protein like 2; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GOLGA2/GM130: golgin A2; GTP: guanosine triphosphate; HEK293T: human embryonic kidney 293 cells, that expresses a mutant version of the SV40 large T antigen; HeLa: Henrietta Lacks-derived cell; HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; HRP: horseradish peroxidase; IGF2R/ciM6PR: insulin like growth factor 2 receptor; LAMP1/2: lysosomal associated membrane protein 1/2; LMAN2/VIP36: lectin, mannose binding 2; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; PCR: polymerase chain reaction; PDL: poly-d-lysine; PGK1p: promotor from human phosphoglycerate kinase 1; PIKFYVE: phosphoinositide kinase, FYVE-type zinc finger containing; PPT1/CLN1: palmitoyl-protein thioesterase 1; RPS6KB1/p70: ribosomal protein S6 kinase B1; STAT3: signal transducer and activator of transcription 3; TAX1BP1: Tax1 binding protein 1; TFEB: transcription factor EB; TGN: trans-Golgi network; TGOLN2/TGN46: trans-Golgi network protein 2; TIRF: total internal reflection fluorescence; TMEM106B: transmembrane protein 106B; TOR: target of rapamycin; TRPM2: transient receptor potential cation channel subfamily M member 2; V-ATPase: vacuolar-type proton-translocating ATPase; VPS35: VPS35 retromer complex component. [ABSTRACT FROM AUTHOR]

According to the quotational theory of meaning ascriptions, sentences like "'Bruder (in German) means brother" are abbreviated synonymy claims, such as "'Bruder (in German) means the same as 'brother'". After discussing a problem with Harman's (1999) version of the quotational theory, I present an amended version defended by Field (2001; 2017). Then, I address Field's responses to two arguments against the theory that revolve around translation and the understanding of foreign expressions. Afterwards, I formulate two original arguments against both Harman's and Field's versions of the theory. One of them targets the hyperintensionality of quotations and the other raises a problem pertaining to variant spellings of words. [ABSTRACT FROM AUTHOR]

Salivary Gland Surveillance: Pathogen sensing in tissues is critical to generating rapid immune responses. Within these tissues, macrophages and resident memory CD8+ T cells (TRM) work together to detect pathogens, and Stolp et al. use intravital imaging of submandibular salivary glands (SMG) to show that TRM follow tissue macrophage topology in a dynamic manner. Macrophage depletion is associated with reduced TRM motility and a diminished clustering in response to inflammatory chemokines. However, although SMG TRM respond to chemoattractants, autonomous motility is also observed and is mediated by friction and insertion of cellular protrusions into microenvironmental gaps. These findings demonstrate that SMG TRM can use different motility modes in proximity to tissue macrophages to patrol the tissue microenvironment. It is well established that tissue macrophages and tissue-resident memory CD8+ T cells (TRM) play important roles for pathogen sensing and rapid protection of barrier tissues. In contrast, the mechanisms by which these two cell types cooperate for homeostatic organ surveillance after clearance of infections is poorly understood. Here, we used intravital imaging to show that TRM dynamically followed tissue macrophage topology in noninflamed murine submandibular salivary glands (SMGs). Depletion of tissue macrophages interfered with SMG TRM motility and caused a reduction of interepithelial T cell crossing. In the absence of macrophages, SMG TRM failed to cluster in response to local inflammatory chemokines. A detailed analysis of the SMG microarchitecture uncovered discontinuous attachment of tissue macrophages to neighboring epithelial cells, with occasional macrophage protrusions bridging adjacent acini and ducts. When dissecting the molecular mechanisms that drive homeostatic SMG TRM motility, we found that these cells exhibit a wide range of migration modes: In addition to chemokine- and adhesion receptor–driven motility, resting SMG TRM displayed a remarkable capacity for autonomous motility in the absence of chemoattractants and adhesive ligands. Autonomous SMG TRM motility was mediated by friction and insertion of protrusions into gaps offered by the surrounding microenvironment. In sum, SMG TRM display a unique continuum of migration modes, which are supported in vivo by tissue macrophages to allow homeostatic patrolling of the complex SMG architecture. [ABSTRACT FROM AUTHOR]