Hemicentin mediated type IV collagen assembly strengthens juxtaposed basement membrane linkage

Basement membrane (BM) matrices surround and separate most tissues. However, through poorly understood mechanisms, BMs of adjacent tissues can also stably link to support organ structure and function. Using endogenous knock-in fluorescent proteins, conditional RNAi, optogenetics, and quantitative live imaging, we identified matrix proteins mediating a BM linkage (B-LINK) between the uterine utse and epidermal seam cell BMs in Caenorhabditis elegans that supports the uterus during egg-laying. We found that hemicentin is secreted by the utse and promotes fibulin-1 assembly to jointly initiate the B-LINK. During egg-laying, however, both proteins decline in levels and are not required for B-LINK maintenance. Instead, we discovered that hemicentin also promotes type IV collagen assembly, which accumulates to high levels during egg-laying and sustains the B-LINK during the mechanically active egg-laying period. This work reveals mechanisms underlying BM-BM connection maturation and identifies a crucial function for hemicentin and fibulin-1 in initiating attachment and type IV collagen in strengthening this specialized form of tissue linkage.

The Function of Immunoproteasomes—An Immunologists’ Perspective

Proteasomes are responsible for intracellular proteolysis and play an important role in cellular protein homeostasis. Cells of the immune system assemble a specialized form of proteasomes, known as immunoproteasomes, in which the constitutive catalytic sites are replaced for cytokine-inducible homologues. While immunoproteasomes may fulfill all standard proteasome’ functions, they seem specially adapted for a role in MHC class I antigen processing and CD8+ T-cell activation. In this way, they may contribute to CD8+ T-cell-mediated control of intracellular infections, but also to the immunopathogenesis of autoimmune diseases. Starting at the discovery of its catalytic subunits in the genome, here, we review the observations shaping our current understanding of immunoproteasome function, and the consequential novel opportunities for immune intervention.

Communication with self, friends and foes in active-sensing animals

ABSTRACT Animals that rely on electrolocation and echolocation for navigation and prey detection benefit from sensory systems that can operate in the dark, allowing them to exploit sensory niches with few competitors. Active sensing has been characterized as a highly specialized form of communication, whereby an echolocating or electrolocating animal serves as both the sender and receiver of sensory information. This characterization inspires a framework to explore the functions of sensory channels that communicate information with the self and with others. Overlapping communication functions create challenges for signal privacy and fidelity by leaving active-sensing animals vulnerable to eavesdropping, jamming and masking. Here, we present an overview of active-sensing systems used by weakly electric fish, bats and odontocetes, and consider their susceptibility to heterospecific and conspecific jamming signals and eavesdropping. Susceptibility to interference from signals produced by both conspecifics and prey animals reduces the fidelity of electrolocation and echolocation for prey capture and foraging. Likewise, active-sensing signals may be eavesdropped, increasing the risk of alerting prey to the threat of predation or the risk of predation to the sender, or drawing competition to productive foraging sites. The evolutionary success of electrolocating and echolocating animals suggests that they effectively counter the costs of active sensing through rich and diverse adaptive behaviors that allow them to mitigate the effects of competition for signal space and the exploitation of their signals.

English-Speaking Adults' Labeling of Child- and Adult-Directed Speech Across Languages and Its Relationship to Perception of Affect

Child-directed speech, as a specialized form of speech directed toward young children, has been found across numerous languages around the world and has been suggested as a universal feature of human experience. However, variation in its implementation and the extent to which it is culturally supported has called its universality into question. Child-directed speech has also been posited to be associated with expression of positive affect or “happy talk.” Here, we examined Canadian English-speaking adults' ability to discriminate child-directed from adult-directed speech samples from two dissimilar language/cultural communities; an urban Farsi-speaking population, and a rural, horticulturalist Tseltal Mayan speaking community. We also examined the relationship between participants' addressee classification and ratings of positive affect. Naive raters could successfully classify CDS in Farsi, but only trained raters were successful with the Tseltal Mayan sample. Associations with some affective ratings were found for the Farsi samples, but not reliably for happy speech. These findings point to a complex relationship between perception of affect and CDS, and context-specific effects on the ability to classify CDS across languages.

Structural and Functional Modulation of Perineuronal Nets: In Search of Important Players with Highlight on Tenascins

The extracellular matrix (ECM) of the brain plays a crucial role in providing optimal conditions for neuronal function. Interactions between neurons and a specialized form of ECM, perineuronal nets (PNN), are considered a key mechanism for the regulation of brain plasticity. Such an assembly of interconnected structural and regulatory molecules has a prominent role in the control of synaptic plasticity. In this review, we discuss novel ways of studying the interplay between PNN and its regulatory components, particularly tenascins, in the processes of synaptic plasticity, mechanotransduction, and neurogenesis. Since enhanced neuronal activity promotes PNN degradation, it is possible to study PNN remodeling as a dynamical change in the expression and organization of its constituents that is reflected in its ultrastructure. The discovery of these subtle modifications is enabled by the development of super-resolution microscopy and advanced methods of image analysis.

Pyroptosis targeting via mitochondria: an educated guess to fast-track COVID-19 therapies

Pyroptosis, is a specialized form of inflammatory cell death which aids the defensive response against invading pathogens. Its tight regulation is lost during infection by the severe acute respiratory coronavirus 2 (SARS-CoV-2) and thus uncontrolled pyroptosis disrupts the immune system and the integrity of organs defining the critical conditions in patients with high viral load. Molecular pathways engaged downstream to the formation and stabilization of the inflammasome -required to execute the process- have been uncovered and drugs are available for their regulation. On the contrary, pharmacological inferring of the upstream events -which are critical to sense and interpret the initial damage by the pathogen- is far from being elucidated. This limits our capacity to identify early markers and targets to ameliorate SARS-CoV-2 linked pyroptosis. Here we aim to raise attention on mitochondria and pathways leading to its dysfunction with the goal to inform early steps of inflammasome and devise tools to interpret and counteract diseases by the SARS-CoV-2.

Relevance of Autophagy and Mitophagy Dynamics and Markers in Neurodegenerative Diseases

During the past few decades, considerable efforts have been made to discover and validate new molecular mechanisms and biomarkers of neurodegenerative diseases. Recent discoveries have demonstrated how autophagy and its specialized form mitophagy are extensively associated with the development, maintenance, and progression of several neurodegenerative diseases. These mechanisms play a pivotal role in the homeostasis of neural cells and are responsible for the clearance of intracellular aggregates and misfolded proteins and the turnover of organelles, in particular, mitochondria. In this review, we summarize recent advances describing the importance of autophagy and mitophagy in neurodegenerative diseases, with particular attention given to multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease. We also review how elements involved in autophagy and mitophagy may represent potential biomarkers for these common neurodegenerative diseases. Finally, we examine the possibility that the modulation of autophagic and mitophagic mechanisms may be an innovative strategy for overcoming neurodegenerative conditions. A deeper knowledge of autophagic and mitophagic mechanisms could facilitate diagnosis and prognostication as well as accelerate the development of therapeutic strategies for neurodegenerative diseases.

Towards trustworthy blockchains: normative reflections on blockchain-enabled virtual institutions

This paper proposes a novel way to understand trust in blockchain technology by analogy with trust placed in institutions. In support of the analysis, a detailed investigation of institutional trust is provided, which is then used as the basis for understanding the nature and ethical limits of blockchain trust. Two interrelated arguments are presented. First, given blockchains’ capacity for being institution-like entities by inviting expectations similar to those invited by traditional institutions, blockchain trust is argued to be best conceptualized as a specialized form of trust in institutions. Keeping only the core functionality and certain normative ideas of institutions, this technology broadens our understanding of trust by removing the need for third parties while retaining the value of trust for the trustor. Second, the paper argues that blockchains’ decentralized nature and the implications and effects of this decentralization on trust issues are double-edged. With the erasure of central points, the systems simultaneously crowd out the pivotal role played by traditional institutions and a cadre of representatives in meeting their assigned obligations and securing the functional systems’ trustworthy performances. As such, blockchain is positioned as a technology containing both disruptive features that can be embedded with meaningful normative values and inherent ethical limits that pose a direct challenge to the actual trustworthiness of blockchain implementations. Such limits are proposed to be ameliorated by facilitating a shift of responsibility to the groups of people directly associated with the engendering of trust in the blockchain context.

LIKE GOLDEN APHRODITE: GRIEVING WOMEN IN THE HOMERIC EPICS AND APHRODITE'S LAMENT FOR ADONIS

One of the more powerful recurring motifs in the Iliad is that of the grief-stricken woman lamenting the death of a hero. As with much else in the Homeric epics, these scenes have a formulaic character; when Briseis laments Patroclus, and Hecuba, Andromache and Helen lament Hector, each is depicted delivering a specialized form of speech, specific to the context of a woman's lament. The narrative depiction of grieving women, as well, is formalized, with specific gestures and recurring images that typify these scenes. One element of this depiction that has largely escaped serious consideration is the comparison of a woman in her initial moment of recognition of the corpse to Aphrodite. In this article, I will argue that the allusion is not merely to her beauty but to the myth of Aphrodite and Adonis, specifically the moment of the goddess’ discovery of the death of her mortal lover. As the earliest surviving explicit reference to Adonis in Greek literature appears c.600 b.c.e., this would require a raising of the terminus ante quem for the transmission of the Adonis myth from the Near East to the mid eighth century.

The Mitochondrial Permeability Transition: Nexus of Aging, Disease and Longevity

The activity of the mitochondrial permeability transition pore, mPTP, a highly regulated multi-component mega-channel, is enhanced in aging and in aging-driven degenerative diseases. mPTP activity accelerates aging by releasing large amounts of cell-damaging reactive oxygen species, Ca2+ and NAD+. The various pathways that control the channel activity, directly or indirectly, can therefore either inhibit or accelerate aging or retard or enhance the progression of aging-driven degenerative diseases and determine lifespan and healthspan. Autophagy, a catabolic process that removes and digests damaged proteins and organelles, protects the cell against aging and disease. However, the protective effect of autophagy depends on mTORC2/SKG1 inhibition of mPTP. Autophagy is inhibited in aging cells. Mitophagy, a specialized form of autophagy, which retards aging by removing mitochondrial fragments with activated mPTP, is also inhibited in aging cells, and this inhibition leads to increased mPTP activation, which is a major contributor to neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases. The increased activity of mPTP in aging turns autophagy/mitophagy into a destructive process leading to cell aging and death. Several drugs and lifestyle modifications that enhance healthspan and lifespan enhance autophagy and inhibit the activation of mPTP. Therefore, elucidating the intricate connections between pathways that activate and inhibit mPTP, in the context of aging and degenerative diseases, could enhance the discovery of new drugs and lifestyle modifications that slow aging and degenerative disease.