Protein synthesis is supported by cellular machineries that ensure polypeptides fold to their native conformation, whilst eliminating misfolded, aggregation prone species. Protein aggregation underlies pathologies including neurodegeneration. Aggregates’ formation is antagonised by molecular chaperones, with cytoplasmic machinery resolving insoluble protein aggregates. However, it is unknown whether an analogous disaggregation system exists in the Endoplasmic Reticulum (ER) where ~30% of the proteome is synthesised. Here we show that the ER of a variety of mammalian cell types, including neurons, is endowed with the capability to resolve protein aggregates under stress. Utilising a purpose-developed protein aggregation probing system with a sub-organellar resolution, we observe steady-state aggregate accumulation in the ER. Pharmacological induction of ER stress does not augment aggregates, but rather stimulate their clearance within hours. We show that this dissagregation activity is catalysed by the stress-responsive ER molecular chaperone – BiP. This work reveals a hitherto unknow, non-redundant strand of the proteostasis-restorative ER stress response.
Monday, May 16, 2022
The post today (my 80th birthday) points to experimental results relevant to my interest in not losing my marbles anytime soon. Fauzia points to work by Avezov and collaborators (open source) showing that the accumulation of aggregates of misfolded proteins in the endoplasmic reticulum of brain cells that is associated with dementia and Alzheimer's can be reversed by stressing cells with chemicals or heat, activating molecular chaperones that in turn untangle or remove protein aggregates. How much stress is just enough, but not to much, isn't clear. The abstract of the work:
Friday, May 13, 2022
It is hard to keep up with the mind boggling advances that pop up in almost every issue of Science Magazine. In a perspective article Liu and Zhang describe the findings of the “Tabula Sapiens Consortium” that has now provided a molecular reference atlas for more than 400 cell types of the human body by measuring the messenger RNA molecules in each of nearly 500,000 cells from 24 tissues and organs. Multiple laboratories used single-cell transcriptomics to measure the messenger RNA molecules in each of nearly 500,000 cells from 24 tissues and organs Here is a single clip summary clip from Liu and Zhang:
...the Tabula Sapiens Consortium discovered that endothelial cells from lung, heart, uterus, liver, pancreas, fat, and muscle exhibit the most distinct transcriptional signatures, suggesting highly specialized functions, whereas endothelial cells from the thymus, vasculature, prostate, and eye resemble one another. The pan-tissue approach led to the discovery of SLC14A1 (solute carrier family 14 member 1) as a marker for heart endothelial cells, likely reflecting specialized metabolism in cardiac blood vessels. Eraslan et al. also found rare cell types, such as neuroendocrine cells in the prostate and enteric neurons in the esophagus. Additionally, the corroborative use of both high-throughput 10X and full-length SMART-seq2 single-cell transcriptome data allowed the quantification of splicing isoform usage at the single-cell level, thereby revealing differential exon usage patterns for genes, including MYL6 (myosin light chain 6) and CD47, in different cell-type compartments.
Wednesday, May 11, 2022
An interesting study from Boxell et al. shows that across 12 advanced democracies, affective polarization, the degree to which people feel more negatively toward other political parties than toward their own, has increased the most since the 1980s in the United States and to a lesser extent in Canada, Denmark, France, New Zealand, and Switzerland, and has decreased in Australia, Britain, (West) Germany, Japan, Norway, and Sweden. The authors derived theses conclusions from harmonizing results from 149 surveys and assembled data on economic, media, demographic, and political trends. Trends in the nonwhite share of the population and in the polarization of political elites were most strongly associated with trends in polarization of the general public.
Monday, May 09, 2022
I would like to pass on this link to Graziano's latest (open source) explication of his theory of consciousness, continuing a MindBlog thread that started with a 2014 post on his 2013 book "Consciousness and the Social Brain." Here is his abstact:
This article argues that consciousness has a logically sound, explanatory framework, different from typical accounts that suffer from hidden mysticism. The article has three main parts. The first describes background principles concerning information processing in the brain, from which one can deduce a general, rational framework for explaining consciousness. The second part describes a specific theory that embodies those background principles, the Attention Schema Theory. In the past several years, a growing body of experimental evidence—behavioral evidence, brain imaging evidence, and computational modeling—has addressed aspects of the theory. The final part discusses the evolution of consciousness. By emphasizing the specific role of consciousness in cognition and behavior, the present approach leads to a proposed account of how consciousness may have evolved over millions of years, from fish to humans. The goal of this article is to present a comprehensive, overarching framework in which we can understand scientifically what consciousness is and what key adaptive roles it plays in brain function.The article is worth a read, and here is Graziano's bottom line, from the last paragraph of his article:
If you start your search for consciousness by assuming the existence of a subjective feeling—a private component that cannot be measured and can only be felt and attested to, experienceness itself—then you are assuming the literal accuracy of an internal model. By principle 1, your conviction that you have consciousness depends on an information set in your brain. By principle 2, the brain’s models are never accurate. You have accepted the literal truth of a caricature, and you will never find the answer to your ill-posed question. When the police draw a sketch of a suspect, and you set yourself the task of finding a flat man made of graphite, you will fail. Yet at the same time, if you take the opposite approach and insist that the sketch is an empty illusion, you are missing the point. Instead, understand the sketch for what it is: a schematic representation of something real. We can explain physical processes in the brain; we can explain the models constructed by the brain to represent those physical processes; we can explain the way those models depict reality in a schematic, imperfect manner; we can explain the cognitive beliefs that stem from those imperfect models; and most importantly, we can explain the adaptive, cognitive benefits served by those models. AST is not just a theory of consciousness. It is a theory of adaptive mechanisms in the brain.
Schaefer et al. (open source) examine the neural underpinnings of how light touching enhances prosocial behavior. Their abstract:
Giving and receiving touch are some of the most important social stimuli we exchange in daily life. By touching someone, we can communicate various types of information. Previous studies have also demonstrated that interpersonal touch may affect our altruistic behavior. A classic study showed that customers give bigger tips when they are lightly touched by a waitress, which has been called the Midas touch effect. Numerous studies reported similar effects of touch on different kinds of helping or prosocial behaviors. Here, we aim to examine the neural underpinnings of this effect by employing a functional magnetic resonance imaging approach. While lying in the scanner, participants played different rounds of the dictator game, a measure of prosocial behavior. Before each round, participants were touched (or not touched in the control condition) by an experimenter. We found that touching the hand increased the likeliness to behave prosocial (but not the general liking of control stimuli), thereby confirming the Midas touch effect. The effect was predicted by activity in the primary somatosensory cortex, indicating that the somatosensory cortex here plays a causal role in prosocial behavior. We conclude that the tactile modality in social life may be much more important than previously thought.
Thursday, May 05, 2022
From DeCasien et al.:
New research has questioned or contradicted multiple long-standing claims about human brain evolution.
Contrary to the social brain hypothesis, new work suggests that ecological factors, rather than social complexity, best predict relative brain size across primate species.
Brain size does not have similar effects or cognitive implications in different phylogenetic lineages since it is associated with different mosaic structural changes.
Although the human prefrontal cortex is proportionally large, this may not represent an adaptive specialization and research emphasis on this region has distracted attention from the importance of wider neural networks.
Functional and anatomical integration, rather than developmental constraints, may primarily explain patterns of brain region size covariation across species.Abstract
Human brains are exceptionally large, support distinctive cognitive processes, and evolved by natural selection to mediate adaptive behavior. Comparative biology situates the human brain within an evolutionary context to illuminate how it has been shaped by selection and how its structure relates to evolutionary function, while identifying the developmental and molecular changes that were involved. Recent applications of powerful phylogenetic methods have uncovered new findings, some of which overturn conventional wisdom about how and why brains evolve. Here, we focus on four long-standing claims about brain evolution and discuss how new work has either contradicted these claims or shown the relevant phenomena to be more complicated than previously appreciated. Throughout, we emphasize studies of non-human primates and hominins, our close relatives and recent ancestors.The authors dispute the following common claims about human brain evolution: (Motivated readers can obtain the whole text with their detailed arguments from me.)
Claim 1. Social complexity is the primary driver of non-human primate and human brain evolution
Claim 2. Brain size has similar effects and cognitive implications across a wide range of species
Claim 3. The proportionally large human PFC reflects selection on PFC-specific functions
Claim 4. Developmental constraints play a major role in the evolution of brain structure
Tuesday, May 03, 2022
From Amer et al.:
Healthy aging is accompanied by declines in control of attention.
These reductions in the control of attention, result in older adults processing too much information, creating cluttered memory representations.
Cluttered representations can impair memory by interfering with the retrieval of target information, but can also provide an advantage on tasks that benefit from extensive knowledge.
Declines in episodic memory in older adults are typically attributed to differences in encoding strategies and/or retrieval processes. These views omit a critical factor in age-related memory differences: the nature of the representations that are formed. Here, we review evidence that older adults create more cluttered (or richer) representations of events than do younger adults. These cluttered representations might include target information along with recently activated but no-longer-relevant information, prior knowledge cued by the ongoing situation, as well as irrelevant information in the current environment. Although these representations can interfere with the retrieval of target information, they can also support other memory-dependent cognitive functions.
Monday, May 02, 2022
On the same morning last week that I read a NYTimes essay by Thomas Edsall "The Politics of Fear Show No Sign of Abating" I received an email from the journal Behavioral and Brain Science soliciting reviews on an upcoming article by Tobias Grossmann with an interesting hypothesis on why we humans are so fearful: "The human fear paradox: Affective origins of cooperative care." His 'fearful ape hypothesis' proposes that, in the context of the strong interdependence reflected in cooperative caregiving and provisioning unique to human great ape group life, heightened fearfulness was adaptive. Here I pass on the abstract of Grossmann's piece, and motivated readers can obtain the whole text from me.
Already as infants humans are more fearful than our closest living primate relatives, the chimpanzees. Yet heightened fearfulness is mostly considered maladaptive, as it is thought to increase the risk of developing anxiety and depression. How can this human fear paradox be explained? The fearful ape hypothesis presented herein stipulates that, in the context of cooperative caregiving and provisioning unique to human great ape group life, heightened fearfulness was adaptive. This is because from early in ontogeny fearfulness expressed and perceived enhanced care-based responding and provisioning from, while concurrently increasing cooperation with, mothers and others. This explanation is based on a synthesis of existing research with human infants and children, demonstrating a link between fearfulness, greater sensitivity to and accuracy in detecting fear in others, and enhanced levels of cooperative behaviors. These insights critically advance current evolutionary theories of human cooperation by adding an early-developing affective component to the human cooperative makeup. Moreover, the current proposal has important cultural, societal and health implications, as it challenges the predominant view in WEIRD societies that commonly construe fearfulness as a maladaptive trait, potentially ignoring its evolutionary adaptive functions.