Spatial control of irreversible protein aggregation

Liquid cellular compartments spatially segregate from the cytoplasm and can regulate aberrant protein aggregation, a process linked to several medical conditions, including Alzheimer's and Parkinson's diseases. Yet the mechanisms by which these droplet-like compartments affect protein aggregation remain unknown. Here, we combine kinetic theory of protein aggregation and liquid-liquid phase separation to study the spatial control of irreversible protein aggregation in the presence of liquid compartments. We find that, even for weak interactions between the compartment constituents and the aggregating monomers, aggregates are strongly enriched inside the liquid compartment relative to the surrounding cytoplasm. We show that this enrichment is caused by a positive feedback mechanism of aggregate nucleation and growth which is mediated by a flux maintaining the phase equilibrium between the compartment and the cytoplasm. Our model predicts that the compartment volume that maximizes aggregate enrichment in the compartment is determined by the reaction orders of aggregate nucleation. The underlying mechanism of aggregate enrichment could be used to confine cytotoxic protein aggregates inside droplet-like compartments suggesting potential new avenues against aberrant protein aggregation. Our findings could also represent a common mechanism for the spatial control of irreversible chemical reactions in general

Editorial.

Welcome to the third issue of our journal . We are delighted to feature in this issue two peer-reviewed papers looking in detail at some of the outcomes of the ring-fenced money used for researcher development in the UK under the guise of Roberts funding. In her paper looking at impact of the training provided by this funding on late stage doctoral student researchers, Walsh and colleagues draw our attention to detailed analysis of impact via a variety of evaluation approaches. She also alerts us to the question of whether such development programmes should run alongside the traditional apprenticeship style training of such students. The second paper by Heading and colleagues provides a detailed example of a development programme event in information management and provides further evidence for impact of such training. Bai and Hudson move the focus to the research –teaching nexus and highlight the difficulty for TEFL staff in Chinese HEIs to develop a research strand in their careers. The importance in developing research capacity, providing support and mentoring to such staff is shown to be pivotal in their development. Finally conceptions of research from a variety of viewpoints are analyzed by Pitcher. Pitcher considers how the PhD itself, alongwith how the knowledge and outcomes of PhD research are perceived. In a preliminary survey of students on these matters, Pitcher highlights the importance of alignment with these concepts between student and supervisor thus avoiding difficulties between apprentice and supervisor as the research progresses which might inhibit development

Parvovirus B19 infection in pediatric transplant patients

Evidence of recent parvovirus virus infection (as determined by the presence of a positive IgM antibody titer) without other identified causes of anemia was found in 5 of 26 pediatric solid-organ transplant recipients evaluated for moderate-to-severe anemia between June 1990 and July 1991. Anemia tended to be chronic (median duration of anemia at the time of diagnosis was 12 weeks) and was associated with normal red blood cell indices in the absence of reticulocytes. The median age of the children at the time of presentation with anemia due to parvovirus was 1.8 years at a median time of 8 months after transplantation. Four of the 5 children were treated with i.v. immunoglobulin because of persistance of anemia requiring blood transfusions. A response characterized by an increase in reticulocyte count and normalization of hemoglobin was seen in each of these patients 2-4 weeks after treatment. The remaining patient experienced a spontaneous recovery from her anemia. Parvovirus infection should be included in the differential diagnosis of solid-organ transplant recipients presenting with severe anemia associated with low or absent reticulocytes

Shared Print on the Move: Collocating Collections

As university libraries devote increasing portions of staff time and budget dollars to electronic resources, many are looking for cost- and labor-efficient ways of storing and ensuring access to legacy print collections. Shared print repositories have emerged as one possible solution, but setting up a shared storage system is never easy. Issues of selection, preservation, access and use, and interoperability must be resolved, but first comes one pivotal question: Where are we going to put all these books? Collocating shared print storage is one answer. Rather than securing holdings in place, The Committee on Institutional Cooperation’s Shared Print Repository selects volumes for preservation from multiple universities, relocating materials as necessary to create a comprehensive print collection. Collocating the collection means more secure conditions can be maintained and better user services supported by holding some bodies of print content in common thus relieving each individual school of the obligation to commit the necessary resources to manage these resources on its own. Nonetheless, physically transferring items, but not ownership, to other locations creates specific challenges. This paper will explore the opportunities and issues associated with collocating shared print storage using the CIC Shared Print Repository as an example

Blue State Exodus?

American businesses and families are leaving Blue states in record numbers for destinations like Texas, Florida, and Georgia. This migration of people, businesses, and tax dollars has prompted claims of a “Blue state exodus” prompted by “leftist politicians imposing leftist ideology.” As expressed by Utah’s Senator Mike Lee, the “exodus” proves that “the Left’s policies don’t work.” But does the movement of taxpayers from Blue to Red states really signal a rejection of progressive policies? This Essay argues that, before accepting that interpretation, we should consider another possibility. Perhaps Blue states aren’t overly progressive, but insufficiently so. Paralyzed by political dynamics that keep them from offering affordable housing and addressing police violence, and prevented by the Supreme Court from taking aggressive action on gun violence and public health, Blue states are losing taxpayers and unable to attract Red state refugees seeking to escape punishing anti-Black, anti-choice, and anti-LGBTQ+ policies, in large measure because they’re unable to offer a sufficiently meaningful alternative to life in Red America to justify their higher cost of living. This account of the Blue state exodus has very different implications from Lee’s. It suggests that, rather than tacking to the center, Blue states should redouble efforts to prioritize affordability, stop subsidizing Red states, and position themselves to insist on a new national settlement—one in which civil rights, economic justice, and sound public administration are respected across the nation

Mechanics and kinetics of dynamic instability.

During dynamic instability, self-assembling microtubules (MTs) stochastically alternate between phases of growth and shrinkage. This process is driven by the presence of two distinct states of MT subunits, GTP- and GDP-bound tubulin dimers, that have different structural properties. Here, we use a combination of analysis and computer simulations to study the mechanical and kinetic regulation of dynamic instability in three-dimensional (3D) self-assembling MTs. Our model quantifies how the 3D structure and kinetics of the distinct states of tubulin dimers determine the mechanical stability of MTs. We further show that dynamic instability is influenced by the presence of quenched disorder in the state of the tubulin subunit as reflected in the fraction of non-hydrolysed tubulin. Our results connect the 3D geometry, kinetics and statistical mechanics of these tubular assemblies within a single framework, and may be applicable to other self-assembled systems where these same processes are at play

Enhanced potency of aggregation inhibitors mediated by liquid condensates

Liquid condensates are membraneless organelles that form via phase separation in living cells. These condensates provide unique heterogeneous environments that have much potential in regulating a range of biochemical processes from gene expression to filamentous protein aggregation—a process linked to Alzheimer's and Parkinson's diseases. Here we theoretically study the physical interplay between protein aggregation, its inhibition, and liquid-liquid phase separation. Our key finding is that the action of protein aggregation inhibitors can be strongly enhanced by liquid condensates. The physical mechanism of this enhancement relies on the partitioning and colocalization of inhibitors with their targets inside the liquid condensate. Our theory uncovers how the physicochemical properties of condensates can be used to modulate inhibitor potency, and we provide experimentally testable conditions under which drug potency is maximal. Our findings suggest design principles for protein aggregation inhibitors with respect to their phase-separation properties