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Many neurodegenerative diseases including frontotemporal lobar degeneration (FTLD), Lewy body disease (LBD), multiple system atrophy (MSA), etc., show colocalized deposits of TDP-43 and α-synuclein (αS) aggregates. To understand whether these colocalizations are driven by specific molecular interactions between the two proteins, we previously showed that the prion-like C-terminal domain of TDP-43 (TDP-43PrLD) and αS synergistically interact to form neurotoxic heterotypic amyloids in homogeneous buffer conditions. However, it remains unclear if αS can modulate TDP-43 present within liquid droplets and biomolecular condensates called stress granules (SGs). Here, using cell culture and in vitro TDP-43PrLD – RNA liquid droplets as models along with microscopy, nanoscale AFM-IR spectroscopy, and biophysical analyses, we uncover the interactions of αS with phase-separated droplets. We learn that αS acts as a Pickering agent by forming clusters on the surface of TDP-43PrLD – RNA droplets. The aggregates of αS on these clusters emulsify the droplets by nucleating the formation of heterotypic TDP-43PrLD amyloid fibrils, structures of which are distinct from those derived from homogenous solutions. Together, these results reveal an intriguing property of αS to act as a Pickering agent while interacting with SGs and unmask the hitherto unknown role of αS in modulating TDP-43 proteinopathies.

 

We design online algorithms for the fair allocation of public goods to a set of N agents over a sequence of T rounds and focus on improving their performance using predictions. In the basic model, a public good arrives in each round, and every agent reveals their value for it upon arrival. The algorithm must irrevocably decide the investment in this good without exceeding a total budget of B across all rounds. The algorithm can utilize (potentially noisy) predictions of each agent’s total value for all remaining goods. The algorithm’s performance is measured using a proportional fairness objective, which informally demands that every group of agents be rewarded proportional to its size and the cohesiveness of its preferences. We show that no algorithm can achieve better than Θ(T/B) proportional fairness without predictions. With reasonably accurate predictions, the situation improves significantly, and Θ(log(T/B)) proportional fairness is achieved. We also extend our results to a general setting wherein a batch of L public goods arrive in each round and O(log(min(N,L) ·T/B)) proportional fairness is achieved. Our exact bounds are parameterized as a function of the prediction error, with performance degrading gracefully with increasing errors. 

Discretization-based approaches to solving online reinforcement learning problems are studied extensively on applications such as resource allocation and cache management. The two major questions in designing discretization-based algorithms are how to create the discretization and when to refine it. There are several experimental results investigating heuristic approaches to these questions but little theoretical treatment. In this paper, we provide a unified theoretical analysis of model-free and model-based, tree-based adaptive hierarchical partitioning methods for online reinforcement learning. We show how our algorithms take advantage of inherent problem structure by providing guarantees that scale with respect to the “zooming” instead of the ambient dimension, an instance-dependent quantity measuring the benignness of the optimal [Formula: see text] function. Many applications in computing systems and operations research require algorithms that compete on three facets: low sample complexity, mild storage requirements, and low computational burden for policy evaluation and training. Our algorithms are easily adapted to operating constraints, and our theory provides explicit bounds across each of the three facets. Funding: This work is supported by funding from the National Science Foundation [Grants ECCS-1847393, DMS-1839346, CCF-1948256, and CNS-1955997] and the Army Research Laboratory [Grant W911NF-17-1-0094]. Supplemental Material: The online appendix is available at https://doi.org/10.1287/opre.2022.2396 . 

We consider the problem of dividing limited resources to individuals arriving over T rounds. Each round has a random number of individuals arrive, and individuals can be characterized by their type (i.e., preferences over the different resources). A standard notion of fairness in this setting is that an allocation simultaneously satisfy envy-freeness and efficiency. The former is an individual guarantee, requiring that each agent prefers the agent’s own allocation over the allocation of any other; in contrast, efficiency is a global property, requiring that the allocations clear the available resources. For divisible resources, when the number of individuals of each type are known up front, the desiderata are simultaneously achievable for a large class of utility functions. However, in an online setting when the number of individuals of each type are only revealed round by round, no policy can guarantee these desiderata simultaneously, and hence, the best one can do is to try and allocate so as to approximately satisfy the two properties. We show that, in the online setting, the two desired properties (envy-freeness and efficiency) are in direct contention in that any algorithm achieving additive counterfactual envy-freeness up to a factor of L T necessarily suffers an efficiency loss of at least [Formula: see text]. We complement this uncertainty principle with a simple algorithm, Guarded-Hope, which allocates resources based on an adaptive threshold policy and is able to achieve any fairness–efficiency point on this frontier. Our results provide guarantees for fair online resource allocation with high probability for multiple resource and multiple type settings. In simulation results, our algorithm provides allocations close to the optimal fair solution in hindsight, motivating its use in practical applications as the algorithm is able to adapt to any desired fairness efficiency trade-off. Funding: This work was supported by the National Science Foundation [Grants ECCS-1847393, DMS-1839346, CCF-1948256, and CNS-1955997] and the Army Research Laboratory [Grant W911NF-17-1-0094]. Supplemental Material: The online appendix is available at https://doi.org/10.1287/opre.2022.2397 . 

We consider the problem of dividing limited resources to individuals arriving over T rounds. Each round has a random number of individuals arrive, and individuals can be characterized by their type (i.e. preferences over the different resources). A standard notion of 'fairness' in this setting is that an allocation simultaneously satisfy envy-freeness and efficiency. For divisible resources, when the number of individuals of each type are known upfront, the above desiderata are simultaneously achievable for a large class of utility functions. However, in an online setting when the number of individuals of each type are only revealed round by round, no policy can guarantee these desiderata simultaneously.We show that in the online setting, the two desired properties (envy-freeness and efficiency) are in direct contention, in that any algorithm achieving additive counterfactual envy-freeness up to a factor of LT necessarily suffers a efficiency loss of at least 1 / LT. We complement this uncertainty principle with a simple algorithm, Guarded-Hope, which allocates resources based on an adaptive threshold policy and is able to achieve any fairness-efficiency point on this frontier. 

Reinforcement learning (RL) has received widespread attention across multiple communities, but the experiments have focused primarily on large-scale game playing and robotics tasks. In this paper we introduce ORSuite, an open-source library containing environments, algorithms, and instrumentation for operational problems. Our package is designed to motivate researchers in the reinforcement learning community to develop and evaluate algorithms on operational tasks, and to consider the true multi-objective nature of these problems by considering metrics beyond cumulative reward. 

We develop a framework for designing simple and efficient policies for a family of online allocation and pricing problems that includes online packing, budget-constrained probing, dynamic pricing, and online contextual bandits with knapsacks. In each case, we evaluate the performance of our policies in terms of their regret (i.e., additive gap) relative to an offline controller that is endowed with more information than the online controller. Our framework is based on Bellman inequalities, which decompose the loss of an algorithm into two distinct sources of error: (1) arising from computational tractability issues, and (2) arising from estimation/prediction of random trajectories. Balancing these errors guides the choice of benchmarks, and leads to policies that are both tractable and have strong performance guarantees. In particular, in all our examples, we demonstrate constant-regret policies that only require resolving a linear program in each period, followed by a simple greedy action-selection rule; thus, our policies are practical as well as provably near optimal.