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Eph receptor tyrosine kinases participate in a variety of normal and pathogenic processes during development and throughout adulthood. This versatility is likely facilitated by the ability of Eph receptors to signal through diverse cellular signalling pathways: primarily by controlling cytoskeletal dynamics, but also by regulating cellular growth, proliferation, and survival. Despite many proteins linked to these signalling pathways interacting with Eph receptors, the specific mechanisms behind such links and their coordination remain to be elucidated. In a proteomics screen for novel EPHB2 multi-effector proteins, we identified human MYC binding protein 2 (MYCBP2 or PAM or Phr1). MYCBP2 is a large signalling hub involved in diverse processes such as neuronal connectivity, synaptic growth, cell division, neuronal survival, and protein ubiquitination. Our biochemical experiments demonstrate that the formation of a complex containing EPHB2 and MYCBP2 is facilitated by FBXO45, a protein known to select substrates for MYCBP2 ubiquitin ligase activity. Formation of the MYCBP2-EPHB2 complex does not require EPHB2 tyrosine kinase activity and is destabilised by binding of ephrin-B ligands, suggesting that the MYCBP2-EPHB2 association is a prelude to EPHB2 signalling. Paradoxically, the loss of MYCBP2 results in increased ubiquitination of EPHB2 and a decrease of its protein levels suggesting that MYCBP2 stabilises EPHB2. Commensurate with this effect, our cellular experiments reveal that MYCBP2 is essential for efficient EPHB2 signalling responses in cell lines and primary neurons. Finally, our genetic studies in Caenorhabditis elegans provide in vivo evidence that the ephrin receptor VAB-1 displays genetic interactions with known MYCBP2 binding proteins. Together, our results align with the similarity of neurodevelopmental phenotypes caused by MYCBP2 and EPHB2 loss of function, and couple EPHB2 to a signalling effector that controls diverse cellular functions.

Cytoplasmic accumulation of TDP-43 in motor neurons is the most prominent pathological feature in amyotrophic lateral sclerosis (ALS). A feedback cycle between nucleocytoplasmic transport (NCT) defect and TDP-43 aggregation was shown to contribute to accumulation of TDP-43 in the cytoplasm. However, little is known about cellular factors that can control the activity of NCT, thereby affecting TDP-43 accumulation in the cytoplasm. Here, we identified via FRAP and optogenetics cytosolic calcium as a key cellular factor controlling NCT of TDP-43. Dynamic and reversible changes in TDP-43 localization were observed in Drosophila sensory neurons during development. Genetic and immunohistochemical analyses identified the cytosolic calcium-Calpain-A-Importin α3 pathway as a regulatory mechanism underlying NCT of TDP-43. In C9orf72 ALS fly models, upregulation of the pathway activity by increasing cytosolic calcium reduced cytoplasmic accumulation of TDP-43 and mitigated behavioral defects. Together, these results suggest the calcium-Calpain-A-Importin α3 pathway as a potential therapeutic target of ALS.

Due to their enormous surface area compared to other cell types, neurons face unique challenges in properly handling supply and retrieval of the plasma membrane (PM)—a process termed PM turnover—in their distal areas. Because of the length and extensiveness of dendritic branches in neurons, the transport of materials needed for PM turnover from soma to distal dendrites will be inefficient and quite burdensome for somatic organelles. To meet local demands, PM turnover in dendrites most likely requires local cellular machinery, such as dendritic endocytic and secretory systems, dysregulation of which may result in dendritic pathology observed in various neurodegenerative diseases (NDs). Supporting this notion, a growing body of literature provides evidence to suggest the pathogenic contribution of dysregulated PM turnover to dendritic pathology in certain NDs. In this article, we present our perspective view that impaired dendritic endocytic and secretory systems may contribute to dendritic pathology by encumbering PM turnover in NDs.

R-trees have been popular for their support of multidimensional data and high-performing queries. FBR-tree is the state-of-the-art concurrent variant of the R-tree for Intel DC Persistent Memory (DCPM). However, its adoption on manycore servers is impeded by concurrency limitations due to lengthy, lock-based synchronization, including structure modification operations, split and merge. Additionally, emerging DCPM-based machines are equipped with multiple CPU sockets, forming a non-uniform memory access (NUMA) architecture. FBR-tree’s lack of NUMA-awareness induces further performance overhead from remote memory accesses. In this paper, we propose MPR-tree, a concurrent, NUMA-aware and persistent future-based R-tree for DCPM servers. MPR-tree focuses on insert operations due to their laborious nature. MPR-tree relies on per-thread local future objects and a global R-tree. To introduce NUMA-awareness and minimize remote memory accesses, MPR-tree adopts per-socket dedicated asynchronous evaluate threads to checkpoint future objects to the global R-tree. MPR-tree employs an in-memory hash table to mitigate the read overhead of key searches over the future objects. We implemented MPR-tree atop FBR-tree and evaluated its performance on a server with 40 physical cores for insert and lookup queries, and it showed that MPR-tree outperforms FBR-tree on average by $2\times $ on log10 scale.

Over the past few years, various indexes have been redesigned for byte-addressable persistent memory. In this work, we design and implement PB+tree (Pivotal B+tree) that resolves the limitations of state-of-the-art fully persistent B+trees. First, PB+tree reduces the number of expensive shift operations by up to half by managing two sub-arrays separated by a pivot key. Second, PB+tree reads cachelines in ascending order, which makes PB+tree benefit from hardware prefetchers and run faster than state-of-the-art persistent B+trees that access cachelines in non-contiguous or descending order. Third, PB+tree employs an optimistic lock-free search algorithm to avoid repeatedly visiting the same tree node. Although the optimistic lock-free search algorithm involves a risk of visiting incorrect child nodes, PB+tree guarantees correct search results using the lazy correction algorithm using doubly linked sibling pointers. Our performance study shows that PB+tree outperforms the state-of-the-art fully persistent indexes by a large margin. A search algorithm without optimistic locking risks visiting the wrong child node, but PB+tree uses a lazy correction algorithm with doubly linked sibling pointers to ensure correct search results. Our performance studies show that PB+trees outperform state-of-the-art fully persistent indexes.