The ability of lysosomes to move within the cytoplasm is important for many cellular functions. This ability is particularly critical in neurons, which comprise vast, highly differentiated domains such as the axon and dendrites. The mechanisms that control lysosome movement in these domains, however, remain poorly understood. Here we show that an ensemble of BORC, Arl8, SKIP, and kinesin-1, previously shown to mediate centrifugal transport of lysosomes in nonneuronal cells, specifically drives lysosome transport into the axon, and not the dendrites, in cultured rat hippocampal neurons. This transport is essential for maintenance of axonal growth-cone dynamics and autophagosome turnover. Our findings illustrate how a general mechanism for lysosome dispersal in nonneuronal cells is adapted to drive polarized transport in neurons, and emphasize the importance of this mechanism for critical axonal processes.

Summary Polarized sorting of newly-synthesized proteins to the somatodendritic and axonal domains of neurons occurs by selective incorporation into distinct populations of vesicular transport carriers. An unresolved issue is how the vesicles themselves become sorted to their corresponding neuronal domains. Previous studies concluded that the axon initial segment (AIS) is an actin-based filter that selectively prevents passage of somatodendritic vesicles into the axon. We find, however, that most somatodendritic vesicles fail to enter the axon at a more proximal region in the axon hillock herein referred to as the “pre-axonal exclusion zone” (PAEZ). Forced coupling of a somatodendritic cargo protein to an axonally-directed kinesin is sufficient to drive transport of whole somatodendritic vesicles through the PAEZ toward the distal axon. Based on these findings, we propose that polarized sorting of transport vesicles occurs at the PAEZ and depends on the ability of the vesicles to acquire an appropriately directed microtubule motor.

abbreviatioNs EOR = extent of resection; GBM = glioblastoma; GTR = gross-total resection; HR = hazard ratio; KPS = Karnofsky Performance Scale; RT = radiotherapy; SRS = stereotactic radiosurgery; STR = subtotal resection; TMZ = temozolomide. obJective The prognosis of elderly patients with glioblastoma (GBM) is universally poor. Currently, few studies have examined postoperative outcomes and the effects of various modern therapies such as bevacizumab on survival in this patient population. In this study, the authors evaluated the effects of various factors on overall survival in a cohort of elderly patients with newly diagnosed GBM. methods A retrospective review was performed of elderly patients (≥ 65 years old) with newly diagnosed GBM treated between 2004 and 2010. Various characteristics were evaluated in univariate and multivariate stepwise models to examine their effects on complication risk and overall survival. results A total of 120 patients were included in the study. The median age was 71 years, and sex was distributed evenly. Patients had a median Karnofsky Performance Scale (KPS) score of 80 and a median of 2 neurological symptoms on presentation. The majority (53.3%) of the patients did not have any comorbidities. Tumors most frequently (43.3%) involved the temporal lobe, followed by the parietal (35.8%), frontal (32.5%), and occipital (15.8%) regions. The majority (57.5%) of the tumors involved eloquent structures. The median tumor size was 4.3 cm. Every patient underwent resection, and 63.3% underwent gross-total resection (GTR). The vast majority (97.3%) of the patients received the postoperative standard of care consisting of radiotherapy with concurrent temozolomide. The majority (59.3%) of patients received additional agents, most commonly consisting of bevacizumab (38.9%). The median survival for all patients was 12.0 months; 26.7% of patients experienced long-term (≥ 2-year) survival. The extent of resection was seen to significantly affect overall survival; patients who underwent GTR had a median survival of 14.1 months, whereas those who underwent subtotal resection had a survival of 9.6 months (p = 0.038). Examination of chemotherapeutic effects revealed that the use of bevacizumab compared with no bevacizumab (20.1 vs 7.9 months, respectively; p < 0.0001) and irinotecan compared with no irinotecan (18.0 vs 9.7 months, respectively; p = 0.027) significantly improved survival. Multivariate stepwise analysis revealed that older age (hazard ratio coNclusioN This study has demonstrated that GTR confers a modest survival benefit on elderly patients with GBM, suggesting that safe maximal resection is warranted. In addition, bevacizumab significantly increased the overall survival of these elderly patients with GBM; older age and preoperative KPS score also were significant prognostic factors. Although elderly patients with GBM have a poor prognosis, they may experience enhanced survival after the administration of the standard of care and the use of additional chemotherapeutics such as bevaciz...

SUMMARY BORC is a multisubunit complex previously shown to promote coupling of mammalian lysosomes and C. elegans synaptic vesicle (SV) precursors (SVPs) to kinesins for anterograde transport of these organelles along microtubule tracks. We attempted to meld these observations into a unified model for axonal transport in mammalian neurons by testing two alternative hypotheses: (1) that SV and lysosomal proteins are co-transported within a single type of “lysosome-related vesicle” and (2) that SVPs and lysosomes are distinct organelles, but both depend on BORC for axonal transport. Analyses of various types of neurons from wild-type rats and mice, as well as from BORC-deficient mice, show that neither hypothesis is correct. We find that SVPs and lysosomes are transported separately, but only lysosomes depend on BORC for axonal transport in these neurons. These findings demonstrate that SVPs and lysosomes are distinct organelles that rely on different machineries for axonal transport in mammalian neurons.

Neurons are highly polarized cells exhibiting axonal and somatodendritic domains with distinct complements of cytoplasmic organelles. Although some organelles are widely distributed throughout the neuronal cytoplasm, others are segregated to either the axonal or somatodendritic domains. Recent findings show that organelle segregation is largely established at a pre-axonal exclusion zone (PAEZ) within the axon hillock. Polarized sorting of cytoplasmic organelles at the PAEZ is proposed to depend mainly on their selective association with different microtubule motors and, in turn, with distinct microtubule arrays. Somatodendritic organelles that escape sorting at the PAEZ can be subsequently retrieved at the axon initial segment (AIS) by a microtubule- and/or actin-based mechanism. Dynamic sorting along the PAEZ-AIS continuum can thus explain the polarized distribution of cytoplasmic organelles between the axonal and somatodendritic domains.

The study of polarized protein trafficking in live neurons is critical for understanding neuronal structure and function. Given the complex anatomy of neurons and the numerous trafficking pathways that are active in them, however, visualization of specific vesicle populations leaving the Golgi complex presents unique challenges. Indeed, several approaches used in non-polarized cells, and even in polarized epithelial cells, have been less successful in neurons. Here, we describe an adaptation of the recently developed Retention Using Selective Hooks (RUSH) system (Boncompain et al., Nat Methods 9:493-498, 2012), previously used in non-polarized cells, to analyze the polarized sorting of proteins from the Golgi complex to dendrites and axons in live neurons. The RUSH system involves the retention of a fluorescently tagged cargo protein fused to the streptavidin-binding peptide (SBP) in the endoplasmic reticulum (ER) through the expression of an ER-hook protein fused to streptavidin. Upon D-biotin addition, the cargo protein is released and its traffic to dendrites and axons can be analyzed in live neurons.

We study the connection of matter density and its tracers from the PDF perspective. One aspect of this connection is the conditional expectation value 〈δtracer|δm〉 when averaging both tracer and matter density over some scale. We present a new way to incorporate a Lagrangian bias expansion of this expectation value into standard frameworks for modelling the PDF of density fluctuations and counts-in-cells statistics. Using N-body simulations and mock galaxy catalogs we confirm the accuracy of this expansion and compare it to the more commonly used Eulerian parametrization. For halos hosting typical luminous red galaxies, the Lagrangian model provides a significantly better description of 〈δtracer|δm〉 at second order in perturbations. A second aspect of the matter-tracer connection is shot-noise, i.e. the scatter of tracer density around 〈δtracer|δm〉. It is well known that this noise can be significantly non-Poissonian and we validate the performance of a more general, two-parameter shot-noise model for different tracers and simulations. Both parts of our analysis are meant to pave the way for forthcoming applications to survey data.

A promising channel for producing binary black hole mergers is the Lidov-Kozai orbital resonance in hierarchical triple systems. While this mechanism has been studied in isolation, the distribution of such mergers in time and across star-forming environments is not well characterized. In this work, we explore Lidov-Kozai-induced black hole mergers in open clusters, combining semi-analytic and Monte Carlo methods to calculate merger rates and delay times for nine different population models. We predict a merger rate density of ∼1–10 Gpc−3 yr−1 for the Lidov-Kozai channel in the local universe, and all models yield delay-time distributions in which a significant fraction of binary black hole mergers (e.g. ∼20 per cent–50 per cent in our baseline model) occur during the open cluster phase. Our findings suggest that a substantial fraction of mergers from hierarchical triples occur within star-forming regions in spiral galaxies.