repeat expansion creates the unstable folate-sensitive fragile site FRA9A.

The hyper-unstable Chr9p21 locus, harbouring the interferon gene cluster, oncogenes and , is linked to multiple diseases. (GGGGCC)n expansions (Exp) are associated with incompletely penetrant amyotrophic lateral sclerosis, frontotemporal dementia and autoimmune disorders. Exp patients display hyperactive cGAS-STING-linked interferon immune and DNA damage responses, but the source of immunostimulatory or damaged DNA is unknown.

Identity and nature of neural stem cells in the adult human subventricular zone.

The existence of neural stem cells (NSCs) in adult human brain neurogenic regions remains unresolved. To address this, we created a cell atlas of the adult human subventricular zone (SVZ) derived from fresh neurosurgical samples using single-cell transcriptomics. We discovered 2 adult radial glia (RG)-like populations, aRG1 and aRG2.

Mitochondria and endomembrane origins.

In this Guest Editorial, Heidi McBride introduces our special issue on membranes with a discussion of the contribution of mitochondria to the emergence of the endomembrane system.

Membrane dynamics and organelle biogenesis-lipid pipelines and vesicular carriers.

Discoveries spanning several decades have pointed to vital membrane lipid trafficking pathways involving both vesicular and non-vesicular carriers. But the relative contributions for distinct membrane delivery pathways in cell growth and organelle biogenesis continue to be a puzzle. This is because lipids flow from many sources and across many paths via transport vesicles, non-vesicular transfer proteins, and dynamic interactions between organelles at membrane contact sites.

The mitochondria-endoplasmic reticulum contact sites: a signalling platform for cell death.

Mitochondria evolved as an endosymbiont providing the cell with a dizzying array of catabolic and anabolic processes essential for life. However, mitochondria have retained the ability to kill from within, and are widely considered the final executioners of programmed cell death. The groundbreaking discovery over 25 years ago that mitochondrial cytochrome c is released into the cytosol shone new and unexpected light onto this old organelle, revitalizing the field.

Benefit of re-operation and salvage therapies for recurrent glioblastoma multiforme: results from a single institution.

The optimal management of recurrent glioblastoma (GBM) has yet to be determined. We aim to assess the benefits of re-operation and salvage therapies (chemotherapy and/or re-irradiation) for recurrent GBM and to identify prognostic factors associated with better survival. All patients who underwent surgery for GBM between January 2005 and December 2012 followed by adjuvant radiotherapy, and who developed GBM recurrence on imaging were included in this retrospective study.

Parkinson's Disease-Related Proteins PINK1 and Parkin Repress Mitochondrial Antigen Presentation.

Antigen presentation is essential for establishing immune tolerance and for immune responses against infectious disease and cancer. Although antigen presentation can be mediated by autophagy, here we demonstrate a pathway for mitochondrial antigen presentation (MitAP) that relies on the generation and trafficking of mitochondrial-derived vesicles (MDVs) rather than on autophagy/mitophagy. We find that PINK1 and Parkin, two mitochondrial proteins linked to Parkinson's disease (PD), actively inhibit MDV formation and MitAP.

Comparison of radiation regimens in the treatment of Glioblastoma multiforme: results from a single institution.

Background: The optimal fractionation schedule of radiotherapy (RT) for Glioblastoma multiforme (GBM) is yet to be determined. We aim to compare different fractionation regimens and identify prognostic factors to better tailor RT for newly diagnosed GBM patients.

Methods: All data for patients who underwent surgery for GBM between January 2005 and December 2012 were compiled.

Open questions: seeking a holistic approach for mitochondrial research.

In addition to their role as energy generators, mitochondria play critical and active roles in diverse signalling pathways, from immunity to cell survival and cell fate decisions. However, there remain many open questions and challenges as we work towards integrating this mighty organelle into established paradigms of cellular physiology.

Robo3: the road taken.

Although axon guidance mechanisms are well conserved across the animal kingdom, neuronal circuit complexity increases dramatically in evolution. Reporting recently in Neuron, Zelina et al. (2014) uncover mammalian-specific changes in Robo3 that result in a switch from repellent to attractive signaling and may have contributed to increased mammalian circuit complexity.

Short Interval Infield Sarcoma Development following Resection of Glioblastoma and Adjuvant Radiotherapy and Temozolomide.

Background. The development of 2 unassociated brain cancers in the same patient is a rare occurrence. Secondary cancers are generally thought to develop as an oncogenic consequence of the radiation therapy delivered to treat the primary cancers, always requiring a significant time interval between radiation treatment and secondary cancer development.

Large dynamic range digital nanodot gradients of biomolecules made by low-cost nanocontact printing for cell haptotaxis.

A novel method is introduced for ultrahigh throughput and ultralow cost patterning of biomolecules with nanometer resolution and novel 2D digital nanodot gradients (DNGs) with mathematically defined slopes are created. The technique is based on lift-off nanocontact printing while using high-resolution photopolymer stamps that are rapidly produced at a low cost through double replication from Si originals. Printed patterns with 100 nm features are shown.

Neurologic determination of death.

Death determined by neurologic criteria or brain death is better understood as brain arrest or the final clinical expression of complete and irreversible neurologic failure. Despite widespread national, international, and legal acceptance of the concept, substantial variation exists in the standards and their application, and there remains a need to clarify and standardize terminology (eg, ancillary and supplementary testing, brain death, or neurologic determination of death). The aim of this article is to review the specific criteria and requirements of brain death, paying special attention to areas of controversy and practice inconsistency.

A p75(NTR) pivoting paradigm propels perspicacity.

The p75 neurotrophin receptor (p75(NTR)) is involved in numerous neuronal signaling paths but its fundamental signaling mechanisms are unknown. In this issue of Neuron, Vilar et al. show that p75NTR functions as a covalently crosslinked dimer to transduce NGF-induced signaling events.

Graded expression of netrin-1 by specific neuronal subtypes in the adult mammalian striatum.

Netrins are a family of secreted proteins that function as axon guidance cues during neural development. High levels of netrin-1 expressed by the embryonic ganglionic eminence, the precursor of the adult striatum, direct axons that pioneer the internal capsule. Here we describe netrin-1 expression by neurons distributed throughout the striatum of the adult mouse.

Shopping centers in the brain.

Knutson et al. performed functional MRI on individuals while the subjects were deciding whether or not to purchase various items. Their results, reported in this issue of Neuron, support the theory that the decision to purchase involves the integration of emotional signals related to the anticipation of both obtaining the desired product and suffering the financial loss of paying for it.

High affinity not in the vicinity?

Functional interactions between the p75 neurotrophin receptor (p75NTR) and the Trk receptors were demonstrated several years ago, but their mechanistic basis remains uncertain. In this issue of Neuron, Wehrman et al. provide a three-dimensional structure of the full TrkA ectodomain complexed to NGF and examine the possibility of a ternary p75NTR-NGF-TrkA complex.

p75 neurotrophin receptor reduces ligand-induced Trk receptor ubiquitination and delays Trk receptor internalization and degradation.

Target-derived neurotrophins regulate neuronal survival and growth by interacting with cell-surface tyrosine kinase receptors. The p75 neurotrophin receptor (p75 NTR) is coexpressed with Trk receptors in long-range projection neurons, in which it facilitates neurotrophin binding to Trk and enhances Trk activity. Here, we show that TrkA and TrkB receptors undergo robust ligand-dependent ubiquitination that is dependent on activation of the endogenous Trk activity of the receptors.

ApTrkl, a Trk-like receptor, mediates serotonin- dependent ERK activation and long-term facilitation in Aplysia sensory neurons.

The Trk family of receptor tyrosine kinases plays a role in synaptic plasticity and in behavioral memory in mammals. Here, we report the discovery of a Trk-like receptor, ApTrkl, in Aplysia. We show that it is expressed in the sensory neurons, the locus for synaptic facilitation, which is a cellular model for memory formation.

p75NTR is positively promiscuous: novel partners and new insights.

Although identified almost 20 years ago, the precise physiological role of the p75 neurotrophin receptor (p75NTR) has remained elusive. Recent studies have revealed that p75NTR is a component of three distinct receptor platforms that bind different ligands and that, under differing circumstances, facilitate cell survival, cell death, or growth inhibition. These recent developments provide new insights into the functions of this enigmatic receptor.

Multiple paths towards repair in multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS, affecting approximately 1/1000 individuals in the Western world. Available treatments limit CNS inflammation and strategies to repair damage in the CNS offer the potential of recovery of both tissue and function. With further fundamental knowledge developing, this area is ripe for 'translation' to clinical application.

NRAGE, a p75 neurotrophin receptor-interacting protein, induces caspase activation and cell death through a JNK-dependent mitochondrial pathway.

The p75 neurotrophin receptor (p75NTR) mediates signaling events leading to activation of the JNK pathway and cell death in a variety of cell types. We recently identified NRAGE, a protein that directly interacts with the p75NTR cytosolic region and facilitates p75NTR-mediated cell death. For the present study, we developed an inducible recombinant NRAGE adenovirus to dissect the mechanism of NRAGE-mediated apoptosis.

Neurotrophin signaling through the p75 neurotrophin receptor.

The neurotrophins are growth factors that play critical roles in the development, maintenance, survival, and death of the nervous system. The signal transducing systems that mediate the diverse biological functions of the neurotrophins are initiated by their interactions with two categories of cell surface receptors, the Trk family of tyrosine kinases and the p75 neurotrophin receptor (p75NTR). While the Trk receptors are responsible for most of the survival and growth properties of the neurotrophins, the actions of p75NTR fall into two categories.

Retrograde signaling by the neurotrophins follows a well-worn trk.

The mechanism that allows a neuron to send cues received at its terminal to its cell body and nucleus has proved elusive. However, a recent study by Howe and colleagues indicates that neurotrophin signaling via the trkA receptor requires formation of a signaling endosome containing NGF and trkA. Thus, endocytosis of the neurotrophin-receptor complex is a crucial step in the generation of intracellular signaling platforms required for activation and compartmentalization of signaling events.

The p75 neurotrophin receptor (p75NTR) alters tumor necrosis factor-mediated NF-kappaB activity under physiological conditions, but direct p75NTR-mediated NF-kappaB activation requires cell stress.

The p75 neurotrophin receptor (p75NTR) has been linked to activation of the NF-kappaB transcriptional complex in oligodendrocytes, Schwann cells, and PCNA cells. In this report, tumor necrosis factor (TNF)- and neurotrophin-mediated NF (nuclear factor)-kappaB activation were compared in several cell lines. All cell types showed TNF-mediated activation of NF-kappaB, but direct neurotrophin-dependent activation of NF-kappaB was never observed under normal growth conditions.