The IB kinase (IKK) complex acts as a gatekeeper of canonical NF-B signaling in response to upstream stimulation. IKK activation requires sensing of ubiquitin chains by the essential IKK regulatory subunit IKK␥/NEMO. However, it has remained enigmatic whether NEMO binding to Lys-63-linked or linear ubiquitin chains is critical for triggering IKK activation. We show here that the NEMO C terminus, comprising the ubiquitin binding region and a zinc finger, has a high preference for binding to linear ubiquitin chains. However, immobilization of NEMO, which may be reminiscent of cellular oligomerization, facilitates the interaction with Lys-63 ubiquitin chains. Moreover, selective mutations in NEMO that abolish association with linear ubiquitin but do not affect binding to Lys-63 ubiquitin are only partially compromising NF-B signaling in response to TNF␣ stimulation in fibroblasts and T cells. In line with this, TNF␣-triggered expression of NF-B target genes and induction of apoptosis was partially compromised by NEMO mutations that selectively impair the binding to linear ubiquitin chains. Thus, in vivo NEMO interaction with linear and Lys-63 ubiquitin chains is required for optimal IKK activation, suggesting that both type of chains are cooperating in triggering canonical NF-B signaling.Induction of gene expression by the transcription factor NF-B controls many physiological processes, including immunity, differentiation, or apoptosis. The IB kinase (IKK) 3 complex acts as the gatekeeper of canonical NF-B signaling. In response to extracellular stimuli, IKKs become activated and catalyze the phosphorylation of NF-B inhibitors (IBs), leading to their ubiquitination and proteasomal degradation (1, 2). The IKK complex consists of the two catalytic domains IKK␣ and IKK␤ and the regulatory subunit IKK␥ or NF-B essential modulator (NEMO). NEMO mutations scattered throughout the entire gene are causing severe pathologies such as anhidrotic ectodermal dysplasia with immunodeficiency and incontinentia pigmenti (3-6).NEMO serves as a critical integrating platform coupling upstream receptor signaling to the canonical NF-B pathway. Biochemical and genetic studies have highlighted a pivotal function of polyubiquitination for IKK/NF-B activation. Upon TNF␣ or T cell receptor/CD28 stimulation, signaling adaptors RIP1 or MALT1 are modified by covalent attachment of Lys-63-linked ubiquitin (Ub) chains to recruit NEMO and thereby promote IKK activation (7-9). Recently, the assembly of linear Ub chains by the linear Ub chain assembly complex was shown to promote cytokine-triggered IKK activation (10). The Ub binding surface in NEMO called UBAN (Ub binding in ABIN and NEMO) or NOA (NEMO-optineurin-ABIN) is required for signal induced IKK activation. NEMO UBAN has been cocrystallized with linear as well as with Lys-63 Ub chains (11,12). The crystal structures reveal a bipartite Ub binding region from amino acids 290 to 330, distinguishing between a proximal and a distal moiety of bound di-Ub.In solution, linear di-Ub was found to bind...

Background Sleep spindles are believed to mediate several sleep-related functions including maintaining disconnection from the external environment during sleep, cortical development, and sleep-dependent memory consolidation. Prior studies that have examined sleep spindles in major depressive disorder (MDD) have not demonstrated consistent differences relative to control subjects, which may be due to sex-related variation and limited spatial resolution of spindle detection. Thus, this study sought to characterize sleep spindles in MDD using high-density electroencephalography (hdEEG) to examine the topography of sleep spindles across the cortex in MDD, as well as sex-related variation in spindle topography in the disorder. Methods All-night hdEEG recordings were collected in 30 unipolar MDD participants (19 women) and 30 age and sex-matched controls. Topography of sleep spindle density, amplitude, duration, and integrated spindle activity (ISA) were assessed to determine group differences. Spindle parameters were compared between MDD and controls, including analysis stratified by sex. Results As a group, MDD subjects demonstrated significant increases in frontal and parietal spindle density and ISA compared to controls. When stratified by sex, MDD women demonstrated increases in frontal and parietal spindle density, amplitude, duration, and ISA; whereas MDD men demonstrated either no differences or decreases in spindle parameters. Limitations Given the number of male subjects, this study may be underpowered to detect differences in spindle parameters in male MDD participants. Conclusions This study demonstrates topographic and sex-related differences in sleep spindles in MDD. Further research is warranted to investigate the role of sleep spindles and sex in the pathophysiology of MDD.

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Objective It has been hypothesized that slow wave activity, a well established measure of sleep homeostasis that increases after waking and decreases after sleep, may reflect changes in cortical synaptic strength. If so, the amplitude of sensory evoked responses should also vary as a function of time awake and asleep in a way that reflects sleep homeostasis. Methods Using 256-channel, high-density electroencephalography (EEG) in 12 subjects, auditory evoked potentials (AEP) and spontaneous waking data were collected during wakefulness before and after sleep. Results The amplitudes of the N1 and P2 waves of the AEP were reduced after a night of sleep. In addition, the decline in N1 amplitude correlated with low-frequency EEG power during non-rapid eye movement sleep and spontaneous wakefulness, both homeostatically regulated measures of sleep need. Conclusion The decline in AEP amplitude after a night of sleep may reflect a homeostatic reduction in synaptic strength. Significance These findings provide further evidence for a connection between synaptic plasticity and sleep homeostasis.

In this study, we report that partial unilateral optic nerve crush in the rat affects the number of retinal ganglion cells of the contralateral eye still in continuity with the ipsilateral superior colliculus. The reduction in cell number of the uncrossed retinal projection was accompanied by a microglia response and could be prevented by the local intravitreal application of the anti-inflammatory agent dexamethasone. Interestingly, the level of neuronal activity after optic nerve crush as evidenced by thallium autometallography was enhanced in the termination area of the uncrossed projection, the rostro-medial superior colliculus, suggesting that a dying-back mechanism is not involved. We propose that injury signals from the damaged optic nerve and retina are transduced to the unaffected eye.