Mutations in peripheral myelin protein 22 (PMP22) result in the most common form of Charcot-Marie-Tooth (CMT) disease, CMT1A. This hereditary form of peripheral neuropathy is characterized by dysmyelination of peripheral nerves, reduced nerve conduction velocity and muscle weakness. A PMP22 point mutation in leucine 16 to proline (L16P) underlies a form of human CMT1A as well as the Trembler-J mouse model of CMT1A. Homozygote Trembler-J mice (TrJ) die early postnatally, fail to make peripheral myelin, and therefore are more similar to congenital hypomyelinating neuropathy (CHN) than CMT1A. Because recent studies of inherited neuropathies in humans and mice have demonstrated that dysfunction and degeneration of neuromuscular synapses or junctions (NMJs) often precede impairments in axonal conduction, the structure and function of NMJs in end-stage TrJ mice was examined. Although synapses appeared normally innervated even in end-stage TrJ mice, the growth and maturation of the NMJ was altered. In addition, the amplitude of nerve-evoked muscle endplate potentials (EPPs) was reduced and transmission failure during sustained nerve stimulation was observed. These results suggest that the severe congenital hypomyelinating neuropathy that characterizes TrJ mice results in structural and functional deficits of the developing NMJ.

Impaired temporal perception of multisensory cues is a common phenomenon observed in older adults that can lead to unreliable percepts of the external world. For instance, the sound induced flash illusion (SIFI) can induce an illusory percept of a second flash by presenting a beep close in time to an initial flash-beep pair. Older adults that have enhanced susceptibility to a fall demonstrate significantly stronger illusion percepts during the SIFI task compared to those older adults without any history of falling. We hypothesize that a global inhibitory deficit may be driving the impairments across both postural stability and multisensory function in older adults with a fall history (FH). We investigated oscillatory activity and perceptual performance during the SIFI task, to understand how active sensory processing, measured by gamma (30–80 Hz) power, was regulated by alpha activity (8–13 Hz), oscillations that reflect inhibitory control. Compared to young adults (YA), the FH and non-faller (NF) groups demonstrated enhanced susceptibility to the SIFI. Further, the FH group had significantly greater illusion strength compared to the NF group. The FH group also showed significantly impaired performance relative to YA during congruent trials (2 flash-beep pairs resulting in veridical perception of 2 flashes). In illusion compared to non-illusion trials, the NF group demonstrated reduced alpha power (or diminished inhibitory control). Relative to YA and NF, the FH group showed reduced phase-amplitude coupling between alpha and gamma activity in non-illusion trials. This loss of inhibitory capacity over sensory processing in FH compared to NF suggests a more severe change than that consequent of natural aging.

Kaposi’s sarcoma (KS) is a highly-vascularized tumor characterized by inflammation and extensive neo-angiogenesis. The KS tumor microenvironment is rich in inflammatory and pro-angiogenic cytokines. Here, we report that the expression of Epidermal growth factor-like domain 7 (EGFL7) is upregulated in Kaposi’s sarcoma-associated herpes virus (KSHV) infected cells. EGFL7 is a secreted pro-angiogenic cytokine that has been implicated in angiogenesis and the proliferation of endothelial cells during many pathological conditions. Our data show that KS tumors as well as primary effusion lymphoma cells have increased levels of EGFL7 compared to the uninfected cells. We determined that the expression of a KSHV latent protein, LANA (latency-associated nuclear antigen), is the main viral factor responsible for this upregulation. The modulation of EGFL7 expression by LANA involves sequestration of death domain-associated protein 6 (Daxx) from the EGFL7 promoter. Daxx acts as a suppressor of promoter activity by binding to the avian erythroblastosis virus E26 oncogene homolog 1 (Ets-1), which is the core transcription factor required for the expression of EGFL7. We additionally show that the upregulation of EGFL7 by LANA contributes to the promotion of angiogenesis since siRNA-mediated knockdown of EGFL7 reduced in vitro tubulogenesis in LANA-expressing HUVEC cells. EGFL7 promotes angiogenesis through autocrine as well as paracrine mechanisms as the supernatant from LANA expressing cells depleted of EGFL7 showed reduced tubulogenesis. This study for the first time demonstrates EGFL7 to be an important angiogenic molecule secreted during KSHV infection that could be exploited for blocking KSHV associated malignancies in conjugation with other anti-angiogenic therapies.

Upon early sensory deprivation, the remaining modalities often exhibit cross-modal reorganization, such as primary auditory cortex (PAC) recruitment for visual motion processing in early deafness (ED). Previous studies of compensatory plasticity in ED individuals have given less attention to tactile motion processing. In the current study, we aimed to examine the effects of early auditory deprivation on tactile motion processing. We simulated four directions of tactile motion on each participant's right index finger and characterized their tactile motion responses and directional-tuning profiles using population receptive field analysis. Similar tactile motion responses were found within primary (SI) and secondary (SII) somatosensory cortices between ED and hearing control groups, whereas ED individuals showed a reduced proportion of voxels with directionally tuned responses in SI contralateral to stimulation. There were also significant but minimal responses to tactile motion within PAC for both groups. While early deaf individuals show significantly larger recruitment of right posterior superior temporal sulcus (pSTS) region upon tactile motion stimulation, there was no evidence of enhanced directional tuning. Greater recruitment of right pSTS region is consistent with prior studies reporting reorganization of multimodal areas due to sensory deprivation. The absence of increased directional tuning within the right pSTS region may suggest a more distributed population of neurons dedicated to processing tactile spatial information as a consequence of early auditory deprivation.

Encoding the temporal properties of external signals that comprise multimodal events is a major factor guiding everyday experience. However, during the natural aging process, impairments to sensory processing can profoundly affect multimodal temporal perception. Various mechanisms can contribute to temporal perception, and thus it is imperative to understand how each can be affected by age. In the current study, using three different temporal order judgement tasks (unisensory, multisensory, and sensorimotor), we investigated the effects of age on two separate temporal processes: synchronization and integration of multiple signals. These two processes rely on different aspects of temporal information, either the temporal alignment of processed signals or the integration/segregation of signals arising from different modalities, respectively. Results showed that the ability to integrate/segregate multiple signals decreased with age regardless of the task, and that the magnitude of such impairment correlated across tasks, suggesting a widespread mechanism affected by age. In contrast, perceptual synchrony remained stable with age, revealing a distinct intact mechanism. Overall, results from this study suggest that aging has differential effects on temporal processing, and general impairments with aging may impact global temporal sensitivity while context-dependent processes remain unaffected.