The Evf2 Ultraconserved Enhancer lncRNA Functionally and Spatially Organizes Megabase Distant Genes in the Developing Forebrain.

Gene regulation requires selective targeting of DNA regulatory enhancers over megabase distances. Here we show that Evf2, a cloud-forming Dlx5/6 ultraconserved enhancer (UCE) lncRNA, simultaneously localizes to activated (Umad1, 1.6 Mb distant) and repressed (Akr1b8, 27 Mb distant) chr6 target genes, precisely regulating UCE-gene distances and cohesin binding in mouse embryonic forebrain GABAergic interneurons (INs). Transgene expression of Evf2 activates Lsm8 (12 Mb distant) but fails to repress Akr1b8, supporting trans activation and long-range cis repression. Through both short-range (Dlx6 antisense) and long-range (Akr1b8) repression, the Evf2-5'UCE links homeodomain and mevalonate pathway-regulated enhancers to IN diversity. The Evf2-3' end is required for long-range activation but dispensable for RNA cloud localization, functionally dividing the RNA into 3'-activator and 5'UCE repressor and targeting regions. Together, these results support that Evf2 selectively regulates UCE interactions with multi-megabase distant genes through complex effects on chromosome topology, linking lncRNA-dependent topological and transcriptional control with interneuron diversity and seizure susceptibility.

Measurements of bone conduction auditory brainstem response with the new audiometric bone conduction transducer Radioear B81.

OBJECTIVE: To compare recordings of bone conduction (BC) stimulated auditory brainstem response (ABR) obtained using the newer BC transducer Radioear B81 and the conventional BC transducer Radioear B71. Balanced electromagnetic separation transducer (BEST) design found in the B81 may influence the ABR magnitudes and latencies, as well as electrical artefacts. DESIGN: ABRs to tone burst stimuli of 500 Hz, 2000 Hz, 4000 Hz, click stimulation, and broad-band chirp stimulation at 20 and 50 dB nHL were recorded. For each device, stimulus and intensity level, the ABR Jewett wave V amplitude and latency were obtained. The device-related electrical stimulus artefacts on the ABR recordings were also analysed by calculating the Hilbert envelope of the peri-stimulus recording segments. STUDY SAMPLE: Twenty-three healthy adults with normal hearing were included in the study. RESULTS: The ABRs obtained by the B81 were similar to that of the B71 in terms of ABR wave V amplitude and latency. However, the B81 produced smaller electrical artefacts than B71 and this difference was statistically significant. CONCLUSIONS: The BC transducer Radioear B81 provides ABRs comparable to Radioear B71 while causing smaller artefacts.

Paediatric non-progression following grandmother-to-child HIV transmission.

BACKGROUND: In contrast to adult HIV infection, where slow disease progression is strongly linked to immune control of HIV mediated by protective HLA class I molecules such as HLA-B*81:01, the mechanisms by which a minority of HIV-infected children maintain normal-for-age CD4 counts and remain clinically healthy appear to be HLA class I-independent and are largely unknown. To better understand these mechanisms, we here studied a HIV-infected South African female, who remained a non-progressor throughout childhood. RESULTS: Phylogenetic analysis of viral sequences in the HIV-infected family members, together with the history of grand-maternal breast-feeding, indicated that, unusually, the non-progressor child had been infected via grandmother-to-child transmission. Although HLA-B*81:01 was expressed by both grandmother and grand-daughter, autologous virus in each subject encoded an escape mutation L188F within the immunodominant HLA-B*81:01-restricted Gag-specific epitope TL9 (TPQDLNTML, Gag 180-188). Since the transmitted virus can influence paediatric and adult HIV disease progression, we investigated the impact of the L188F mutant on replicative capacity. When this variant was introduced into three distinct HIV clones in vitro, viral replicative capacity was abrogated altogether. However, a virus constructed using the gag sequence of the non-progressor child replicated as efficiently as wildtype virus. CONCLUSION: These findings suggest alternative sequences of events: the transmission of the uncompensated low fitness L188F to both children, potentially contributing to slow progression in both, consistent with previous studies indicating that disease progression in children can be influenced by the replicative capacity of the transmitted virus; or the transmission of fully compensated virus, and slow progression here principally the result of HLA-independent host-specific factors, yet to be defined.

Effects of aging on ocular vestibular-evoked myogenic potential using ER-3A insert earphone and B81 bone vibrator.

Purpose: Aging is a process associated with degeneration and dysfunction of peripheral vestibular system or apparatus. This study aimed to investigate the influence of aging on ocular vestibular-evoked myogenic potential (oVEMP) response rates and recording parameters using the B81 bone vibrator and compare them with air conduction stimuli (ACS) oVEMP response characteristics. Methods: In 60 healthy participants aged 10-71 years (mean age 39.9; 29 male participants), the oVEMP response was elicited using a B81 bone vibrator and an ER-3A insert earphone. The effects of age and stimulus on oVEMP response rates and recording parameters were evaluated. Results: Response rates and amplitudes declined with aging using either ACS or bone-conducted vibration (BCV) stimulation, particularly in individuals over 60 years of age, whereas thresholds increased and N1 latencies were prolonged. BCV showed fewer risks of absent oVEMP response than ACS (p = 0.002). BCV acquired higher amplitudes (p < 0.001), lower thresholds, and shorter N1 and P1 latencies (all p < 0.001) than ACS. Conclusions: The absence of an oVEMP response may be attributed to aging rather than a concurrent vestibular disorder. B81-BCV likely produces higher mechanical drives to the vestibular hair cells at safer and non-traumatic levels compared with ACS and therefore may be more likely to evoke a response in the elderly cohort, whose vestibular function and mechanical sensitivity have declined. Thus, B81-BCV stimulation is more effective and safer to elicit oVEMPs, and it should be recommended when ACS fails in the clinic, particularly in the elderly population.

B81 Bone Vibrator-Induced Vestibular-Evoked Myogenic Potentials: Normal Values and the Effect of Age.

Objective: To define the normal values and examine the influence of aging on B81 bone vibrator-induced cervical vestibular-evoked myogenic potentials (B81-cVEMPs) and ocular vestibular-evoked myogenic potentials (B81-oVEMPs). Methods: Seventy healthy subjects, divided into seven groups according to their ages, were enrolled in this study. The 4-9-, 10-19-, 20-29-, 30-39-, 40-49-, 50-59-, and 60-70-year-old participants were divided into groups I-VII, respectively. B81-cVEMP and B81-oVEMP were recorded in each group. Results: The B81-cVEMP response rates for groups I-VII were 100, 100, 100, 100, 95, 95, and 75%, respectively, with significant differences only between groups I-VI and group VII (p = 0.047, p < 0.05). The B81-oVEMP response rates for groups I-VII were 100, 100, 100, 100, 70, 65, and 40%, respectively, with significant differences only between groups I-IV and groups V-VII (p = 0.020, p = 0.008, p = 0.000; p < 0.05). The threshold, P13, and N23 latencies of B81-cVEMP positively correlated with age (r = 0.756, p = 0.000; r = 0.357, p = 0.003; r = 0.316, p = 0.009; p < 0.05). The raw amplitudes and corrected amplitudes negatively correlated with age (r = -0.641, p = 0.000; r = -0.609, p = 0.000, p < 0.05). For B81-oVEMP, the corrected amplitudes negatively correlated with age (r = -0.638, p = 0.000, p<0.05), but the threshold and N10 latency positively correlated with age (r = 0.768, p = 0.000; r = 0.334, p = 0.009, p < 0.05). Moreover, the interaural asymmetry ratio did not significantly correlate with age for B81-cVEMP and B81-oVEMP. Conclusion: As age increased, the B81-cVEMP response rate decreased, the thresholds increased, P13 and N23 latencies were prolonged, and the raw amplitude and corrected amplitude decreased. The B81-oVEMP response rate and corrected amplitude decreased, the thresholds increased, and N10 latency was prolonged with age. These changes are probably due to the occurrence of morphological and functional changes in the vestibular system with aging. Therefore, we suggest establishing different reference values according to different age groups when evaluating the VEMP results in patients with vestibular diseases.

Effects of External Auditory Meatus Occlusion on Ocular Vestibular Evoked Myogenic Potentials Induced by Bone Conducted Sound.

To facilitate more reliable recordings of the ocular vestibular evoked myogenic potentials (oVEMP) induced by bone-conducted sound using the B81 bone conduction transducer, we preliminarily studied the effects of external auditory meatus occlusion using an earplug on such oVEMP. Eight healthy volunteers (four males and four females, 26-48 years of age, mean age: 34. 5 years) and 14 patients with vestibular disease (2 males and 12 females, 18-59 years of age, mean age: 41.5 years) were enrolled. oVEMP testing was performed using a B81 placed on the temple. Tone bursts (500 Hz, rise/fall time: 2 ms, plateau time: 2 ms, and 70 dB nHL) were presented at a rate of 5.1 Hz. N1-P1 amplitudes were measured and analyzed. Occlusion resulted in significantly larger N1-P1 amplitudes [mean ± SE (SD): 12.3 ± 1.67 (6.71) µV vs. 9.55 ± 1.55 (6.21) µV; p = 0.020, paired t-test]. While four patients did not exhibit any response on either side in the absence of occlusion, all of them showed unilateral or bilateral responses when occlusion was employed. In any patient occlusion did not result in loss of oVEMP responses. External auditory meatus occlusion using an earplug could allow more reliable recordings of bone conduction transducer-induced oVEMP.

Air and bone-conducted vestibular evoked myogenic potentials in children with large vestibular aqueduct syndrome.

BACKGROUND: There are few studies focused on vestibular symptoms and function of the children with LVAS. OBJECTIVES: This study aimed to find the characteristics of air and bone-conducted VEMPs among children with LVAS, and to investigate the relationship between VEMPs and vestibular symptoms. MATERIAL AND METHODS: A total of 44 children with LVAS and 10 healthy children were recruited as the case group and control group. Air and bone-conducted VEMP were performed to the participants. RESULTS: For air-conducted measurement, there was elevated amplitude of cVEMP in case group than control group. There was no significant difference at oVEMP parameters between the case group and control group. For bone-conducted measurement, significantly longer P1 latency and shorter P1-N1 latency of cVEMP were observed among the case group; there were a series of changes in oVEMP parameters among the case group. Logistic regression model revealed that air-conducted oVEMP asymmetric ratio was valuable to predict vestibular symptoms' development among the kids with LVAS. CONCLUSION: Asymmetric ratio of oVEMP could be used as one predictor of developing vestibular symptoms of the children with LVAS. Applying bone-conducted VEMP as one alternative parameter of vestibular syndrome is novel and will certainly remain an area of continued investigation.