Function of bidirectional sensitivity in the otolith organs established by transcription factor Emx2

Otolith organs of the inner ear are innervated by two parallel afferent projections to the brainstem and cerebellum. These innervations were proposed to segregate across the line of polarity reversal (LPR) within each otolith organ, which divides the organ into two regions of hair cells (HC) with opposite stereociliary orientation. The relationship and functional significance of these anatomical features are not known.Here, we show regional expression of Emx2 in otolith organs, which establishes LPR, mediates the neuronal segregation across LPR and constitutes the bidirectional sensitivity function. Conditional knockout (cKO) of Emx2 in HCs lacks LPR. Tmie cKO, in which mechanotransduction was abolished selectively in HCs within the Emx2 expression domain also lacks bidirectional sensitivity. Analyses of both mutants indicate that LPR is specifically required formice to swimcomfortably and to traverse a balance beam efficiently, but LPR is not required formice to stay on a rotating rod

Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial.

BackgroundTreatment with bone-marrow-derived mesenchymal stromal cells (MSCs) has shown benefits in preclinical models of acute respiratory distress syndrome (ARDS). Safety has not been established for administration of MSCs in critically ill patients with ARDS. We did a phase 2a trial to assess safety after administration of MSCs to patients with moderate to severe ARDS.MethodsWe did a prospective, double-blind, multicentre, randomised trial to assess treatment with one intravenous dose of MSCs compared with placebo. We recruited ventilated patients with moderate to severe ARDS (ratio of partial pressure of oxygen to fractional inspired oxygen <27 kPa and positive end-expiratory pressure [PEEP] ≥8 cm H2O) in five university medical centres in the USA. Patients were randomly assigned 2:1 to receive either 10 × 106/kg predicted bodyweight MSCs or placebo, according to a computer-generated schedule with a variable block design and stratified by site. We excluded patients younger than 18 years, those with trauma or moderate to severe liver disease, and those who had received cancer treatment in the previous 2 years. The primary endpoint was safety and all analyses were done by intention to treat. We also measured biomarkers in plasma. MSC viability was tested in a post-hoc analysis. This trial is registered with ClinicalTrials.gov, number NCT02097641.FindingsFrom March 24, 2014, to Feb 9, 2017 we screened 1038 patients, of whom 60 were eligible for and received treatment. No patient experienced any of the predefined MSC-related haemodynamic or respiratory adverse events. One patient in the MSC group died within 24 h of MSC infusion, but death was judged to be probably unrelated. 28-day mortality did not differ between the groups (30% in the MSC group vs 15% in the placebo group, odds ratio 2·4, 95% CI 0·5-15·1). At baseline, the MSC group had numerically higher mean scores than the placebo group for Acute Physiology and Chronic Health Evaluation III (APACHE III; 104 [SD 31] vs 89 [33]), minute ventilation (11·1 [3·2] vs 9·6 [2·4] L/min), and PEEP (12·4 [3·7] vs 10·8 [2·6] cm H2O). After adjustment for APACHE III score, the hazard ratio for mortality at 28 days was 1·43 (95% CI 0·40-5·12, p=0·58). Viability of MSCs ranged from 36% to 85%.InterpretationOne dose of intravenous MSCs was safe in patients with moderate to severe ARDS. Larger trials are needed to assess efficacy, and the viability of MSCs must be improved.FundingNational Heart, Lung, and Blood Institute

Hearing in Cavefishes

Caves and associated subterranean habitats represent some of the harshest environments on Earth, yet many organisms, including fishes, have colonized and thrive in these habitats despite the complete absence of light, and other abiotic and biotic constraints. Over 170 species of fishes are considered obligate subterranean inhabitants (stygobionts) that exhibit some degree of troglomorphy, including degeneration of eyes and reduction in pigmentation. To compensate for lack of vision, many species have evolved constructive changes to non-visual sensory modalities. In this chapter we review hearing in cavefishes, with particular emphasize on our own studies on amblyopsid cavefishes. Hearing in cavefishes has not been well studied to date, as hearing ability has only been examined in four species. Two species show no differences in hearing ability relative to their surface relatives, while the other two species (family Amblyopsidae) exhibit regression in the form of reduced hearing range and reduction in hair cell densities on sensory epithelia. In addition to reviewing our current knowledge on cavefish hearing, we offer suggestions for future avenues of research on cavefish hearing and discuss the influence of Popper and Fay on the field of cavefish bioacoustics