Resistance to neomycin ototoxicity in the extreme basal (hook) region of the mouse cochlea

Aminoglycoside ototoxicity results in permanent loss of the sensory hair cells in the mammalian cochlea. It usually begins at the basal turn causing high-frequency hearing loss. Here we describe previously unreported resistance of hair cells to neomycin ototoxicity in the extreme basal (hook) region of the developing cochlea of the C57BL/6 mouse. Organ of Corti explants from mice at postnatal day 3 were incubated (37 °C, 5% CO₂) in normal culture medium for 19.5 h prior to and after exposure to neomycin (1 mM, 3 h). To study neomycin uptake in the hair cells, cochlear explants were incubated with Neomycin Texas-red (NTR) conjugate. As expected, exposure to neomycin significantly reduced the survival of inner (IHC) and outer hair cells (OHC). IHC survival rate was high in the apical segment and low in the basal segment. OHC were well preserved in the apical and hook regions, with substantial OHC loss in the basal segment. The NTR uptake study demonstrated that the high survival rate in the extreme basal turn OHC was associated with low NTR uptake. Treatment with a calcium chelator (BAPTA), which disrupts the opening of mechanoelectrical (MET) transduction channels, abolished or reduced NTR uptake in the hair cells throughout the cochlea. This confirmed the essential role of MET channels in neomycin uptake and implied that the transduction channels could be impaired in the hook region of the developing mouse cochlea, possibly as a result of the cadherin 23 mutation responsible for the progressive deafness in C57BL/6 mice.     

Efficacy of different interaction devices using non-immersive virtual tasks in individuals with Amyotrophic Lateral Sclerosis: a cross-sectional randomized trial

Background

Amyotrophic Lateral Sclerosis (ALS) is a rapid progressive neurodegenerative disease, characterized by a selective loss of motor neurons, brain stem and spinal cord which leads to deterioration of motor abilities. Devices that promote interaction with tasks on computers can enhance performance and lead to greater independence and utilization of technology.

Objective

To evaluate performance on a computer task in individuals with ALS using three different commonly used non-immersive devices.

Method

Thirty individuals with ALS (18 men and 12 women, mean age 59?years, range 44–74?years) with a mean score of 26, (minimum score of 14 and maximum 41) on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and 30 healthy controls matched for age and gender, participated. All participants were randomly divided into three groups, each using a different device system (motion tracking, finger motion control or touchscreen) to perform three task phases (acquisition, retention and transfer).

Results

Both the ALS and control group (CG) showed better performance on the computer task when using the touchscreen device, but there was limited transfer of performance onto the task performed on the Finger Motion control or motion tracking. However, we found that using the motion tracking device led to transfer of performance to the touchscreen.

Conclusion

This study presents novel and important findings when selecting interaction devices for individuals with ALS to access technology by demonstrating immediate performance benefits of using a touchscreen device, such as improvement of motor skills. There were possible transferable skills obtained when using virtual systems which may allow flexibility and enable individuals to maintain performance overtime.

Trial registration

Registration name: Virtual Task in Amyotrophic Lateral Sclerosis; Registration number: NCT03113630; retrospectively registered on 04/13/2017. Date of enrolment of the first participant to the trial: 02/02/2016.

     

Bivalence of EGF-like ligands drives the ErbB signaling network.

Signaling by epidermal growth factor (EGF)-like ligands is mediated by an interactive network of four ErbB receptor tyrosine kinases, whose mechanism of ligand-induced dimerization is unknown. We contrasted two existing models: a conformation-driven activation of a receptor-intrinsic dimerization site and a ligand bivalence model. Analysis of a Neu differentiation factor (NDF)-induced heterodimer between ErbB-3 and ErbB-2 favors a bivalence model; the ligand simultaneously binds both ErbB-3 and ErbB-2, but, due to low-affinity of the second binding event, ligand bivalence drives dimerization only when the receptors are membrane anchored. Results obtained with a chimera and isoforms of NDF/neuregulin predict that each terminus of the ligand molecule contains a distinct binding site. The C-terminal low-affinity site has broad specificity, but it prefers interaction with ErbB-2, an oncogenic protein acting as a promiscuous low-affinity subunit of the three primary receptors. Thus, ligand bivalence enables signal diversification through selective recruitment of homo- and heterodimers of ErbB receptors, and it may explain oncogenicity of erbB-2/HER2.     

Arctic and North Atlantic Oscillation phase changes are recorded in the isotopes (δ18O and δ13C) of Cassiope tetragona plants

The Arctic and North Atlantic Oscillations (AO/NAO) are large‐scale annual modes of atmospheric circulation that have shifted in the last 30 years. Recent changes in arctic climate, including increasing surface air temperature, declining sea ice extent, and shifts in the amounts seasonality of precipitation are linked to the strong positive phase of the AO/NAO. Here, we show that phase changes in the AO/NAO are recorded in the isotopic (δ¹⁸O and Δ‐carbon isotope discrimination) characteristics of the long‐lived circum‐arctic plant, Cassiope tetragona, as summer rain has become a more important water source than snowmelt water which in turn has lead to decreases in Δ and reductions in plant stem growth. These isotopic records in C. tetragona may facilitate reconstructions of climate, plant–soil water relations, plant gas exchange attributes and a mechanistic understanding of growth responses to shifts in atmospheric circulation. If plant specimens were available for populations across the arctic as part of the International Polar Year, these archives could provide a circum‐arctic record of historical climate change and associated shifts in physiological plant performance and growth.     

The oral gold compound auranofin triggers arachidonate release and cyclooxygenase metabolism in the alveolar macrophage

We examined the effect of in vitro incubation with the oral gold compound auranofin (AF) on arachidonic acid (AA) release and metabolism by rat alveolar macrophages (AMs). AF stimulated dose- and time-dependent release of 14C-AA from prelabeled AMs, which reached 4.7 +/- 0.3% (mean +/- SEM) of incorporated radioactivity at 10 micrograms/ml for 90 min, as compared to 0.5 +/- 0.1% release following control incubation for 90 min (p less than 0.001). Similar dose- and time-dependent synthesis of thromboxane (Tx) A2 (measured as TxB2) and prostaglandin (PG) E2 was demonstrated by radioimmunoassay of medium from unlabeled cultures, reaching 18-fold and 9-fold, respectively, of the control values at 10 micrograms/ml AF for 90 min (p less than 0.001 for both). AF-induced TxB2 and PGE2 synthesis was inhibited by indomethacin as well as by pretreatment with methylprednisolone. No increase in the synthesis of immunoreactive leukotrienes (LT) B4 or C4 was noted at any dose or time of AF. High performance liquid chromatographic separation of 14C-eicosanoids synthesized by prelabeled AMs confirmed that AF induced the release of free AA and its metabolism to cyclooxygenase, but not 5-lipoxygenase, metabolites. The ability of AF to trigger macrophage AA metabolism may be relevant to the exacerbation of certain inflammatory processes which sometimes accompany gold therapy.     

Sequestration of 3-oxygenated α-ionone derivatives in the male rectal gland of the solanaceous fruit fly, Bactrocera latifrons

The solanaceous fruit fly, Bactrocera latifrons (Hendel) (Diptera: Tephritidae), infests various solanaceous fruits including eggplant and chili peppers. We found that a freshly cut fruit of an eggplant cultivar [ Solanum melongena L. cv. Long Purple Oriental (Solanaceae)] selectively attracted and provoked voracious feeding behavior in adult B. latifrons males (but not in females) in an indoor test. One of the male-specific attractants/feeding stimulants in eggplant was identified as 3-hydroxy-α-ionone. Sexually mature males that fed on the eggplant pulp selectively accumulated a series of 3-oxygenated α-ionone/α-ionol analogs (e.g., 3-oxo-α-ionol and 3-oxo-7,8-dihydro-α-ionol) in the rectal gland, a suspected pheromone reservoir in male flies. Males fed on synthetic 3-hydroxy-α-ionone, 3-oxo-α-ionol, or 3-oxo-α-ionone partially biotransformed the compounds into 3-oxo-α-ionol, 3-oxo-α-ionone, and 3-oxo-7,8-dihydro-α-ionol and sequestered substantial quantities (as high as 5 µg/gland as a mixture) in a similar ratio in the rectal gland within 6 h after ingestion. These results suggest that the rectal sequestrates may serve as a sex pheromone similar to other Bactrocera species that use phenylpropanoid volatiles to attract conspecific females.     

Rhythm of a life within life: role of viral suppressors in hijacking the host cell

Virus–host interaction at cellular and intra-cellular level is a constantly evolving process which results either in the host to resist or the virus to break host immunity and to establish the disease. We have put extensive efforts to understand the genomic organization and gene functions of important viral proteins involved in resisting or avoiding host antiviral responses mediated by RNA interference or Ubiquitin–Proteasome Pathway. Nearly two decades of dedicated research on three agriculturally important viruses revealed genetic and epigenetic regulation of host to induce the defense/immunity responses. The microRNA and auxin regulated development of disease symptoms and the role of temperature in optimizing the interactions of viral protein with host small RNAs are intriguing observations. Owing to the complexity of the dynamic interactions between plant and virus, this research field will always be challenging and fascinating.