Myosin VIIA is required for aminoglycoside accumulation in cochlear hair cells.

Myosin VIIA is expressed by sensory hair cells and has a primary structure predicting a role in membrane trafficking and turnover, processes that may underlie the susceptibility of hair cells to aminoglycoside antibiotics. [3H]Gentamicin accumulation and the effects of aminoglycosides were therefore examined in cochlear cultures of mice with different missense mutations in the myosin VIIA gene, Myo7a, to see whether myosin VIIA plays a role in aminoglycoside ototoxicity. Hair cells from homozygous mutant Myo7a(sh1) mice, with a mutation in a non-conserved region of the myosin VIIA head, respond rapidly to aminoglycoside treatment and accumulate high levels of gentamicin. Hair cells from homozygous mutant Myo7a(6J) mice, with a mutation at a highly conserved residue close to the ATP binding site of the myosin VIIA head, do not accumulate [3H]gentamicin and are protected from aminoglycoside ototoxicity. Hair cells from heterozygotes of both alleles accumulate [3H]gentamicin and respond to aminoglycosides. Although aminoglycoside uptake is thought to be via apical surface-associated endocytosis, coated pit numbers on the apical membrane of heterozygous and homozygous Myo7a(6J) hair cells are similar. Pulse-chase experiments with cationic ferritin confirm that the apical endocytotic pathway is functional in homozygous Myo7a(6J) hair cells. Transduction currents can be recorded from both heterozygous and homozygous Myo7a(6J) hair cells, suggesting it is unlikely that the drug enters via diffusion through the mechanotransducer channel. The results show that myosin VIIA is required for aminoglycoside accumulation in hair cells. Myosin VIIA may transport a putative aminoglycoside receptor to the hair cell surface, indirectly translocate it to sites of membrane retrieval, or retain it in the endocytotic pathway

Influence of biogenic amines on the growth of xenografted human colorectal carcinomas.

The influence of some biogenic amines and amine-receptor-blocking drugs in the growth rate of human colorectal carcinomas propagated as s.c. xenografts in immune-deprived mice was studied. In mice treated with adrenaline, a beta-adrenergic agonist, the growth of xenografts was suppressed for 2 days, after which growth was resumed at a rate similar to that in control animals. Treatment with the phosphodiesterase inhibitor theophylline prolonged the adrenaline-induced inhibition of growth. Treatment with the beta-adrenergic antagonist sotalol or practolol increased the rate of tumour growth. Treatment with either serotonin or the histamine H2-receptor agonist Dimiprit had no effect on tumour growth rate. However, the antiserotoninergic drug BW 501C and the histamine H2-receptor antagonist cimetidine each caused short-term suppression of tumour growth

Clonogenic cell survival in cryopreserved human tumour cells.

Cells from 3 human tumours have been grown in soft agar contained in Millipore diffusion chambers and implanted i.p. in mice. Clonal growth was obtained from fresh biopsy samples, from cryopreserved tissue, and from xenografts of the tissues in immune-suppressed mice. The radiosensitivities of a melanoma and an ovarian carcinoma were evaluated by in vitro irradiation before assay for colony formation. Xenografting did not modify the radiosensitivity of the melanoma. Cells from another tumour were exposed to Adriamycin or cyclophosphamide whilst contained within i.p. diffusion chambers; the sensitivity was similar for cryopreserved and xenografted cells. The results encourage further attempts to quantify the sensitivity of human tumour cells by these methods

A tradeoff in simultaneous quantum-limited phase and loss estimation in interferometry

Interferometry with quantum light is known to provide enhanced precision for estimating a single phase. However, depending on the parameters involved, the quantum limit for the simultaneous estimation of multiple parameters may not attainable, leading to trade-offs in the attainable precisions. Here we study the simultaneous estimation of two parameters related to optical interferometry: phase and loss, using a fixed number of photons. We derive a trade-off in the estimation of these two parameters which shows that, in contrast to single-parameter estimation, it is impossible to design a strategy saturating the quantum Cramer-Rao bound for loss and phase estimation in a single setup simultaneously. We design optimal quantum states with a fixed number of photons achieving the best possible simultaneous precisions. Our results reveal general features about concurrently estimating Hamiltonian and dissipative parameters, and has implications for sophisticated sensing scenarios such as quantum imaging.Comment: 9 pages, 6 figure

Multimorbidity, access to services and diagnosis of new health conditions during the COVID-19 pandemic

Excess deaths from conditions other than COVID-19 have been reported during the COVID-19 pandemic. Reduced access to health and social care services during lockdown may have disproportionately affected older people and those with multiple medical conditions. The English Longitudinal Study of Ageing COVID-19 Substudy provided an opportunity to evaluate older people’s experiences of receiving needed health and social care, and changes in reported anxiety, depression and loneliness. We found that the rates of diagnosis of new conditions during the pandemic in the second half of 2020 were substantially different from the pre pandemic rates reported in 2018 to 2019. Rates of newly diagnosed dementia dropped to below half the pre pandemic rate for reasons that are not clear. The increased isolation during lockdown may have meant that cognitive decline went unnoticed by friends and relatives, or barriers to accessing healthcare may have been experienced more by those with early dementia. Conversely, other conditions were diagnosed more frequently than before the pandemic, including arthritis, chronic lung disease, diabetes and hypertension. Again, the reasons for these increases are not clear, but fewer opportunities for physical activity and social interaction may have played a part. Those with multiple medical conditions were more likely to be unable to access healthcare, and 1 in 5 of them had a hospital operation or treatment STUDY RESULT 2 cancelled. We found that mental health worsened during the pandemic, with higher reported rates of anxiety, depression and loneliness, and again the rise was steeper for respondents with multimorbidity. These results show that older people experienced poor mental health and difficulty accessing basic health care during the pandemic, and those with multiple conditions and early dementia had the greatest difficulties. Particular attention should be paid to the health needs of these vulnerable groups as health care access improves and the backlog of cancelled and delayed care is addressed

Assimilation to the Unmarked

Steel, JC ORCiD: 0000-0003-3608-7542Intravitreal injection of recombinant adeno-associated virus (AAV) might be an alternative approach for retinal gene therapy for certain applications. Although the jelly-like substance consists mainly of water, anti-viral antibodies against various viruses such as HIV or HSV have been observed in the human vitreous and anti-AAV neutralising antibodies (NAbs) in rhesus macaque vitreous have also been detected. In this study, the human vitreous humour was obtained from 70 post mortem unpaired eye cups and 10 paired eye cups from the Queensland Eye Bank. The transduction efficiency of 1-3 · 108 vcg of recombinant AAV-2, -5, -6 and -8 expressing secreted nanoluciferase was measured following transduction of ARPE-19 and Cos-7 cells at vitreous humour dilutions from 1:2 to 1:10 000. At vitreous humour dilution of 1:2, a reduction in transduction of over 50% was observed for AAV2 in 50.5% of samples and for AAV6 in 66.2% of samples. Only 23.2% of tested samples showed similar reduction in transduction efficiency for AAV5, and for AAV8 only 2.5% of samples inhibited transduction by 50% at 1:2 dilution. Differences in serum antibody levels have been previously observed in a similar Australian population, but low transduction inhibition at vitreous humour dilutions of 1:100 suggests that the concentration of NAbs within the vitreous humour is lower than in human serum. In addition, this study also reported an increase in transduction efficiency for AAV8 at highest vitreous humour concentrations, supporting previous reports that human albumin can increase AAV transduction but only in some serotypes