40 research outputs found
Transport of Ascorbic and Dehydroascorbic Acids across Protoplast and Vacuole Membranes Isolated from Barley (Hordeum vulgare L. cv Gerbel) Leaves
Prospects and challenges of environmental DNA (eDNA) monitoring in freshwater ponds
Environmental DNA (eDNA) analysis is a rapid, non-invasive, cost-efficient biodiversity monitoring tool with enormous potential to inform aquatic conservation and management. Development is ongoing, with strong commercial interest, and new uses are continually being discovered. General applications of eDNA and guidelines for best practice in freshwater systems have been established, but habitat-specific assessments are lacking. Ponds are highly diverse, yet understudied systems that could benefit from eDNA monitoring. However, eDNA applications in ponds and methodological constraints specific to these environments remain unaddressed. Following a stakeholder workshop in 2017, researchers combined knowledge and expertise to review these applications and challenges that must be addressed for the future and consistency of eDNA monitoring in ponds. The greatest challenges for pond eDNA surveys are representative sampling, eDNA capture, and potential PCR inhibition. We provide recommendations for sampling, eDNA capture, inhibition testing, and laboratory practice, which should aid new and ongoing eDNA projects in ponds. If implemented, these recommendations will contribute towards an eventual broad standardisation of eDNA research and practice, with room to tailor workflows for optimal analysis and different applications. Such standardisation will provide more robust, comparable, and ecologically meaningful data to enable effective conservation and management of pond biodiversity
Combinations of QT-prolonging drugs: towards disentangling pharmacokinetic and pharmaco-dynamic effects in their potentially additive nature.
Background: Whether arrhythmia risks will increase if drugs with electrocardiographic (ECG)
QT-prolonging properties are combined is generally supposed but not well studied. Based on
available evidence, the Arizona Center for Education and Research on Therapeutics (AZCERT)
classification defines the risk of QT prolongation for exposure to single drugs. We aimed to
investigate how combining AZCERT drug categories impacts QT duration and how relative drug
exposure affects the extent of pharmacodynamic drugâdrug interactions.
Methods: In a cohort of 2558 psychiatric inpatients and outpatients, we modeled whether
AZCERT class and number of coprescribed QT-prolonging drugs correlates with observed
rate-corrected QT duration (QTc) while also considering age, sex, inpatient status, and other
QTc-prolonging risk factors. We concurrently considered administered drug doses and
pharmacokinetic interactions modulating drug clearance to calculate individual weights of
relative exposure with AZCERT drugs. Because QTc duration is concentration-dependent, we
estimated individual drug exposure with these drugs and included this information as weights
in weighted regression analyses.
Results: Drugs attributing a âknownâ risk for clinical consequences were associated with the
largest QTc prolongations. However, the presence of at least two versus one QTc-prolonging
drug yielded nonsignificant prolongations [exposure-weighted parameter estimates with
95% confidence intervals for âknownâ risk drugs + 0.93 ms (â8.88;10.75)]. Estimates for
the âconditionalâ risk class increased upon refinement with relative drug exposure and coadministration of a âknownâ risk drug as a further risk factor.
Conclusions: These observations indicate that indiscriminate combinations of QTc-prolonging
drugs do not necessarily result in additive QTc prolongation and suggest that QT prolongation
caused by drug combinations strongly depends on the nature of the combination partners and
individual drug exposure. Concurrently, it stresses the value of the AZCERT classification also
for the risk prediction of combination therapies with QT-prolonging drugs
Loss of IGF1R in human astrocytes alters complex I activity and support for neurons
The insulin/insulin-like growth factor 1 (IGF1) signalling pathways are implicated in longevity and in progression of Alzheimer's disease. Previously, we showed that insulin-like growth factor 1 receptor (IGF1R) and downstream signalling transcripts are reduced in astrocytes in human brain with progression of Alzheimer's neuropathology and developed a model of IGF1 signalling impairment in human astrocytes using an IGF1R-specific monoclonal antibody, MAB391. Here, we have established a novel human astrocyte-neuron co-culture system to determine whether loss of astrocytic IGF1R affects their support for neurons. Astrocyte-neuron co-cultures were developed using human primary astrocytes and differentiated Lund Human Mesencephalic Cells (LUHMES). Neurite outgrowth assays, performed to measure astrocytic support for neurons, showed astrocytes provided contact-mediated support for neurite outgrowth. Loss of IGF1R did not affect neurite outgrowth under control conditions but when challenged with hydrogen peroxide IGF1R-impaired astrocytes were less able to protect LUHMES. To determine how loss of IGF1R affects neuronal support MAB391-treated astrocytes were FACS sorted from GFP-LUHMES and their transcriptomic profile was investigated using microarrays. Changes in transcripts involved in astrocyte energy metabolism were identified, particularly NDUFA2 and NDUFB6, which are related to complex I assembly. Loss of complex I activity in MAB391-treated astrocytes validated these findings. In conclusion, reduced IGF1 signalling in astrocytes impairs their support for neurons under conditions of stress and this is associated with defects in the mitochondrial respiratory chain in astrocytes