Electrochemically stimulating developments in bioelectronic medicine

Cellular homeostasis is in part controlled by biological generated electrical activity. By interfacing biology with electronic devices this electrical activity can be modulated to actuate cellular behaviour. There are current limitations in merging electronics with biology sufficiently well to target and sense specific electrically active components of cells. By addressing this limitation, researchers give rise to new capabilities for facilitating the twoway transduction signalling mechanisms between the electronic and cellular components. This is required to allow significant advancement of bioelectronic technology which offers new ways of treating and diagnosing diseases. Most of the progress that has been achieved to date in developing bioelectronic therapeutics stimulate neural communication, which ultimately orchestrates organ function back to a healthy state. Some devices used in therapeutics include cochlear and retinal implants and vagus nerve stimulators. However, all cells can be effected by electrical inputs which gives rise to the opportunity to broaden the use of bioelectronic medicine for treating disease. Electronic actuation of non-excitable cells has been shown to lead to ‘programmed’ cell behaviour via application of electronic input which alter key biological processes. A neglected form of cellular electrical communication which has not yet been considered when developing bioelectronics therapeutics is faradaic currents. These are generated during redox reactions. A precedent of electrochemical technology being used to modulate these reactions thereby controlling cell behaviour has already been set. In this mini review we highlight the current state of the art of electronic routes to modulating cell behaviour and identify new ways in which electrochemistry could be used to contribute to the new field of bioelectronic medicine

Understanding how children are coping with climate change anxiety by exploring coping strategies and supportive interventions.

Climate change presents a significant threat to both the planet and human prosperity which impacts our physical health and mental well-being. There is an imminent requirement for significant global action. This means (a) our children have been born into unprecedented times and (b) as future adults, they will find themselves facing the major consequences of climate change. These can negatively affect their mental health and well-being. This paper reports the effect of climate anxiety on this population group through an exploration of coping strategies and supportive interventions. Empowering children to engage in climate action has been identified as a coping strategy. Whilst equipping them with knowledge and resources on climate change and providing safe spaces and experiences in nature are identified as supportive interventions. However, further empirical research evidence is needed to determine the next steps to address the extent of the impact of climate anxiety and prepare our children for the future

Closed-loop control of continuous piperacillin delivery: an in silico study

Background and objective: Sub-therapeutic dosing of piperacillin-tazobactam in critically-ill patients is associated with poor clinical outcomes and may promote the emergence of drug-resistant infections. In this paper, an in silico investigation of whether closed-loop control can improve pharmacokinetic-pharmacodynamic (PK-PD) target attainment is described. Method: An in silico platform was developed using PK data from 20 critically-ill patients receiving piperacillin-tazobactam where serum and tissue interstitial fluid (ISF) PK were defined. Intra-day variability on renal clearance, ISF sensor error, and infusion constraints were taken into account. Proportional-integral-derivative (PID) control was selected for drug delivery modulation. Dose adjustment was made based on ISF sensor data with a 30-minute sampling period, targeting a serum piperacillin concentration between 32-64 mg/L. A single tuning parameter set was employed across the virtual population. The PID controller was compared to standard therapy, including bolus and continuous infusion of piperacillin-tazobactam. Results: Despite significant inter-subject and simulated intra-day PK variability and sensor error, PID demonstrated a significant improvement in target attainment compared to traditional bolus and continuous infusion approaches. Conclusion: A PID controller driven by ISF drug concentration measurements has the potential to precisely deliver piperacillin-tazobactam in critically-ill patients undergoing treatment for sepsis

Reversible, High-Affinity Surface Capturing of Proteins Directed by Supramolecular Assembly

The ability to design surfaces with reversible, high-affinity protein binding sites represents a significant step forward in the advancement of analytical methods for diverse biochemical and biomedical applications. Herein, we report a dynamic supramolecular strategy to directly assemble proteins on surfaces based on multivalent host–guest interactions. The host–guest interactions are achieved by one-step nanofabrication of a well-oriented β-cyclodextrin host-derived self-assembled monolayer on gold (β-CD-SAM) that forms specific inclusion complexes with hydrophobic amino acids located on the surface of the protein. Cytochrome c, insulin, α-chymotrypsin, and RNase A are used as model guest proteins. Surface plasmon resonance and static time-of-flight secondary ion mass spectrometry studies demonstrate that all four proteins interact with the β-CD-SAM in a specific manner via the hydrophobic amino acids on the surface of the protein. The β-CD-SAMs bind the proteins with high nanomolar to single-digit micromolar dissociation constants (KD). Importantly, while the proteins can be captured with high affinity, their release from the surface can be achieved under very mild conditions. Our results expose the great advantages of using a supramolecular approach for controlling protein immobilization, in which the strategy described herein provides unprecedented opportunities to create advanced bioanalytic and biosensor technologies

Multiplex in situ hybridization within a single transcript: RNAscope reveals dystrophin mRNA dynamics

Dystrophin plays a vital role in maintaining muscle health, yet low mRNA expression, lengthy transcription time and the limitations of traditional in-situ hybridization (ISH) methodologies mean that the dynamics of dystrophin transcription remain poorly understood. RNAscope is highly sensitive ISH method that can be multiplexed, allowing detection of individual transcript molecules at sub-cellular resolution, with different target mRNAs assigned to distinct fluorophores. We instead multiplex within a single transcript, using probes targeted to the 5’ and 3’ regions of muscle dystrophin mRNA. Our approach shows this method can reveal transcriptional dynamics in health and disease, resolving both nascent myonuclear transcripts and exported mature mRNAs in quantitative fashion (with the latter absent in dystrophic muscle, yet restored following therapeutic intervention). We show that even in healthy muscle, immature dystrophin mRNA predominates (60–80% of total), with the surprising implication that the half-life of a mature transcript is markedly shorter than the time invested in transcription: at the transcript level, supply may exceed demand. Our findings provide unique spatiotemporal insight into the behaviour of this long transcript (with implications for therapeutic approaches), and further suggest this modified multiplex ISH approach is well-suited to long genes, offering a highly tractable means to reveal complex transcriptional dynamics

Valence Band Dependent Charge Transport in Bulk Molecular Electronic Devices Incorporating Highly Conjugated Multi-[(Porphinato)Metal] Oligomers

Molecular electronics offers the potential to control device functions through the fundamental electronic properties of individual molecules, but realization of such possibilities is typically frustrated when such specialized molecules are integrated into a larger area device. Here we utilize highly conjugated (porphinato)metal-based oligomers (PMn structures) as molecular wire components of nanotransfer printed (nTP) molecular junctions; electrical characterization of these "bulk" nTP devices highlights device resistances that depend on PMn wire length. Device resistance measurements, determined as a function of PMn molecular length, were utilized to evaluate the magnitude of a phenomenological β corresponding to the resistance decay parameter across the barrier; these data show that the magnitude of this β value is modulated via porphyrin macrocycle central metal atom substitution [β(PZnn; 0.065 Å-1) < β(PCun; 0.132 Å-1) < β(PNin; 0.176 Å-1)]. Cyclic voltammetric data, and ultraviolet photoelectron spectroscopic studies carried out at gold surfaces, demonstrate that these nTP device resistances track with the valence band energy levels of the PMn wire, which were modulated via porphyrin macrocycle central metal atom substitution. This study demonstrates the ability to fabricate "bulk" and scalable electronic devices in which function derives from the electronic properties of discrete single molecules, and underscores how a critical device function - wire resistance - may be straightforwardly engineered by PMn molecular composition

Glassy Phase Transition and Stability in Black Holes

Black hole thermodynamics, confined to the semi-classical regime, cannot address the thermodynamic stability of a black hole in flat space. Here we show that inclusion of correction beyond the semi-classical approximation makes a black hole thermodynamically stable. This stability is reached through a phase transition. By using Ehrenfest's scheme we further prove that this is a glassy phase transition with a Prigogine-Defay ratio close to 3. This value is well placed within the desired bound (2 to 5) for a glassy phase transition. Thus our analysis indicates a very close connection between the phase transition phenomena of a black hole and glass forming systems. Finally, we discuss the robustness of our results by considering different normalisations for the correction term.Comment: v3, minor changes over v2, references added, LaTeX-2e, 18 pages, 3 ps figures, to appear in Eour. Phys. Jour.

Exploring the pharmacokinetics of phenoxymethylpenicillin (Penicillin-V) in adults: a healthy volunteer study

This healthy volunteer study aimed to explore Phenoxymethylpenicillin (Penicillin-V) pharmacokinetics (PK) to support the planning of large, dosing studies in adults. Volunteers were dosed with penicillin-V at steady state. Total and unbound penicillin-V serum concentration was determined and a base population PK model were fitted to the data