Creating a Novel Mathematical Model of the Kv10.1 Ion Channel and Controlling Channel Activity with Nanoelectromechanical Systems

Featured Application Nanoelectromechanical systems and nanorobots can be used to treat cancers associated with the Kv10.1 voltage-gated ion channel activity. The Kv10.1 model was developed by applying the control engineering theory. Nanoelectromechanical systems play the role of a PID regulator. The use of nanoelectromechanical systems or nanorobots offers a new concept for sensing and controlling subcellular structures, such as ion channels. We present here a novel method for mathematical modeling of ion channels based on control system theory and system identification. We investigated the use of nanoelectromechanical devices to control the activity of ion channels, particularly the activity of the voltage-gated ion channel Kv10.1, an important channel in cancer development and progression. A mathematical model of the dynamic behavior of the selected ion channel Kv10.1 in the Laplace (s) domain was developed, which is given in the representation of a transfer function. In addition, we addressed the possibilities of controlling ion channel activity by nanoelectromechanical devices and nanorobots and finally presented a control algorithm for the Kv10.1 as a control object. A use case demonstrates the potential of a Kv10.1 controlled nanorobot for cancer treatment at a single-cell level

A hyperspectral imaging system for mapping haemoglobin and cytochrome-c-oxidase concentration changes in the exposed cerebral cortex

We present a novel hyperspectral imaging (HSI) system using visible and near-infrared (NIR) light on the exposed cerebral cortex of animals, to monitor and quantify in vivo changes in the oxygenation of haemoglobin and in cellular metabolism via measurement of the redox states of cytochrome-c-oxidase (CCO). The system, named hNIR, is based on spectral scanning illumination at 11 bands (600, 630, 665, 784, 800, 818, 835, 851, 868, 881 and 894 nm), using a supercontinuum laser coupled with a rotating Pellin-Broca prism. Image reconstruction is performed with the aid of a Monte Carlo framework for photon pathlength estimation and post-processing correction of partial volume effects. The system is validated on liquid optical phantoms mimicking brain tissue haemodynamics and metabolism, and finally applied in vivo on the exposed cortex of mice undergoing alternating oxygenation challenges. The results of the study demonstrate the capacity of hNIR to map and quantify the haemodynamic and metabolic states of the exposed cortex at microvascular levels. This represents (to the best of our knowledge) the first example of simultaneous mapping and quantification of cerebral haemoglobin and CCO in vivo using visible and NIR HSI, which can potentially become a powerful tool for better understanding brain physiology

Ion Channel Modeling beyond State of the Art: A Comparison with a System Theory-Based Model of the Shaker-Related Voltage-Gated Potassium Channel Kv 1.1

The mathematical modeling of ion channel kinetics is an important tool for studying the electrophysiological mechanisms of the nerves, heart, or cancer, from a single cell to an organ. Common approaches use either a Hodgkin–Huxley (HH) or a hidden Markov model (HMM) description, depending on the level of detail of the functionality and structural changes of the underlying channel gating, and taking into account the computational effort for model simulations. Here, we introduce for the first time a novel system theory-based approach for ion channel modeling based on the concept of transfer function characterization, without a priori knowledge of the biological system, using patch clamp measurements. Using the shaker-related voltage-gated potassium channel Kv1.1 (KCNA1) as an example, we compare the established approaches, HH and HMM, with the system theory-based concept in terms of model accuracy, computational effort, the degree of electrophysiological interpretability, and methodological limitations. This highly data-driven modeling concept offers a new opportunity for the phenomenological kinetic modeling of ion channels, exhibiting exceptional accuracy and computational efficiency compared to the conventional methods. The method has a high potential to further improve the quality and computational performance of complex cell and organ model simulations, and could provide a valuable new tool in the field of next-generation in silico electrophysiology

Use of modified U1 snRNAs to inhibit HIV-1 replication

Control of RNA processing plays a central role in regulating the replication of HIV-1, in particular the 3′ polyadenylation of viral RNA. Based on the demonstration that polyadenylation of mRNAs can be disrupted by the targeted binding of modified U1 snRNA, we examined whether binding of U1 snRNAs to conserved 10 nt regions within the terminal exon of HIV-1 was able to inhibit viral structural protein expression. In this report, we demonstrate that U1 snRNAs complementary to 5 of the 15 regions targeted result in significant suppression of HIV-1 protein expression and viral replication coincident with loss of viral RNA. Suppression of viral gene expression is dependent upon appropriate assembly of a U1 snRNP particle as mutations of U1 snRNA that affect binding of U1 70K or Sm proteins significantly reduced efficacy. However, constructs lacking U1A binding sites retained significant anti-viral activity. This finding suggests a role for these mutants in situations where the wild-type constructs cause toxic effects. The conserved nature of the sequences targeted and the high efficacy of the constructs suggests that this strategy has significant potential as an HIV therapeutic

The misogyny of iron deficiency

Anaemia is common, particularly in women and the commonest underlying cause, iron deficiency, is often overlooked. Anaemia is associated with increased morbidity and mortality in patients undergoing anaesthesia; however, women are defined as being anaemic at a lower haemoglobin level than men. In this narrative review, we present the history of iron deficiency anaemia and how women’s health has often been overlooked. Iron deficiency was first described as ‘chlorosis’ and a cause of ‘hysteria’ in women and initial treatment was by iron filings in cold wine. We present data of population screening demonstrating how common iron deficiency is, affecting 12–18% of apparently ‘fit and healthy’ women, with the most common cause being heavy menstrual bleeding; both conditions being often unrecognised. We describe a range of symptoms reported by women, that vary from fatigue to brain fog, hair loss and eating ice. We also describe experiments exploring the physical impact of iron deficiency, showing that reduced exercise performance is related to iron deficiency independent of haemoglobin concentration, as well as the impact of iron supplementation in women improving oxygen consumption and fitness. Overall, we demonstrate the need to single out women and investigate iron deficiency rather than accept the dogma of normality and differential treatment; this is to say, the need to change the current standard of care for women undergoing anaesthesia

The importance of combined NGS and MLPA genetic tests for differential diagnosis of maturity onset diabetes of the young

Introduction: Maturity onset diabetes of the young (MODY) is a rare form of monogenic diabetes. Being clinically and genetically heterogeneous, it is often misdiagnosed as type 1 or type 2 diabetes, leading to inappropriate therapy. MODY is caused by a single gene mutation. Thirteen genes, defining 13 subtypes, have been identified to cause MODY. A correct diagnosis is important for the right therapy, prognosis, and genetic counselling.Material and methods: Twenty-nine unrelated paediatric patients clinically suspected of having MODY diabetes were analysed using TruSight One panel for next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) assay.Results: In this study we identified variants in MODY genes in 22 out of 29 patients (75.9%). Using two genetic tests, NGS and MLPA, we detected both single nucleotide variants and large deletions in patients. Most of the patients harboured a variant in the GCK gene (11/22), followed by HNF1B (5/22). The rest of the variants were found in the NEUROD1 and HNF1A genes. We identified one novel variant in the GCK gene: c.596T>C, p.Val199Ala. The applied genetic tests excluded the suspected diagnosis of MODY in two patients and revealed variants in other genes possibly associated with the patient’s clinical phenotype.Conclusions: In our group of MODY patients most variants were found in the GCK gene, followed by variants in HNF1B, NEUROD1, and HNF1A genes. The combined NGS and MLPA-based genetic tests presented a comprehensive approach for analysing patients with suspected MODY diabetes and provided a successful differential diagnosis of MODY subtypes