A new HCN1 channelopathy: implications for epilepsy

This scientific commentary refers to ‘Cation leak underlies neuronal excitability in an HCN1 developmental and epileptic encephalopathy’ by Bleakley et al. (doi:10.1093/brain/awab145)

Bio-Treatment of Energetic Materials Using White-Rot Fungus

The nitramine explosive, octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX), is used by militaries around the world in high yield munitions and often in combination with hexahydro- 1,3,5-trirdtro- 1,3,5- triazine (RDX). Improper handling and disposal of manufacturing wastewater may lead to environmental contamination. In the past wastewater was collected in disposal lagoons where it evaporated, and deposited large amounts of explosives on the lagoon floor. Although lagoon disposal is no longer practiced, thousands of acres have been already contaminated. RDX and, to a lesser extent, HMX have leached through the soil subsurface and contaminated groundwater ( 1,2). Likewjse, burning of substandard material or demilitarization of out-of-date muriitions has also led to environmental contamination. The current stockpile of energetic materials at DOE sites requires resource recovery or disposition (RRD). A related challenge exists in the clean-up of the DOE sites where soil and ground water are contaminated with explosives. Current technologies such as incineration, molten salt process, supercritical water oxidation are expensive and have technical hurdles. Open burning and open detonation(OB/OD) is not encouraged by regulatory agencies for disposal of explosives. Hence, there is need for a safe . technology to degrade these contaminants. The fi.mgal process does not employ open burning or open detonation to destroy energetic materials. The fimgal process can be used by itself, or it can augment or support other technologies for the treatment of energetic materials. The proposed enzyme technology will not release any air pollutants and will meet the regulations of Clean Air Act amendments, the Resource Conservation and Recovery Act, and the Federal. Facilities Compliance Act. The goal for this project was to test the ability of white-rot fungus to degrade HMX. In our study, we investigated the biodegradation of HMX using white-rot fungus in liquid and solid cultures. The degradation of HMX was studied at 1, 10, 100 and 1000 ppm levels. In all cases, HMX was degraded. In general, the rate of degradation of HMX increased with increase in HMX concentration. Because of encouraging findings, further optimization of this method and eventual field testing of this technology is recommended. This research was pefiormed in collaboration with Utah State University

Recording Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Currents (Ih) in Neurons

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are voltage-gated ion channels that play a crucial role in many physiological processes such as memory formation and spatial navigation. Alterations in expression and function of HCN channels have also been associated with multiple disorders including epilepsy, neuropathic pain, and anxiety/depression. Interestingly, neuronal HCN currents (Ih) have diverse biophysical properties in different neurons. This is likely to be in part caused by the heterogeneity of the HCN subunits expressed in neurons. This variation in biophysical characteristics is likely to influence how Ih affects neuronal activity. Thus, it is important to record Ih directly from individual neurons. This protocol describes voltage-clamp methods that can be used to record neuronal Ih under whole-cell voltage-clamp conditions, in cell-attached mode, or with outside-out patches. The information obtained using this approach can be used in combination with other techniques such as computational modeling to determine the significance of Ih for neuronal function

Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Currents in Neurons

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are voltage-gated ion channels that activate at potentials more negative than -50 mV and are predominantly permeable to Na(+) and K(+) ions. Four HCN subunits (HCN1-4) have been cloned. These subunits have distinct expression patterns and biophysical properties. In addition, cyclic nucleotides as well as multiple intracellular substances including various kinases and phosphatases modulate the expression and function of the subunits. Hence, the characteristics of the current, Ih, are likely to vary among neuronal subtypes. In many neuronal subtypes, Ih is present postsynaptically, where it plays a critical role in setting the resting membrane potential and the membrane resistance. By influencing these intrinsic properties, Ih will affect synaptic potential shapes and summation and thereby affect neuronal excitability. Additionally, Ih can have an effect on resonance properties and intrinsic neuronal oscillations. In some neurons, Ih may also be present presynaptically in axons and synaptic terminals, where it modulates neuronal transmitter release. Hence the effects of Ih on neuronal excitability are complex. It is, however, necessary to fully understand these as Ih has a significant impact on physiological conditions such as learning as well as pathophysiological states such as epilepsy

Neuronal HCN channel Function and Plasticity

The hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channel is a voltage-gated cation channel that is activated with hyperpolarization. Four subunits, HCN1–4, have thus far been identified. All four subunits are expressed in the central nervous system (CNS), though their expression pattern varies considerably. In many CNS neurons, HCN channels are localised to somato-dendritic compartments where they regulate the resting membrane potential and membrane resistance, and thereby affect synaptic potential shapes and integration and neuronal firing patterns. Emerging evidence suggests that HCN channels are also present within certain axons and synaptic terminals. Modulation of presynaptic HCN channel activity leads to altered synaptic release in a synapsespecific manner. Given that HCN channel function can be modified by activity-dependent and neurotransmitter receptor activation, HCN channels may diversely affect neuronal and network excitability, thereby affecting physiological states such as learning and memory as well as pathophysiological conditions such as epilepsy and depression

Correction: Detecting antimicrobial resistance in Escherichia coli using benchtop attenuated total reflectance-Fourier transform infrared spectroscopy and machine learning.

Correction for 'Detecting antimicrobial resistance in Escherichia coli using benchtop attenuated total reflectance-Fourier transform infrared spectroscopy and machine learning' by Hewa G. S. Wijesinghe et al., Analyst, 2021, DOI: 10.1039/d1an00546d

A Model of Basic Surgical Skills Course to Supplement the Training of Foundation-Year Doctors by Efficient Use of Local Resources

INTRODUCTION: This study investigates the efficiency of teaching basic surgical skills to foundation-year doctors and medical students by using local resources. METHODS: A course comprising 4 workshops, once a week, of 3 hours duration per session was delivered using local education center facilities and using the local faculty of consultants and surgical trainees. Teaching methods include practical skill stations supplemented with short didactic lectures and group discussion. Precourse and postcourse assessments were completed by candidates and analyzed to measure outcomes of the course both subjectively and objectively. RESULTS: A total number of 20 participants completed the course. On completion of the course, (1) participants' theoretical knowledge improved significantly (p < 0.0001), as measured by multiple-choice questions, and scores improved by 35% (mean 44%, standard deviation = 16%) before the course compared to (mean = 79%, standard deviation = 13) after the course; (2) the level of confidence in knowledge and skills was measured by a questionnaire on a scale of 1 to 5, and there was a significant (p < 0.0001) improvement on postcourse assessment (mean difference = 1.5, 95% CI: 0.7-2.4); and (3) practical skills such as suture position, knot tying, and wound apposition significantly improved after the course, χ(2) (2) = 16, p < 0.001; χ(2) (2) = 18, p < 0.001; and χ(2) (2) = 22, p < 0.0001, respectively. CONCLUSION: Effective delivery of basic surgical skills to foundation-year doctors by using local resources can be achieved at low cost

Loss of Dendritic HCN1 Subunits Enhances Cortical Excitability and Epileptogenesis

Hyperpolarization-activated cation nonselective 1 (HCN1) plasticity in entorhinal cortical (EC) and hippocampal pyramidal cell dendrites is a salient feature of temporal lobe epilepsy. However, the significance remains undetermined. We demonstrate that adult HCN1 null mice are more susceptible to kainic acid-induced seizures. After termination of these with an anticonvulsant, the mice also developed spontaneous behavioral seizures at a significantly more rapid rate than their wild-type littermates. This greater seizure susceptibility was accompanied by increased spontaneous activity in HCN1(-/-) EC layer III neurons. Dendritic I-h in these neurons was ablated, too. Consequentially, HCN1(-/-) dendrites were more excitable, despite having significantly more hyperpolarized resting membrane potentials (RMPs). In addition, the integration of EPSPs was enhanced considerably such that, at normal RMP, a 50 Hz train of EPSPs produced action potentials in HCN1(-/-) neurons. As a result of this enhanced pyramidal cell excitability, spontaneous EPSC frequency onto HCN1(-/-) neurons was considerably greater than that onto wild types, causing an imbalance between normal excitatory and inhibitory synaptic activity. These results suggest that dendritic HCN channels are likely to play a critical role in regulating cortical pyramidal cell excitability. Furthermore, these findings suggest that the reduction in dendritic HCN1 subunit expression during epileptogenesis is likely to facilitate the disorder

Dendritic ion channel trafficking and plasticity.

Dendritic ion channels are essential for the regulation of intrinsic excitability as well as modulating the shape and integration of synaptic signals. Changes in dendritic channel function have been associated with many forms of synaptic plasticity. Recent evidence suggests that dendritic ion channel modulation and trafficking could contribute to plasticity-induced alterations in neuronal function. In this review we discuss our current knowledge of dendritic ion channel modulation and trafficking and their relationship to cellular and synaptic plasticity. We also consider the implications for neuronal function. We argue that to gain an insight into neuronal information processing it is essential to understand the regulation of dendritic ion channel expression and properties

In vivo measurement of surface pressures and retraction distances applied on abdominal organs during surgery

This study undertook the in vivo measurement of surface pressures applied by the fingers of the surgeon during typical representative retraction movements of key human abdominal organs during both open and hand-assisted laparoscopic surgery. Surface pressures were measured using a flexible thin-film pressure sensor for 35 typical liver retractions to access the gall bladder, 36 bowel retractions, 9 kidney retractions, 8 stomach retractions, and 5 spleen retractions across 12 patients undergoing open and laparoscopic abdominal surgery. The maximum and root mean square surface pressures were calculated for each organ retraction. The maximum surface pressures applied to these key abdominal organs are in the range 1 to 41 kPa, and the average maximum surface pressure for all organs and procedures was 14 ± 3 kPa. Surface pressure relaxation during the retraction hold period was observed. Generally, the surface pressures are higher, and the rate of surface pressure relaxation is lower, in the more confined hand-assisted laparoscopic procedures than in open surgery. Combined video footage and pressure sensor data for retraction of the liver in open surgery enabled correlation of organ retraction distance with surface pressure application. The data provide a platform to design strategies for the prevention of retraction injuries. They also form a basis for the design of next-generation organ retraction and space creation surgical devices with embedded sensors that can further quantify intraoperative retraction forces to reduce injury or trauma to organs and surrounding tissues