Microglia in Alzheimer's disease: a role for ion channels

Alzheimer's disease is the most common form of dementia, it is estimated to affect over 40 million people worldwide. Classically, the disease has been characterized by the neuropathological hallmarks of aggregated extracellular amyloid-β and intracellular paired helical filaments of hyperphosphorylated tau. A wealth of evidence indicates a pivotal role for the innate immune system, such as microglia, and inflammation in the pathology of Alzheimer's disease. The over production and aggregation of Alzheimer's associated proteins results in chronic inflammation and disrupts microglial clearance of these depositions. Despite being non-excitable, microglia express a diverse array of ion channels which shape their physiological functions. In support of this, there is a growing body of evidence pointing to the involvement of microglial ion channels contributing to neurodegenerative diseases such as Alzheimer's disease. In this review, we discuss the evidence for an array of microglia ion channels and their importance in modulating microglial homeostasis and how this process could be disrupted in Alzheimer's disease. One promising avenue for assessing the role that microglia play in the initiation and progression of Alzheimer's disease is through using induced pluripotent stem cell derived microglia. Here, we examine what is already understood in terms of the molecular underpinnings of inflammation in Alzheimer's disease, and the utility that inducible pluripotent stem cell derived microglia may have to advance this knowledge. We outline the variability that occurs between the use of animal and human models with regards to the importance of microglial ion channels in generating a relevant functional model of brain inflammation. Overcoming these hurdles will be pivotal in order to develop new drug targets and progress our understanding of the pathological mechanisms involved in Alzheimer's disease

Post-ischaemic immunological response in the brain: targeting microglia in ischaemic stroke therapy

Microglia, the major endogenous immune cells of the central nervous system, mediate critical degenerative and regenerative responses in ischaemic stroke. Microglia become "activated", proliferating, and undergoing changes in morphology, gene and protein expression over days and weeks post-ischaemia, with deleterious and beneficial effects. Pro-inflammatory microglia (commonly referred to as M1) exacerbate secondary neuronal injury through the release of reactive oxygen species, cytokines and proteases. In contrast, microglia may facilitate neuronal recovery via tissue and vascular remodelling, through the secretion of anti-inflammatory cytokines and growth factors (a profile often termed M2). This M1/M2 nomenclature does not fully account for the microglial heterogeneity in the ischaemic brain, with some simultaneous expression of both M1 and M2 markers at the single-cell level. Understanding and regulating microglial activation status, reducing detrimental and promoting repair behaviours, present the potential for therapeutic intervention, and open a longer window of opportunity than offered by acute neuroprotective strategies. Pharmacological modulation of microglial activation status to promote anti-inflammatory gene expression can increase neurogenesis and improve functional recovery post-stroke, based on promising preclinical data. Cell-based therapies, using preconditioned microglia, are of interest as a method of therapeutic modulation of the post-ischaemic inflammatory response. Currently, there are no clinically-approved pharmacological options targeting post-ischaemic inflammation. A major developmental challenge for clinical translation will be the selective suppression of the deleterious effects of microglial activity after stroke whilst retaining (or enhancing) the neurovascular repair and remodelling responses of microglia

Nd:YLF laser for airborne/spaceborne laser ranging

In order to meet the need for light weight, long lifetime, efficient, short pulse lasers, a diode-pumped, Nd:YLF oscillator and regenerative amplifier is being developed. The anticipated output is 20 mJ per 10 picosecond pulse, running at a repetition rate of 40 Hz. The fundamental wavelength is at 1047 nm. The oscillator is pumped by a single laser diode bar and mode locked using an electro-optic, intra-cavity phase modulator. The output from the oscillator is injected as a seed into the regenerative amplifier. The regenerative amplifier laser crystal is optically pumped by two 60W quasi-cw laser diode bars. Each diode is collimated using a custom designed micro-lens bar. The injected 10 ps pulse from the oscillator is kept circulating within the regenerative amplifier until this nanojoule level seed pulse is amplified to 2-3 millijoules. At this point the pulse is ejected and sent on to a more standard single pass amplifier where the energy is boosted to 20 mJ. The footprint of the entire laser (oscillator-regenerative amplifier-amplifier) will fit on a 3 by 4 ft. optical pallet

Heat flow measurements on a hydrothermally-active, slow-spreading ridge: The Escanaba Trough

Maximum heat flow measurements at three locations in the sediment-filled Escanaba Trough of the Gorda ridge exceed 1200 mW/m². At other ridge crests with thick sediment cover, heat flow values of this magnitude are accompanied by high temperature hydrothermal vent activity and massive sulfide deposition. A dredge haul from the southernmost high heat flow location recovered pyrrhotite, thereby confirming the presence of recent high temperature venting

Effects of Stocking Density on Steer Performance and Carcass Characteristics in Bedded Hoop Barns

Use of bedded hoop barns for feeding cattle has grown in part due to increased regulations regarding open feedlot runoff. In 2010, ISU estimated almost 700 hoop barns in Iowa used for beef cattle and more than 80% were used for cattle feeding. Work in Iowa also has documented that cattle confined in a bedded hoop barn perform similarly to cattle fed in an open feedlot with shelter. The work was done with a stocking density of 50 sq ft per steer in the bedded hoop barn. A hoop barn is a more expensive facility system compared with open lot configurations. Fixed costs per steer (facilities) are partially determined by stocking density. The objective of this study was to determine the effects of increased stocking density on performance and carcass characteristics of steers fed in bedded hoop and bedded open front facilities. The trials were conducted in 2008 to 2011 at the ISU Armstrong Research Farm, Lewis, IA. The hoop barn was stocked with 40, 45 and 50 head per pen resulting in 50, 45 and 40 sq ft per steer, respectively. There was one stocking density per housing type per trial. The diet fed was 45.0% dry corn, 14.8% ground hay, 36.8% modified distillers grains and 3.4% supplement on an as-fed basis. The total diet was approximately 69% dry matter. Cattle growth rate (ADG), feed intake (DMI), feed efficiency (F/G) and mean mud score did not differ based on stocking density (P\u3e0.05). However, the cattle given more square feet numerically had greater feed intake and were more efficient (about 4-5%) than the more densely stocked cattle. This study may not have had enough replications to detect statistically significant differences. Also the mean carcass characteristics (fat cover, rib eye area, marbling score, quality grade and yield grade) did not differ by stocking density (P\u3e0.05). When comparing seasons only, steers fed in summer tended to have heavier market liveweight, heavier carcass weight, required less feed per liveweight and less marbling compared with steers fed in winter (P≤0.10). Also, the summer-fed steers grew faster and gained more liveweight than the winter-fed steers (P\u3c0.005). These results suggest that this study may not have reached the maximum stocking density for feeding beef cattle in a bedded hoop barn. In other words, market cattle can probably be stocked at less square footage per steer than the 40 sq ft per steer used in this study. Observations of farmers with hoop barns suggest that 37 or 35 sq ft per steer may be feasible. Several factors may affect stocking density including genetics or frame size of the cattle and may interact with season. Also, it should be noted that as the density of cattle increases, more management is required, i.e., more bedding, more bunk space, more waterer space and observing individual cattle for health issues becomes more difficult

Advances in ion channel high throughput screening: where are we in 2023?

Introduction: Automated Patch Clamp (APC) technology has become an integral element in ion channel research, drug discovery and development pipelines to overcome the use of the highly time-consuming manual patch clamp (MPC) procedures. This automated technology offers increased throughput and promises a new model in obtaining ion channel recordings, which has significant relevance to the development of novel therapies and safety profiling of candidate therapeutic compounds. Areas covered: This article reviews the recent innovations in APC technology, including platforms, and highlights how they have facilitated usage in both industry and academia. The review also provides an overview of the ion channel research endeavors and how APC platforms have contributed to the understanding of ion channel research, pharmacological tools and therapeutics. Furthermore, the authors provide their opinion on the challenges and goals for APC technology going forward to accelerate academic research and drug discovery across a host of therapeutic areas. Expert opinion: It is clear that APC technology has progressed drug discovery programs, specifically in the field of neuroscience and cardiovascular research. The challenge for the future is to keep pace with fundamental research and improve translation of the large datasets obtained

Nutrient Retention Performance of a Crushed Limestone Floor Surface in a Bedded Hoop Barn with Confined Beef Cattle

Bedded confinement systems with partial concrete floors are increasingly being adopted by beef cattle feeders. The objective of this study was to determine the extent that manure nutrients moved into the soil below the geotextile fabric and packed limestone screenings floor of a bedded hoop barn used for beef cattle feeding at the ISU Armstrong Research and Demonstration Farm. Soil samples were taken (shallow and deep) before construction in 2004 and in 2008 after 7 groups of cattle were fed. Although single samples before and after animal feeding cannot provide conclusive evidence of moisture or nutrient migration, comparison of the sample results confirm a trend consistent with slow migration of manure nutrients into the soil profile. Phosphorus, calcium and magnesium did not show consistent or major trends with time. Organic matter showed a consistent increasing trend in both shallow and deep samples. Shallow sampling showed a marked increase only in nitrate-nitrogen, from 1.51 ppm to 11.47 ppm. These results are consistent with measurable, but very slow migration of moisture and nutrients into the soil profile. Additional soil tests over time and performance of an infiltration ring study may give more conclusive answers in the future

The Effects of Bedding Pack Clean-out in Hoop Barns for Feedlot Cattle

Bedded hoop barns have become popular for feeding beef cattle. The cattle are kept in the hoop barn, which is bedded to form a manure pack. ISU work has shown that the cattle perform well. However, producers question how to manage the pack and when to clean out. The objective of this study was to compare three clean-out strategies (none, once, and twice) for beef cattle fed in hoop barns

Effects of Stocking Density on Steer Performance and Carcass Characteristics in Bedded Hoop and Open Front Confinement Facilities: Progress Report

Interest in feeding cattle in bedded confinement facilities has grown in part due to increased regulations regarding open feedlot runoff. Work in Iowa has documented that cattle confined in a bedded hoop barn perform similarly to cattle fed in an open feedlot with shelter. The work was done with a stocking density of 50 sq ft per steer in the bedded hoop barn. A hoop barn is a more expensive facility system compared with open lot configurations. Fixed costs (facilities) are partially determined by stocking density. The objective of this study was to determine the effects of increased stocking density on performance and carcass characteristics of steers fed in bedded hoop and bedded open front facilities. The trials were conducted in 2008 and 2009 at the ISU Armstrong Research Farm, Lewis, IA. The hoop barn was stocked with 40, 45, and 50 head per pen resulting in 50, 45, and 40 sq ft per steer, respectively. In the open front cattle feeding facility, pens were constructed to confine the cattle on concrete with bedding. Again the stocking density was 50, 45, and 40 sq ft per steer. In all trials, there was one stocking density per housing type per trial. The diet fed was 45.0% dry corn, 14.8% ground hay, 36.8% modified distillers grains, and 3.4% supplement on an as fed basis. The total diet was approximately 69% dry matter. Because the project is on going, no statistical analysis was performed. However, the cattle performance and carcass characteristics seemed to be similar across all facilities and stocking densities. There may be a trend for slightly less average daily gain for the highest stocking densities (6% less in the hoop and 3% less in the open front). Bunk space may be a factor in cattle performance as well as density. However, without more replications and statistical analysis, no conclusions can be made at this time

Synthetic, non-intoxicating 8,9-dihydrocannabidiol for the mitigation of seizures

There can be a fine line between therapeutic intervention and substance abuse, and this point is clearly exemplified in herbal cannabis and its products. Therapies involving cannabis have been the treatment of last resort for some cases of refractory epilepsy, and this has been among the strongest medical justifications for legalization of marijuana. In order to circumvent the narcotic effects of 9-tetrahydrocannabinol (THC), many studies have concentrated on its less intoxicating isomer cannabidiol (CBD). However, CBD, like all natural cannabinoids, is a controlled substance in most countries, and its conversion into THC can be easily performed using common chemicals. We describe here the anticonvulsant properties of 8,9-dihydrocannibidiol (H2CBD), a fully synthetic analogue of CBD that is prepared from inexpensive, non-cannabis derived precursors. H2CBD was found to have effectiveness comparable to CBD both for decreasing the number and reducing the severity of pentylenetetrazole-induced seizures in rats. Finally, H2CBD cannot be converted by any reasonable synthetic route into THC, and thus has the potential to act as a safe, noncontroversial drug for seizure mitigation