Contribution of electrostatic and structural properties of Kv4.3 S4 arginine residues to the regulation of channel gating

AbstractPrevious work has demonstrated that replacing individual arginine (R) residues in the S4 domain of Kv4.3 with alanine (A) not only altered activation and deactivation processes, but also those of closed-state inactivation (CSI) and recovery. R → A mutants eliminated individual positive charge while substantially reducing side chain volume and hydrophilic character. Their novel effects on gating may thus have been the result of electrostatic and/or structural perturbations. To address this issue, and to gain further insights into the roles that S4 plays in the regulation of Kv4.3 gating transitions, we comparatively analyzed arginine to glutamine (R → Q) mutations at positions 290, 293, and 296. This maneuver maintained positive charge elimination of the R → A mutants, while partially restoring native side chain volume and hydrophilic properties. R → A and R → Q mutant pairs produced similar effects on the forward gating process of activation. In contrast, significant differences between the two substitutions were discovered on deactivation, CSI, and recovery, with the R → Q mutants partially restoring wild type characteristics. Our results argue that modification of individual S4 residue properties may result in altered localized interactions within unique microenvironments encountered during forward and reverse gating transitions. As such, predominant effects appear on the reverse gating transitions of deactivation and recovery. These results are consistent with the proposal that arginine residues in S4 are involved in regulating Kv4.3 CSI and recovery

The effect of surgical approach on the histology of the femoral head following resurfacing of the hip : analysis of retrieval specimens

Objectives: We aimed to determine the effect of surgical approach on the histology of the femoral head following resurfacing of the hip. Methods: We performed a histological assessment of the bone under the femoral component taken from retrieval specimens of patients having revision surgery following resurfacing of the hip. We compared the number of empty lacunae in specimens from patients who had originally had a posterior surgical approach with the number in patients having alternative surgical approaches. Results: We found a statistically significant increase in the percentage of empty lacunae in retrieval specimens from patients who had the posterior approach compared with other surgical approaches (p < 0.001). Conclusions: This indicates that the vascular compromise that occurs during the posterior surgical approach does have long-term effects on the bone of the femoral head, even if it does not cause overt avascular necrosis

Reaction Bonded Silicon Carbide: SFF, Process Refinement and Applications

Reaction bonded silicon carbide (RBSiC) has a wide variety of industrial applications and a manufacturing process based on Selective Laser Sintering (SLS) has been demonstrated in previous research at the University of Texas. That study was directed toward semiconductor manufacturing applications and was based on prior indirect SLS methods. Several key research questions were addressed for three main manufacturing phases: preform SLS, binder burnout and reactive infiltration. The current research is focused on development of material systems and manufacturing capability and is directed toward a broader set of potential applications. Preform formation utilizes SiC powder of an appropriate average particle size mixed with a multicomponent binder. The preform or green part is then placed in a vacuum furnace to carbonize the binder. The details of the binder chemistry must support accurate SFF shapes and acceptable surface roughness, a strong green part and maintenance of the part shape during the first furnace operation. Finally, the physics and chemistry of the infiltration process, based on the microstructure of the initial green preform, determine the viability of the manufacturing process and the characteristics of the final composite material. The functionality of metal, polymer and ceramic matrix composites can support the growing SFF industry desire to move beyond functional prototyping and into manufacturing arenas. This project is being explored for more general application to matrix composite materials, especially highly functional systems tailored specifically for SLS. The goal is to establish the governing principles of binder function, carbonization and infiltration as well as to understand the interdependence of these phases in terms of manufacturing application. With this understanding new applications and special SLS composites can support the development of new products and a greater SFF manufacturing presence. This paper provides an introduction to the material, a look at basic rapid manufacturing trends, an overview of the previous work, a review of relevant RBSiC material science issues, and an outline of the current study.Mechanical Engineerin

The Development of an Open Source Intelligence Gathering Exercise for Teaching Information Security & Privacy

This research-in-progress paper describes the development of a pedagogical exercise on open source intelligence gathering (OSINT). Exercise materials will include instructions, teaching notes, assessment criteria, and a preconfigured virtual machine (VM), which acts as a local web server. The VM will host multiple websites containing vulnerable information pertinent to a fictitious target organization, in effect creating a capture the flag (CTF) scenario. The exercise will not only teach students how to find public information, but also help students realize the importance of protecting such information. While this exercise is primarily geared towards those pursuing a career in information security, the exercise is appropriate for all students as it shows how personal information could be used against them, as well as their organizations

Racial Differences in Vascular Function in Response to Mental Stress

African Americans (AA) have a higher prevalence of hypertension and other cardiovascular (CV) complications compared to other populations. While the reasons for this elevated CV disease risk are multifactorial, vascular dysfunction is a key contributing factor. It has been previously shown that mental stress, induced by mental arithmetic, results in a significant increase in forearm blood flow (FBF). This response has been predominantly attributed to the release and vasodilatory effect of Nitric Oxide (NO). In this regard, a previous study has reported that AA have an attenuated increase in FBF as compared to Caucasians (CA) in response to mental stress, which may be related to impaired vascular function and thus elevated CV disease risk in AA. However, this study was conducted in a middle-age cohort (mid to late 40’s). Whether this attenuation is present in a young relatively healthy population is unknown. PURPOSE: The purpose of this study was to test the hypothesis that the vasodilatory response to mental stress is blunted in a relatively young and healthy AA population. METHODS: 6 relatively healthy young AA and 6 CA males (AA age: 22 + 2.6, CA age: 23 + 4.6) participated in this study. All measurements were obtained in the morning following an overnight fast. Brachial artery diameter and blood velocity were assessed using high resolution duplex ultrasound. Mental stress was induced by asking subjects to subtract 7 continuously from a 3-digit number while attempting to report answers at a pace set by a 60 bpm metronome. The 3-digit number was changed at 20 second intervals. FBF was measured during a two minute baseline followed by 3 minutes of mental stress. Vascular function was assessed as the absolute peak blood flow response (ml/min) as well as peak conductance (ml/min/mmHg) during the mental stress. RESULTS: The absolute peak flow (AA: 183 + 39 ml/min, CA: 307 + 127 ml/min; P = 0.05) were significantly greater in CA compared to AA. The maximum increase in conductance (AA: 2.03 + 0.32 ml/min/mmHg, CA: 3.69 + 1.39 ml/min/mmHg; P = .02) was also significantly higher in CA as compared to AA. CONCLUSION: This preliminary data supports our hypothesis that vascular function in response to mental stress is attenuated in young healthy AA as compared to their CA counterparts

Relationships Between Indices of Macrovascular and Microvascular Function in Young, Black Women

Blacks (BL) exhibit an exaggerated prevalence of and mortality from cardiovascular disease (CVD) relative to other populations. Macro- and microvascular dysfunction is often a hallmark of heightened CVD risk, with both demonstrated in BL. However, data regarding this dysfunction remains sparse, particularly in BL women. Common indices of vascular function include flow-mediated dilation (FMD) and reactive hyperemia (RH) following a brief period of suprasystolic cuff occlusion and cutaneous thermal reactivity to local heating (LH). However, the relationship between these indices has not been established in BL women. PURPOSE: The present study aimed to test the relationship between indices of vascular function in BL women as assessed by FMD, RH, and LH. METHODS: To test this hypothesis, 6 white women (WW) and 6 BW (age: 22±2 vs. 21±3, respectively) were studied. FMD and RH were assessed following a period of suprasystolic cuff occlusion. Briefly, a rapid inflation cuff was secured just distal to the antecubital fossa for arterial occlusion. Blood velocity (Vmean; cm ∙ s-1) and vessel diameter (d; mm) were measured continuously via high-resolution, duplex Doppler ultrasound during a 2-min baseline, 5-min of cuff occlusion, and 3-min of recovery. FMD was determined as the percent dilation from baseline (%FMD) while RH was determined as the peak and area under the curve (AUC) responses for shear rate (8 ∙ Vmean ∙ d-1) and blood flow (Vmean ∙ π ∙ (d ∙ 20-1)2 ∙ 60). Cutaneous thermal reactivity was assessed using laser-Doppler flowmetry during a standard LH protocol and reported as cutaneous vascular conductance (CVC; red blood cell flux/mean arterial pressure). Following a baseline with local skin temperature clamped at 33°C, a 39°C heat stimulus was applied to induce cutaneous vasodilation for ~30-min. The sustained vasodilation at the end of heating is predominantly nitric oxide mediated and provides an index of microvascular function. As the LH component served as part of a larger intradermal microdialysis protocol, maximal blood flow responses were elicited via combined intradermal sodium nitroprusside (28mM) infusion and 43°C heating. CVC during the 39°C plateau was normalized to maximal CVC (%CVCmax) to account for intersite variability. Pearson correlations were then performed between the FMD, RH, and LH responses. RESULTS: Significant relationships were observed between %FMD and shear AUC (r = 0.89; P = 0.02), and blood flow AUC (r = 0.92; P = 0.01) in WW, but not in BW (r = 0.63; P = 0.18 and r = -0.24; P = 0.65, respectively). However, neither FMD nor RH correlated with the cutaneous blood flow responses to LH (P \u3e 0.05) in either WW or BW. CONCLUSION: These preliminary data suggest that FMD is highly correlated to some indices of RH in WW, but that this relationship does not hold in BW. Further, there appears to be no relationship between microvascular function as assessed by RH and LH in either population

VIRTUAL EXPERIENCE, REAL LEARNING

BACKGROUND Students rarely appreciate the interdisciplinarity of medical sciences or reflect upon broader applications of their studies. COVID-19 forced us to develop online learning experiences that are authentic, engaging and scalable because our 540 first-year Human Biology students see the Medical Science program only as a gateway to studying Medicine. Our aim was to explore an environment that challenged their perceptions of medical science. DESCRIPTION OF INTERVENTION We used a Ricoh Theta Z1 360°-camera and 3DVista© software to create a virtual tour of the Chau Chak Wing Museum, a facility co-locating The University of Sydney’s collections. The tour included mummified remains, the Jericho skull, and an anatomical clastic model, but also taxidermised thylacine, extant animals, and items of anthropologic interest. Local and remote students had identical experience of the collections. RESULTS Students engaged positively with an activity that was not demanding. Most reflected new appreciation of how historical models advance our understanding, especially with response to disease. Many also expressed a desire to visit the museum in person. CONCLUSIONS 3D virtual experiences are increasingly popular for asynchronous learning, including remote/hazardous locations and workplace induction. This is a relatively inexpensive, easily developed and deployed option for online teaching in medical sciences, especially in laboratory demonstrations

1006. ANTHORRHIZA ECHINELLA: An ant‐plant of the Rubiaceae

The rare ant-plant Anthorrhiza echinella C.R.Huxley & Jebb from Papua New Guinea is described and illustrated. The outlook of the species and the importance of ex situ conservation strategies for this and other ant-plants are discussed in the context of botanic garden collections. Based on the plant's likely current distribution, we have assessed the species under the IUCN Red List as Endangered (EN) under criteria B1ab(iii) + 2ab(iii)

Differential effects of calcium antagonist subclasses on markers of nephropathy progression

Differential effects of calcium antagonist subclasses on markers of nephropathy progression.BackgroundNumerous studies suggest that the dihydropyridine calcium antagonists (DCAs) and nondihydropyridine calcium antagonists (NDCAs) have differential antiproteinuric effects. Proteinuria reduction is a correlate of the progression of renal disease. In an earlier systematic review, calcium antagonists were shown as effective antihypertensive drugs, but there was uncertainty about their renal benefits in patients with proteinuria and renal insufficiency.MethodsA systematic review was conducted to assess the differential effects of DCAs and NDCAs on proteinuria in hypertensive adults with proteinuria, with or without diabetes, and to determine whether these differential effects translate into altered progression of nephropathy. Studies included in the review had to be randomized clinical trials with at least 6months of treatment, include a DCA or NDCA treatment arm, have one or more renal end points, and have been initiated after 1986. Summary data were extracted from 28 studies entered into two identical but separate databases, which were compared and evaluated by independent reviewers. The effects of each drug class on blood pressure (N = 1338) and proteinuria (N = 510) were assessed.ResultsAfter adjusting for sample size, study length, and baseline value, there were no statistically significant differences in the ability of either class of calcium antagonist to decrease blood pressure. The mean change in proteinuria was +2% for DCAs and -30% for NDCAs (95% CI, 10% to 54%, P = 0.01). Consistently greater reductions in proteinuria were associated with the use of NDCAs compared with DCAs, despite no significant differences in blood pressure reduction or presence of diabetes.ConclusionThis analysis supports (1) similar efficacy between subclasses of calcium antagonists to lower blood pressure, and (2) greater reductions in proteinuria by NDCAs compared to DCAs in the presence or absence of diabetes. Based on these findings, NDCAs, alone or in combination with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB), are suggested as preferred agents to lower blood pressure in hypertensive patients with nephropathy associated with proteinuria

Multiscale Genetic Structure of Yellowstone Cutthroat Trout in the Upper Snake River Basin.

Populations of Yellowstone cutthroat trout Oncorhynchus clarkii bouvierii have declined throughout their native range as a result of habitat fragmentation, overharvest, and introductions of nonnative trout that have hybridized with or displaced native populations. The degree to which these factors have impacted the current genetic population structure of Yellowstone cutthroat trout populations is of primary interest for their conservation. In this study, we examined the genetic diversity and genetic population structure of Yellowstone cutthroat trout in Idaho and Nevada with data from six polymorphic microsatellite loci. A total of 1,392 samples were analyzed from 45 sample locations throughout 11 major river drainages. We found that levels of genetic diversity and genetic differentiation varied extensively. The Salt River drainage, which is representative of the least impacted migration corridors in Idaho, had the highest levels of genetic diversity and low levels of genetic differentiation. High levels of genetic differentiation were observed at similar or smaller geographic scales in the Portneuf River, Raft River, and Teton River drainages, which are more altered by anthropogenic disturbances. Results suggested that Yellowstone cutthroat trout are naturally structured at the major river drainage level but that habitat fragmentation has altered this structuring. Connectivity should be restored via habitat restoration whenever possible to minimize losses in genetic diversity and to preserve historical processes of gene flow, life history variation, and metapopulation dynamics. However, alternative strategies for management and conservation should also be considered in areas where there is a strong likelihood of nonnative invasions or extensive habitat fragmentation that cannot be easily ameliorated