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Our ability to tackle the looming human, animal, and global ecosystem health threats arising from the issues of climate change and extreme weather events will require effective and creative cross-disciplinary collaboration. There is a growing national and international interest in equipping the next generation of clinicians and health scientists for success in facing these important challenges by providing interprofessional training opportunities. This paper describes how we assembled an interdisciplinary team of experts to design and deliver a case-based discussion on a cross-species illness outbreak in animals and humans using a One Health framework. The small group, case-based approach highlighted the impact of climate change-driven extreme weather events on human and animal health using a diarrhea outbreak associated with a contaminated community water supply precipitated by extreme flooding. Post-activity survey data indicated that this team-taught learning activity successfully engaged a cross-disciplinary cohort of medical, veterinary, and public health students in the issues of environmental public health threats and helped them understand the importance of an integrative, cross-functional, team-based approach for solving complex problems. The data from this study is being used to plan similar interprofessional, One Health learning activities across the health sciences curriculum in our institution., Competing Interests: Competing InterestsThe authors declare no competing interests., (© The Author(s) under exclusive licence to International Association of Medical Science Educators 2023.)

Anisomycin is known to inhibit eukaryotic protein synthesis and has been established as an antibiotic and anticancer drug. However, the molecular targets of anisomycin and its mechanism of action have not been explained in macrophages. Here, we demonstrated the anti-inflammatory effects of anisomycin both in vivo and in vitro. We found that anisomycin decreased the mortality rate of macrophages in cecal ligation and puncture (CLP)- and lipopolysaccharide (LPS)-induced acute sepsis. It also declined the gene expression of proinflammatory mediators such as inducible nitric oxide synthase, tumor necrosis factor-α, and interleukin-1β as well as the nitric oxide and proinflammatory cytokines production in macrophages subjected to LPS-induced acute sepsis. Furthermore, anisomycin attenuated nuclear factor (NF)-κB activation in LPS-induced macrophages, which correlated with the inhibition of phosphorylation of NF-κBinducing kinase and IκB kinase, phosphorylation and IκBα proteolytic degradation, and NF-κB p65 subunit nuclear translocation. These results suggest that anisomycin prevented acute inflammation by inhibiting NF-κB-related inflammatory gene expression and could be a potential therapeutic candidate for sepsis. [BMB Reports 2021; 54(11): 545-550].

Aims: Organophosphates (OPCs), useful agents as pesticides, also represent a serious health hazard. Standard therapy with atropine and established oxime-type enzyme reactivators is unsatisfactory. Experimental data indicate that superior therapeutic results can be obtained when reversible cholinesterase inhibitors are administered before OPC exposure. Comparing the protective efficacy of five such cholinesterase inhibitors (physostigmine, pyridostigmine, ranitidine, tacrine, or K-27), we observed best protection for the experimental oxime K-27. The present study was undertaken in order to determine if additional administration of K-27 immediately after OPC (paraoxon) exposure can improve the outcome., Methods: Therapeutic efficacy was assessed in rats by determining the relative risk of death (RR) by Cox survival analysis over a period of 48 h. Animals that received only pretreatment and paraoxon were compared with those that had received pretreatment and paraoxon followed by K-27 immediately after paraoxon exposure., Results: Best protection from paraoxon-induced mortality was observed after pretreatment with physostigmine (RR = 0.30) and K-27 (RR = 0.34). Both substances were significantly more efficacious than tacrine (RR = 0.67), ranitidine (RR = 0.72), and pyridostigmine (RR = 0.76), which were less efficacious but still significantly reduced the RR compared to the no-treatment group (paraoxon only). Additional administration of K-27 immediately after paraoxon exposure (posttreatment) did not further reduce mortality. Statistical analysis between pretreatment before paraoxon exposure alone and pretreatment plus K-27 posttreatment did not show any significant difference for any of the pretreatment regimens., Conclusions: Best outcome is achieved if physostigmine or K-27 are administered prophylactically before exposure to sublethal paraoxon dosages. Therapeutic outcome is not further improved by additional oxime therapy immediately thereafter.

Sepsis is a life-threatening condition that is caused by an abnormal immune response to infection and can lead to tissue damage, organ failure, and death. Erastin is a small molecule capable of initiating ferroptotic cell death in cancer cells. However, the function of erastin in the inflammatory response during sepsis remains unknown. Here, we showed that erastin ameliorates septic shock induced by cecal ligation and puncture or lipopolysaccharides (LPS) in mice, which was associated with a reduced production of inflammatory mediators such as nitric oxide, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β. Pretreatment with erastin in bone marrow-derived macrophages (BMDMs) significantly attenuated the expression of inducible nitric oxide synthase, cyclooxygenase-2, TNF-α, and IL-1β mRNA in response to LPS treatment. Furthermore, we also showed that erastin suppresses phosphorylation of IκB kinase β, phosphorylation and degradation of IκBα, and nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in LPS-stimulated BMDMs. Our findings suggest that erastin attenuates the inflammatory response by suppressing the NF-κB signaling pathway, resulting in inhibition of sepsis development. This study provides new insights regarding the potential therapeutic properties of erastin in sepsis.

Organophosphates, useful agents as pesticides, also represent a serious danger due to their high acute toxicity. There is indication that oximes, when administered before organophosphate exposure, can protect from these toxic effects. We have tested at equitoxic dosage (25% of LD 01 ) the prophylactic efficacy of five experimental (K-48, K-53, K-74, K-75, K-203) and two established oximes (pralidoxime and obidoxime) to protect from mortality induced by the organophosphate paraoxon. Mortalities were quantified by Cox analysis and compared with those observed after pretreatment with a strong acetylcholinesterase inhibitor (10-methylacridine) and after the FDA-approved pretreatment compound pyridostigmine. All nine tested substances statistically significantly reduced paraoxon-induced mortality. Best protection was conferred by the experimental oxime K-48, reducing the relative risk of death (RR) to 0.10, which was statistically significantly superior to pyridostigmine (RR = 0.31). The other oximes reduced the RR to 0.13 (obidoxime), 0.20 (K-203), 0.21 (K-74), 0.24 (K-75) and 0.26 (pralidoxime), which were significantly more efficacious than 10-methylacridine (RR = 0.65). These data support the hypothesis that protective efficacy is not primarily due to cholinesterase inhibition and indicate that the tested experimental oximes may be considered promising alternatives to the established pretreatment compound pyridostigmine., (© 2019 John Wiley & Sons, Ltd.)

When living tissues are injured, they undergo a sequential process of homeostasis, inflammation, proliferation and maturation, which is called wound healing. The working mechanism of wound healing has not been wholly understood due to its complex environments with various mechanical and chemical factors. In this study, we propose a novel in vitro wound healing model using a microfluidic system that can manipulate the topography of the wound bed. The topography of the extracellular matrix (ECM) in the wound bed is one of the most important mechanical properties for rapid and effective wound healing. We focused our work on the topographical factor which is one of crucial mechanical cues in wound healing process by using various nano-patterns on the cell attachment surface. First, we analyzed the cell morphology and dynamic cellular behaviors of NIH-3T3 fibroblasts on the nano-patterned surface. Their morphology and dynamic behaviors were investigated for relevance with regard to the recovery function. Second, we developed a highly reproducible and inexpensive research platform for wound formation and the wound healing process by combining the nano-patterned surface and a microfluidic channel. The effect of topography on wound recovery performance was analyzed. This in vitro wound healing research platform will provide well-controlled topographic cue of wound bed and contribute to the study on the fundamental mechanism of wound healing., Competing Interests: The authors have declared that no competing interests exist.

Background: Reversible cholinesterase inhibitors, when given prophylactically before exposure to organophosphates, are able to decrease organophosphate-induced mortality. However, the efficacy of pyridostigmine, the only pre-treatment substance approved by the US Federal Drug Administration, is unsatisfactory., Methods: In search of a better prophylactic compound, we determined in vivo the protection conferred by five cholinesterase inhibitors (ranitidine, physostigmine, tacrine, K-27 and pyridostigmine), which were administered in equitoxic dosage (1/4 of LD01) 30 minutes before exposure to the organophosphate dicrotophos. Efficacy was measured in rats by Cox analysis calculating the relative risk of death (RR), RR being 1 for the reference group which received dicrotophos and no prophylaxis., Results: K-27 (RR=0.06), physostigmine (RR=0.15), pyridostigmine (RR=0.22) and tacrine (RR=0.28) significantly (p ≤ 0.05) reduced dicrotophos-induced mortality in comparison to the reference group (dicrotophos without pre-treatment), whereas ranitidine (RR=0.86) had no significant influence. The experimental oxime K-27, when given before dicrotophos exposure, conferred the best in vivo protection. This was significantly (p ≤ 0.05) more efficacious than pre-treatment with any other tested compound. The differences in efficacy between the second best compound, physostigmine, and the less efficacious substances (tacrine and pyridostigmine) were also statistically significant., Conclusion: These data indicate that K-27 can be considered a very efficacious prophylactic agent for organophosphate exposure., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Objective: To identify the clinical characteristics of proper robot-assisted gait training group using exoskeletal locomotor devices in non-ambulatory subacute stroke patients., Methods: A total of 38 stroke patients were enrolled in a 4-week robotic training protocol (2 sessions/day, 5 times/week). All subjects were evaluated for their general characteristics, Functional Ambulatory Classification (FAC), Fugl-Meyer Scale (FMS), Berg Balance Scale (BBS), Modified Rankin Scale (MRS), Modified Barthel Index (MBI), and Mini-Mental Status Examination (MMSE) at 0, 2, and 4 weeks. Statistical analysis were performed to determine significant clinical characteristics for improvement of gait function after robot-assisted gait training., Results: Paired t-test showed that all functional parameters except MMSE were improved significantly (p<0.05). The duration of disease and baseline BBS score were significantly (p<0.05) correlated with FAC score in multiple regression models. Receiver operating characteristic (ROC) curve showed that a baseline BBS score of '9' was a cutoff value (AUC, 0.966; sensitivity, 91%-100%; specificity, 85%). By repeated-measures ANOVA, the differences in improved walking ability according to time were significant between group of patients who had baseline BBS score of '9' and those who did not have baseline BBS score of '9'., Conclusion: Our results showed that a baseline BBS score above '9' and a short duration of disease were highly correlated with improved walking ability after robot-assisted gait training. Therefore, baseline BBS and duration of disease should be considered clinically for gaining walking ability in robot-assisted training group.

Background: Robot-assisted and treadmill-gait training are promising neurorehabilitation techniques, with advantages over conventional gait training, but the neural substrates underpinning locomotor control remain unknown particularly during different gait training modes and speeds., Objective: The present optical imaging study compared cortical activities during conventional stepping walking (SW), treadmill walking (TW), and robot-assisted walking (RW) at different speeds., Methods: Fourteen healthy subjects (6 women, mean age 30.06, years ± 4.53) completed three walking training modes (SW, TW, and RW) at various speeds (self-selected, 1.5, 2.0, 2.5, and 3.0  km/h). A functional near-infrared spectroscopy (fNIRS) system determined cerebral hemodynamic changes associated with cortical locomotor network areas in the primary sensorimotor cortex (SMC), premotor cortex (PMC), supplementary motor area (SMA), prefrontal cortex (PFC), and sensory association cortex (SAC)., Results: There was increased cortical activation in the SMC, PMC, and SMA during different walking training modes. More global locomotor network activation was observed during RW than TW or SW. As walking speed increased, multiple locomotor network activations were observed, and increased activation power spectrum., Conclusions: This is the first empirical evidence highlighting the neural substrates mediating dynamic locomotion for different gait training modes and speeds. Fast, robot-assisted gait training best facilitated cortical activation associated with locomotor control.

Pre-treatment with reversible acetylcholinesterase (AChE) inhibitors before organophosphorous compound (OPC) exposure can reduce OPC-induced mortality. However, pyridostigmine, the only substance employed for such prophylaxis, is merely efficacious against a limited number of OPCs. In search of more efficacious and broad-range alternatives, we have compared in vivo the ability of five reversible AChE inhibitors (pyridostigmine, physostigmine, ranitidine, tacrine and K-27) to reduce mortality induced by the OPC azinphos-methyl. Protection was quantified using Cox analysis by determining the relative risk (RR) of death in rats that were administered these AChE inhibitors in equitoxic dosage (25% of LD01) 30 min before azinphos-methyl exposure. Azinphos-methyl-induced mortality was significantly reduced by all five tested compounds as compared with the reference group that was only exposed to azinphos-methyl without prior pre-treatment (RR = 1). The most efficacious prophylactic agents were K-27 (RR = 0.15) and physostigmine (RR = 0.21), being significantly more efficacious than ranitidine (RR = 0.62) and pyridostigmine (RR = 0.37). Pre-treatment with tacrine (RR = 0.29) was significantly more efficacious than pre-treatment with ranitidine, but the difference between tacrine and pyridostigmine was not significant. Our results indicate that prophylactic administration of the oxime K-27 may be a promising alternative in cases of imminent OPC exposure., (Copyright © 2014 John Wiley & Sons, Ltd.)

Background: This study was conducted to investigate awareness of clinical trials (CTs) including perceptions of favorable feelings about, necessity for, and safety of CTs, the ultimate beneficiary of CTs and the factors associated with willingness to participate in CTs among the general population in South Korea., Methods: A cross sectional survey study was conducted in a randomly selected national sample of 1,515 Korean., Results: Perception toward CTs was measured using a scale from 0 (strongly disagree) to 10 (strongly agree). Respondents readily understood the necessity for CTs (M = 7.27, SD = 2.15); had moderately favorable feelings (M = 5.32, SD = 2.31) toward CTs and felt that these CTs were moderately safe (M =  .71, SD = 1.90). Twenty-five percent of the respondents answered that they would be willing to participate in a CT in the future. Perception of the ultimate benefits of CTs, awareness, favorable feelings, safety, and necessity regarding CTs were identified as significant predictors of willingness to participate in CTs., Conclusion: An awareness of CTs and the perceptions toward CTs were associated with general public willingness to participate in a CT. Findings from this study can be used in planning outreach and recruitment strategies, and to understand the predictors of CT participation.

For the efficient cytoplasmic delivery of siRNA in a receptor-specific fashion, we designed a p19-YSA fusion protein composed of p19 RNA binding protein and ephrin mimetic peptide (YSA peptide). The resulting recombinant protein had the high affinity for EphA2 receptor overexpressed on cancer cells as well as the complexing ability with siRNA, thus leading to tumor-targeted delivery of siRNA. The buried structure of siRNA within p19-YSA/siRNA complexes allowed the bound siRNAs to be protected from the external RNases, resulting in the enhanced stability of siRNA in serum conditions. The p19-YSA carriers could complex with siRNA in a size-dependent and sequence-independent manner and showed the pH-dependent complexing/dissocation behaviors with siRNA. In contrast to electrostatic interaction-mediated siRNA delivery systems such as cationic polymers/siRNA or cationic polypeptides/siRNA complexes, the bound siRNA within p19-YSA/siRNA complexes showed enhanced stability against large polyanions found outside cells, due to the nanomolar levels of affinity. Here, we demonstrated the superior efficiency of p19-YSA/siRNA complexes in RFP gene silencing, compared to untreated cells. These results provide an alternative approach to enhance the stability of siRNA as well as to achieve the targeted siRNA delivery.

Renewable energy powered membrane systems that are directly-connected must take account of both the inherent fluctuations and the intermittency of the energy resource. In order to determine the effect of intermittent operation, a membrane system was tested with variables of (i) amplitude from 60 to 300 W and (ii) length of time with no power from 0.5 to 3 min. This was performed over one hour periods with six on/off cycles to simulate the system operating under intermittent operation for short periods of time when directly-connected to a small wind turbine. The setup used a Filmtec BW30-4040 brackish water reverse osmosis membrane with feed waters of 2,750 mg/L and 5,500 mg/L NaCl. The results showed that the membrane system produced potable water under the majority of intermittency experiments performed. There was a relatively large increase in the average salt concentration of the permeate, especially when the system was off for shorter periods of time (0.5-1 min). Longer periods of no power (1-3 min) did not have as significant an effect on the average water quality. This is important when the need for energy buffering or short term storage is considered for these systems as it shows the potential for improving the overall flux and water quality using temporary energy storage.

Cloud computing is a new information technology trend that moves computing and data away from desktops and portable PCs into large data centers. The basic principle of cloud computing is to deliver applications as services over the Internet as well as infrastructure. A cloud is a type of parallel and distributed system consisting of a collection of inter-connected and virtualized computers that are dynamically provisioned and presented as one or more unified computing resources. The large-scale distributed applications on a cloud require adaptive service-based software, which has the capability of monitoring system status changes, analyzing the monitored information, and adapting its service configuration while considering tradeoffs among multiple QoS features simultaneously. In this paper, we design and develop a Run-Time Monitor (RTM) which is a system software to monitor the application behavior at run-time, analyze the collected information, and optimize cloud computing resources for multi-core architectures. RTM monitors application software through library instrumentation as well as underlying hardware through a performance counter optimizing its computing configuration based on the analyzed data.

In our efforts to develop orally active GPIIb-IIIa antagonists with improved pharmaceutical properties, we have utilized a novel 2,8-diazaspiro[4.5]decane scaffold as a template. We describe here our investigation of a variety of templates including spiropiperidinyl-gamma-lactams, spiropiperidinylimide, spiropiperidinylureas, and spiropiperidinylhydantoins. With the appropriate acidic and basic pharmacophores in place, each template yielded analogues with potent GPIIb-IIIa inhibitory activity. One of the compounds, 59 (CT50787), was also used to demonstrate for the first time the use of a pharmacological agent which is alphaIIbbeta3 specific to display biological activity in a lower species such as mouse and to extend bleeding times. Evaluation of the pharmacokinetic properties of selected compounds from each series in rat, dog, and cynomolgus monkey has led to the identification of 22 (CT51464), a double prodrug, with excellent pharmacokinetic properties. It exhibited good pharmacokinetic profile across species (F% = 33 (Cyno), 73 (dog), 22 (rat); t(1/2)(beta)() = 14.2 h (Cyno), 8.97 h (dog), 1.81 h (rat)). The biologically active form, 23 (CT50728), displayed inhibition of platelet aggregation in platelet rich plasma (PRP) with an IC(50) value of 53 nM in citrate buffer, 110 nM in PPACK anticoagulated PRP, and 4 nM in solid-phase GPIIb-IIIa competition binding assay (ELISA). Both 23 and 22 were stable in human liver microsomes, did not inhibit the P450 3A4 isozyme, and had low protein binding (18.22% for 23) and a desirable log P (0.45 +/- 0.06 for 22, and -0.91 +/- 0.32 for 23). It is predicted that the high oral bioavailability for these compounds in multiple species should translate into lower intra- and intersubject variability in man. The long plasma half-life of the lead is consistent with once or twice daily administration for chronic therapy. Analogue 22 (CT51464) thus appears to be a promising oral GPIIb-IIIa inhibitor with significantly improved pharmacokinetic properties over the previously described clinical candidates and may be found useful in the treatment of arterial occlusive disorders.

From cell cultures of Taxus chinensis var. mairei, yunnanxane [2 alpha, 5 alpha, 10-beta triacetoxy-14 beta-(2'-methyl-3'-hydroxyl)-butyryloxy-4(20),11-taxadiene, [1], and four new homologous esters, 2 alpha, 5 alpha, 10 beta, 14 beta- tetra-acetoxy-4(20),11-taxadiene [2], 2 alpha, 5 alpha, 10 beta- triacetoxy-14 beta-propionyloxy-4(20),11-taxadiene [3], 2 alpha, 5 alpha, 10 beta- triacetoxy-14 beta-isobutyryloxy-4(20),11- taxadiene [4], and 2 alpha, 5 alpha, 10 beta- triacetoxy-14 beta-(2'-methyl)-butyryloxy-4(20),11- taxadiene [5] have been isolated. Their structures were determined by spectroscopic methods.

Four new taxoids were isolated from cell cultures of Taxus baccata. Their structures were elucidated by spectroscopic analyses. Two were the aglycones corresponding to previously isolated 7-O-xylosides of taxol C [1] and 10-deacetyltaxol C [2]. The third [3] had an N-methylated side-chain, while the fourth, named taxcultine [4], contained an n-propyl group on the side-chain. All four compounds actively promoted tubulin assembly. Taxol C [1] showed potent and selective cytotoxicity in the NCI human cell line screen.

A method has been developed for rapidly determining the amounts of alpha-carotene, beta-carotene, and cryptoxanthin in orange juice. The procedure includes extraction, saponification, and high-speed liquid chromatography. Limits of detection for the 3 carotenoids are 0.04, 0.02, and 0.04 mug/ml, respectively.