Rate In Response Research Articles

Design of ROS-Triggered Sesquiterpene Lactone SC Prodrugs as TrxR1 Covalent Inhibitors for the Treatment of Non-Small Cell Lung Cancer.

Thioredoxin reductase 1 (TrxR1) is an important therapeutic target for nonsmall cell lung cancer (NSCLC) treatment due to its overexpression in NSCLC cells. In this work, to address the deficiency that sesquiterpene lactone containing α-methylene-γ-lactone moiety was rapidly metabolized by endogenous nucleophiles, series of novel thioether derivatives were designed and synthesized based on a reactive oxygen species (ROS)-triggered prodrug strategy. Among them, prodrug 5u exhibited potent cytotoxicity against NSCLC cells and better release rates in response to ROS. The active compound 6a released from 5u covalently binds to Cys475 and Sec498 sites on TrxR1, resulting in inhibition on TrxR1 activity, which led to redox homeostasis disorder, and caused apoptosis and ferroptosis. Moreover, prodrug 5u exhibited significant antitumor efficiency in nude mice and NSCLC organoids. Our results deliver ROS-triggered prodrug 5u as a novel TrxR1 inhibitor for the treatment of NSCLC and provide a promising strategy of ROS-activated prodrug for covalent compounds in cancer therapy.

Changes in marine iguana (Amblyrhynchus cristatus) heart rates suggest reduced metabolism during El Niño events

AbstractMarine iguanas occasionally face severe food shortages because of algal dieback during El Niño events. Research on their adaptations to these periods has highlighted their unique ability to shrink in body length, which reduces their energetic needs. Additional mechanisms, like sustaining lower body temperatures and metabolic rates, could potentially also lower energy consumption, but have never been examined. We measured 665 iguanas over an 11‐year period including three El Niño events, and examined how heart rates (a proxy for metabolic rates) and body temperatures change with sea‐surface temperature oscillations (Oceanic Niño Index, ONI). Heart rate (adjusting for body size, temperature, season, and study site) was negatively correlated with ONI and lower during El Niño, whereas the adjusted body temperature did not correlate with ONI or differ between El Niño and other periods. We therefore hypothesize that marine iguanas can depress their metabolic rates in response to the harsh conditions, an adaptation that is complementary to shrinking and may further enhance their survival through periods of limited food. Direct metabolic measurements are needed to test this hypothesis.

Chronotropic effects of milrinone in a guinea pig ex vivo model: a pilot study to screen for new mechanisms of action.

Positive inotropic responses upon administration of milrinone, an inhibitor of the phosphodiesterase enzyme (PDE), involve a well-pronounced positive chronotropic effect. Here we tested whether milrinone evokes this chronotropic response solely by PDE inhibition or by a concerted action that involve additional pharmacological targets. Milrinone stimulated increases in heart rate were studied in right atrial preparations of guinea pig in the presence or absence of inhibitors of putative ancillary molecular pathways or ion channels: i.e. β receptor blockers with distinct selectivities (propranolol, metoprolol, and carvedilol), α1 receptor blocker (prazosin), inhibitor of the small conductance Ca2+ activated K+ (SK) channels (apamin), L-type Ca2+ channel blockers (verapamil and diltiazem), and different Na+ channel blockers (lidocaine, tetrodotoxin, and quinidine). Carvedilol, which inhibits β1, β2, α1 and 5-HT receptors, limited the positive chronotropic effects of milrinone to about 40%, (p<0.01). In the presence of another non-selective blocker of the β receptors, propranolol, and blockers of the L-type Ca2+ channels, only non-significant trends towards reductions of the milrinone effects were seen. The α1 receptor blocker prazosin did not limit the milrinone evoked positive chronotropy. Blockers of Na+ channels, SK channels, or the β1 receptor blocker, metoprolol also did not affect the positive chronotropy evoked by milrinone. We conclude that milrinone increases heart rate in response to adrenergic signaling, that besides PDE inhibition, may involve a 5-HT-receptor-dependent component. Our exploratory approach paves the way to more focused experiments with the use of selective 5-HT-receptor antagonists to confirm or reject the involvement of a specific 5-HT-receptor dependent pathway.

Growth response of Emiliania huxleyi to ocean alkalinity enhancement

Abstract. The urgent necessity of reducing greenhouse gas emissions is coupled with a pressing need for widespread implementation of carbon dioxide removal (CDR) techniques to limit the increase in mean global temperature to levels below 2 °C compared to pre-industrial times. One proposed CDR method, ocean alkalinity enhancement (OAE), mimics natural rock weathering processes by introducing suitable minerals into the ocean, thereby increasing ocean alkalinity and promoting CO2 chemical absorption. While theoretical studies hold promise for OAE as a climate mitigation strategy, careful consideration of its ecological implications is essential. Indeed, the ecological impact of enhanced alkalinity on marine organisms remains a subject of investigation, as it may lead to changes in species composition. OAE implicates favorable conditions for calcifying organisms by enhancing the saturation state of calcium carbonate and decreasing the energetic costs for calcification. This may affect marine primary production by improving conditions for calcifying phytoplankton, among which coccolithophores play the leading role. They contribute &lt; 10 % to the global marine primary production but are responsible for a large proportion of the marine calcite deposition. While previous research has extensively studied the effects of ocean acidification on coccolithophores, fewer studies have explored the impacts of elevated pH and alkalinity. In this context, we studied the sensitivity of Emiliania huxleyi, the most widespread coccolithophore species, to ocean alkalinity enhancement in a culture experiment. We monitored the species' growth and calcification response to progressively increasing levels of total alkalinity (TA). Above a change in total alkalinity (ΔTA) of ∼ 600 µmol kg−1, as CO2 concentrations decreased, the E. huxleyi growth rate diminished, suggesting a threshold CO2 concentration of ∼ 100 µatm necessary for optimal growth. The cellular calcite to organic carbon ratio (PIC : POC) remained stable over the total alkalinity range. Due to the decreasing growth rate in response to alkalinity enhancement, total carbonate formation was lower. OAE is rapidly advancing and has already reached the field-testing stage. Hence, our study contributes to the most critical part of investigations required to comprehend potential biological implications before large-scale OAE is adopted.

Thrush nightingales adjust the peak frequency and structure of their songs in response to different types of experimental noise

Animals employ various strategies to minimize the overlap of their vocalizations with other sounds, thereby enhancing the effectiveness of their communication. However, little attention has been given to experimentally examining how the structure of the acoustic signal changes in response to various kinds of disturbances in the soundscape. In this study, I experimentally investigated whether male thrush nightingales (Luscinia luscinia) adjust their singing rate, song frequency, and song type in response to different types of artificial sounds. While males did not reduce the intensity of their singing in noise, they did adjust the peak frequency of their songs—raising it in the presence of low-frequency noise and lowering it in response to high-frequency noise. These bidirectional changes were associated with selective use of phrases from their repertoire. The proportion of low- to high-frequency phrases was significantly reduced under low-frequency noise and increased under high-frequency noise. The results suggest that disturbing sounds can modify the peak frequency and structure of songbird vocalizations, at least in the short term. Birds may enhance the signal-to-noise ratio by selecting phrases from their repertoire that are less affected by noise. For species with a large repertoire, new sounds transmitted within a species-specific frequency range may play an important role in the process of cultural song transmission.

Decision support guided fluid challenges and stroke volume response during high-risk surgery: a post hoc analysis of a randomized controlled trial.

Intravenous fluid is administered during high-risk surgery to optimize stroke volume (SV). To assess ongoing need for fluids, the hemodynamic response to a fluid bolus is evaluated using a fluid challenge technique. The Acumen Assisted Fluid Management (AFM) system is a decision support tool designed to ease the application of fluid challenges and thus improve fluid administration during high-risk surgery. In this post hoc analysis of data from a randomized controlled trial, we compared the rates of fluid responsiveness (defined as an increase in SV of ≥ 10%) after AFM-guided or clinician-initiated (control) fluid challenges. Patients undergoing high-risk abdominal surgery were randomly allocated to AFM-guided or clinician-initiated groups for fluid challenges titration, which consisted of 250-mL boluses of crystalloid or albumin given over 5min. The fluid responsiveness rates and the mean SV increase in the two groups were compared. The original study included 86 patients (44 in the AFM group and 42 in the clinician-initiated group) and this sub-study analysed 85 patients with a total of 448 fluid challenges. The median rate of fluid responsiveness was greater in the AFM than in the control group (50 [44-71] % vs 33 [20-40] %, p<0.001). The mean increase in SV after fluid challenge was also higher in the AFM than in the control group (12 [9-16] % vs 6 [3-10] %, p<0.001). AFM-initiated fluid challenges were more often associated with the desired increase in SV than were clinician-initiated fluid challenges, and absolute SV increases were greater.

Correlating autonomic physiology with symptoms of autonomic dysreflexia after spinal cord injury.

Individuals with spinal cord injury (SCI) commonly have autonomic dysreflexia (AD) with increased sympathetic activity. After SCI, individuals have decreased baroreflex sensitivity and increased vascular responsiveness. To evaluate the relationship between baroreflex and blood vessel sensitivity with AD symptoms. Case control. Tertiary academic center. 14 individuals with SCI, 17 matched uninjured controls. All participants quantified AD symptoms using the Autonomic Dysfunction Following SCI (ADFSCI)-AD survey. Participants received three intravenous phenylephrine boluses, reproducibly increasing systolic blood pressure (SBP) 15-40 mmHg. Continuous heart rate (R-R interval, ECG), beat-to-beat blood pressures (Finapres), and popliteal artery flow velocity were recorded. Vascular responsiveness (α1 adrenoreceptor sensitivity) and heart rate responsiveness to increased SBP (baroreflex sensitivity) were calculated. Baroreflex sensitivity after increased SBP; Vascular responsiveness through quantified mean arterial pressure (MAP) 2-minute area under the curve and change in vascular resistance. SCI and control cohorts were well matched with mean age 31.9 and 29.6 years (p = .41); 21.4% and 17.6% female, respectively. Baseline MAP (p = .83) and R-R interval (p = .39) were similar. ADFSCI-AD scores were higher following SCI (27.9 ± 22.9 vs. 4.2 ± 2.9 in controls, p = .002). To quantify SBP response, MAP area under the curve was normalized to dose/body weight. Individuals with SCI had significantly larger responses (0.26 ± 0.19 mmHg*s/kg*μg) than controls (0.06 ± 0.06 mmHg*s/kg*μg, p = .002). Similarly, leg vascular resistance increased after SCI (24% vs. 6% to a normalized dose, p = .007). Baroreflex sensitivity was significantly lower after SCI (15.0 ± 8.3 vs. 23.7 ± 9.3 ms/mmHg, p = .01). ADFSCI-AD subscore had no meaningful correlation with vascular responsiveness (R2 = 0.008) or baroreflex sensitivity (R2 = 0.092) after SCI. Although this confirms smaller previous studies suggesting increased α1 adrenoreceptor sensitivity and lower baroreflex sensitivity in individuals with SCI, contrary to our hypothesis these differences lacked correlation to increased symptoms of AD. Further research into physiologic mechanisms is needed to explain why some individuals with SCI develop symptoms.

What is the optimal display range? Exploring the impacts of area and shape on in-vehicle head-up display efficiency.

In-vehicle Head-Up Displays (HUDs) are expected to incorporate more information in the future, necessitating deeper understandings of design properties that can enhance display safety and efficiency. However, the optimal display characteristics-particularly in terms of area and shape-remain inadequately understood. This study investigated these two factors by manipulating horizontal and vertical Field of View (FOV) angles within a simulated in-vehicle HUD. Thirty-one participants participated in this laboratory-based study they completed a digit matching task while driving within a driving simulator. The accuracy and response time of the task served as indicators for efficiency. The standard deviation of lateral position (SDLP) was employed to assess area and shape's impacts on driving performance, alongside subjective ease-of-use evaluations. Results indicated that an increase in horizontal FOV angle significantly delay response times and reduce ease-of-use ratings. We also observed significant effects of area and shape on response time and ratings; specifically, participants responded faster in smaller display area conditions, which were also rated as the easiest to use. Accuracy, however, was largely unaffected by size and shape. Importantly, most manipulations did not interfere with driving performance, except for the area 500 condition, wherein landscape shape was associated with better lane-keeping performance. Our findings provide valuable insights for the design of in-vehicle HUDs.

A dual thermo/pH-sensitive hydrogel as 5-Fluorouracil carrier for breast cancer treatment.

Intelligent hydrogels are promising in constructing scaffolds for the controlled delivery of drugs. Here, a dual thermo- and pH-responsive hydrogel called PCG [poly (N-isopropyl acrylamide-co-itaconic acid)/chitosan/glycerophosphate (PNI/CS/GP)] was established as the carrier of 5-fluorouracil (5-FU) for triple-negative breast cancer (TNBC) treatment. The PCG hydrogel was fabricated by blending synthesized [poly (N-isopropyl acrylamide-co-itaconic acid), pNIAAm-co-IA, PNI] with CS in the presence of GP as a crosslinking agent. The interaction between PCG hydrogel compositions was characterized by Fourier transforms infrared, NMR spectroscopy, and scanning electron microscopy. The PCG hydrogel presented an interconnected and porous structure with similar pore size, rapid swelling/deswelling rate in response to both temperature and pH change, and biocompatibility, upon which it was proposed as a great drug carrier. 5-FU had a dual thermo- and pH-responsive controlled release behavior from the PCG hydrogel and displayed an accelerated release rate in an acidic pH environment than in a neutral pH condition. The application of 5-FU-loaded PCG hydrogel exhibited a more promoted anticancer activity than 5-FU against the growth of TNBC cells both in vitro and in vivo. The outcomes suggested that the PCG hydrogel could be an excellent platform for local drug-delivery systems in the clinical therapy of TNBC.

Increased sea level rise accelerates carbon sequestration in a macro-tidal salt marsh.

Salt marshes are known as key ecosystems for nature-based climate mitigation through organic carbon sequestration into their sediment beds, but at the same time they are affected by accelerating sea level rise induced by climate warming. Consequently, an important question is how organic carbon accumulation rates (OCAR) of salt marshes will respond to future accelerating rates of relative sea level rise (RSLR). To date, existing insights are either based on (1) comparison of geographically distant marsh sites, differing in local RSLR rates but also in other environmental conditions that additionally can affect OCAR, or (2) experiments in given marsh sites, in which proxies for RSLR are manipulated, but run over periods of years instead of decades, the latter being the relevant time scale of marsh responses to RSLR. Here we bridge these shortcomings by studying the OCAR over four decades at two nearby salt marsh sites in the Netherlands, with similar environmental conditions, but with one site experiencing an accelerated RSLR rate of 9.7-11.7mmyr-1 (i.e., within the range of projected global mean sea level rise rates by 2100) due to local land subsidence induced by gas extraction, while the other site does not experience subsidence and has a low background RSLR rate of 2.0mmyr-1 (i.e. close to the current global mean sea level rise rate). Our results reveal that the salt marsh site experiencing the accelerated RSLR rates shows OCAR values that are on average twice as high as those found in the marsh site experiencing the low background RSLR rates. Moreover, the increase of OCAR in response to faster RSLR was even more pronounced (i.e. 63% increase) on marsh levees within 10m from tidal creeks, while this was more subtle (i.e. 27% increase) in marsh basins at a distance of 30-40m from the creeks. These observations of increased OCAR are mainly attributed to increased sediment accretion rates (SAR) in response to (1) increased tidal inundation due to accelerated RSLR and (2) larger sediment supply due to closer proximity to creeks, while sediment organic carbon content was relatively little affected. Our findings support expectations that nature-based climate mitigation actions, through salt marsh conservation and restoration, are sustainable on the long term of the coming decades, and are even likely to become more effective with future accelerations in global sea level rise, at least for macrotidal sites not limited by sediment supply.

Scalp high-frequency oscillation spatial distribution is consistent over consecutive nights, while rates vary with antiseizure medication changes.

This study aimed to investigate two key aspects of scalp high-frequency oscillations (HFOs) in pediatric focal lesional epilepsy: (1) the stability of scalp HFO spatial distribution across consecutive nights, and (2) the variation in scalp HFO rates in response to changes in antiseizure medication (ASM). We analyzed 81 whole-night scalp electroencephalography (EEG) recordings from 20 children with focal lesional epilepsy. We used a previously validated automated HFO detector to assess scalp HFO rates (80-250 Hz) during non-rapid eye movement (NREM) sleep. The spatial distribution of HFO rates across consecutive nights was evaluated using Hamming similarity, and changes in ASM were classified as increased, decreased, or stable. For each patient, we analyzed 3 ± 1 whole-night scalp EEG recordings, with a mean duration of 650 ± 215 min per recording. The distribution of HFO remained stable across consecutive nights, with a Hamming similarity of 88% ± 6%. Four patients had at least one ASM dosage decrease, nine patients had both ASM dosage decreases and increases, two patients had only ASM dosage increases, and five patients had no changes in ASM during the study period. A decrease in ASM dosage was associated with increased HFO rates (from .16 ± .32 to .22 ± .36 HFO/min; p = .03), whereas an increase in ASM dosage led to decreased HFO rates (from .32 ± .54 HFO/min to .22 ± .38 HFO/min; p = .005) when comparing the last night to the first. The spatial distribution of scalp HFOs remained consistent across multiple nights, whereas fluctuations in HFO rates correlated with changes in ASM dosage. These findings suggest that scalp HFOs may not only help identify epileptogenic brain tissue but also monitor treatment response.

Alkene Epoxidation and Oxygen Evolution Reactions Compete for Reactive Surface Oxygen Atoms on Gold Anodes.

Rates and selectivities for the partial oxidation of organic molecules on reactive electrodes depend on the identity and prevalence of reactive and spectator species. Here, we investigate the mechanism for the epoxidation of 1-hexene (C6H12) with reactive oxygen species formed by electrochemical oxidation of water (H2O) on gold (Au) in an aqueous acetonitrile (CH3CN) electrolyte. Cyclic voltammetry measurements demonstrate that oxygen (O2) evolution competes with C6H12 epoxidation, and the Au surface must oxidize before either reaction occurs. In situ Raman spectroscopy reveals reactive oxygen species and spectators (CH3CN) on the active anode as well as species within the electrochemical double layer. The Faradaic efficiencies toward epoxidation and the ratios of epoxide formation to O2 evolution rates increase linearly with the concentration of C6H12 and depend inversely on the concentration of H2O, which agree with analytical expressions that describe rates for reaction between C6H12 and chemisorbed oxygen atoms (O*) and exclude proposals for other forms of reactive oxygen (e.g., O2*, OOH*, OH*). These findings show that the epoxidation and O2 evolution reactions share a set of common steps that form O* through electrochemical H2O activation but then diverge. Subsequently, epoxides form when O* reacts with C6H12 through a non-Faradaic process, whereas O2 evolves when O* reacts with H2O through a Faradaic process to form OOH*, which then deprotonates. These differences lead to distinct changes in rates in response to electrode potential, and hence, disparate Tafel slopes. Collectively, these results provide a self-consistent mechanism for C6H12 epoxidation that involves reactive O*.

Dopamine-Sensitive Anterior Cingulate Cortical Glucose-Monitoring Neurons as Potential Therapeutic Targets for Gustatory and Other Behavior Alterations.

Background: The anterior cingulate cortex (ACC) is known for its involvement in various regulatory functions, including in the central control of feeding. Activation of local elements of the central glucose-monitoring (GM) neuronal network appears to be indispensable in these regulatory processes. Destruction of these type 2 glucose transporter protein (GLUT2)-equipped chemosensory cells results in multiple feeding-associated functional alterations. Methods: In order to examine this complex symptomatology, (1) dopamine sensitivity was studied in laboratory rats by means of the single-neuron-recording multibarreled microelectrophoretic technique, and (2) after local bilateral microinjection of the selective type 2 glucose transporter proteindemolishing streptozotocin (STZ), open-field, elevated plus maze, two-bottle and taste reactivity tests were performed. Results: A high proportion of the anterior cingulate cortical neurons changed their firing rate in response to microelectrophoretic administration of D-glucose, thus verifying them as local elements of the central glucose-monitoring network. Approximately 20% of the recorded cells displayed activity changes in response to microelectrophoretic application of dopamine, and almost 50% of the glucose-monitoring units here proved to be dopamine-sensitive. Moreover, taste stimulation experiments revealed even higher (80%) gustatory sensitivity dominance of these chemosensory cells. The anterior cingulate cortical STZ microinjections resulted in extensive behavioral and taste-associated functional deficits. Conclusions: The present findings provided evidence for the selective loss of glucose-monitoring neurons in the anterior cingulate cortex leading to motivated behavioral and gustatory alterations. This complex dataset also underlines the varied significance of the type 2 glucose transporter protein-equipped, dopamine-sensitive glucose-monitoring neurons as potential therapeutic targets. These units appear to be indispensable in adaptive control mechanisms of the homeostatic-motivational-emotional-cognitive balance for the overall well-being of the organism.

Flexible Vertical Federated Learning With Heterogeneous Parties.

We propose flexible vertical federated learning (Flex-VFL), a distributed machine algorithm that trains a smooth, nonconvex function in a distributed system with vertically partitioned data. We consider a system with several parties that wish to collaboratively learn a global function. Each party holds a local dataset; the datasets have different features but share the same sample ID space. The parties are heterogeneous in nature: the parties' operating speeds, local model architectures, and optimizers may be different from one another and, further, they may change over time. To train a global model in such a system, Flex-VFL utilizes a form of parallel block coordinate descent (P-BCD), where parties train a partition of the global model via stochastic coordinate descent. We provide theoretical convergence analysis for Flex-VFL and show that the convergence rate is constrained by the party speeds and local optimizer parameters. We apply this analysis and extend our algorithm to adapt party learning rates in response to changing speeds and local optimizer parameters. Finally, we compare the convergence time of Flex-VFL against synchronous and asynchronous VFL algorithms, as well as illustrate the effectiveness of our adaptive extension.

The direct yaw-moment control based on adaptive fuzzy LQR for distributed drive electric vehicles

This paper introduced a hierarchical control strategy for direct yaw moment (DYC) to enhance the handling and stability of distributed drive electric vehicles (DDEVs) at medium to high speeds. The upper controller entailed a speed-following PI controller and an adaptive fuzzy linear quadratic regulator (AFLQR) controller, with the control objectives centered on reducing the absolute value of the sideslip angle and tracking the desired yaw rate. The proposed approach utilizes a fuzzy logic-based AFLQR controller, which could dynamically adjust the weighting parameters for sideslip angle and yaw rate in response to the vehicle speed and sideslip angle, offering better adaptability to varying driving conditions. At the lower control level, a tire-dynamic-load-based torque distribution method was applied. The control strategy’s efficacy was demonstrated through co-simulation involving CarSim and Simulink. This evaluation compared AFLQR control against non-yaw control, conventional LQR control and sliding mode control (SMC), focusing on handling and stability during sinusoidal steering wheel input test and double lane change maneuver. Results highlight that AFLQR reduces the sideslip angle by 7.88% and the yaw rate error by 84.29% compared to LQR, enhancing vehicle handling and stability. Lastly, a hardware-in-the-loop (HIL) experiment verified the control strategy’s validity.

Dopamine Transporter and CYP2D6 Gene Relationships with Attention-Deficit/Hyperactivity Disorder Treatment Response in the Methylphenidate and Atomoxetine Crossover Study.

Background: Few biological or clinical predictors guide medication selection and/or dosing for attention-deficit/hyperactivity disorder (ADHD). Accumulating data suggest that genetic factors may contribute to clinically relevant pharmacodynamic (e.g., dopamine transporter-SLC6A3 also commonly known as DAT1) or pharmacokinetic (e.g., the drug metabolizing enzyme Cytochrome P450 2D6 CYP2D6) effects of methylphenidate (stimulant) and atomoxetine (non-stimulant), which are commonly prescribed medications. This is the first study of youth with ADHD exposed to both medications examining the clinical relevance of genetic variation on treatment response. Methods: Genetic variations in DAT1 and CYP2D6 were examined to determine how they modified time relationships with changes in ADHD symptoms over a 4-week period in 199 youth participating in a double-blind crossover study following a stepped titration dose optimization protocol. Results: Our results identified trends in the modification effect from CYP2D6 phenotype and the time-response relationship between ADHD total symptoms for both medications (atomoxetine [ATX]: p = 0.058, Methylphenidate [MPH]: p = 0.044). There was also a trend for the DAT1 3' untranslated region (UTR) variable number of tandem repeat (VNTR) genotype to modify dose relationships with ADHD-RS total scores for atomoxetine (p = 0.029). Participants with DAT1 9/10 repeat genotypes had a more rapid dose-response to ATX compared to 10/10, while those with 9/9 genotypes did not respond as doses were increased. Regardless of genotype, ADHD symptoms and doses were similar across CYP2D6 metabolizer groups after 4 weeks of treatment. Conclusions: Most children with ADHD who were CYP2D6 normal metabolizers or had DAT1 10/10 or 9/10 genotypes responded well to both medications. While we observed some statistically significant effects of CYP2D6 and DAT1 with treatment response over time, our data indicate that genotyping for clinical purposes may have limited utility to guide treatment decisions for ATX or MPH because both medications were generally effective in the studied cohort after 3 weeks of titration to higher doses. The potential DAT1 association with ATX treatment is a novel finding, consistent with prior reports suggesting an association of the DAT1 in 9/9 genotypes with lower responsive rates to treatment at low and moderate doses.

Large language model doctor: assessing the ability of ChatGPT-4 to deliver interventional radiology procedural information to patients during the consent process

PurposeThe study aims to evaluate how current interventional radiologists view ChatGPT in the context of informed consent for interventional radiology (IR) procedures.MethodsChatGPT-4 was instructed to outline the risks, benefits, and alternatives for IR procedures. The outputs were reviewed by IR physicians to assess if outputs were 1) accurate, 2) comprehensive, 3) easy to understand, 4) written in a conversational tone, and 5) if they were comfortable providing the output to the patient. For each criterion, outputs were measured on a 5-point scale. Mean scores and percentage of physicians rating output as sufficient (4 or 5 on 5-point scale) were measured. A linear regression correlated mean rating with number of years in practice. Intraclass correlation coefficient (ICC) measured agreement among physicians.ResultsThe mean rating of the ChatGPT responses was 4.29, 3.85, 4.15, 4.24, 3.82 for accuracy, comprehensiveness, readability, conversational tone, and physician comfort level, respectively. Percentage of physicians rating outputs as sufficient was 84%, 71%, 85%, 85%, and 67% for accuracy, comprehensiveness, readability, conversational tone, and physician comfort level, respectively. There was an inverse relationship between years in training and output score (coeff = -0.03413, p = 0.0128); ICC measured 0.39 (p = 0.003).ConclusionsGPT-4 produced outputs that were accurate, understandable, and in a conversational tone. However, GPT-4 had a decreased capacity to produce a comprehensive output leading some physicians to be uncomfortable providing the output to patients. Practicing IRs should be aware of these limitations when counseling patients as ChatGPT-4 continues to develop into a clinically usable AI tool.

A Study on Dynamic Pricing in the Airline Industry Using Reinforcement Learning Analyzing the Impact of Reinforcement Learning on Airline Pricing Strategies

Dynamic pricing serves as an essential tactic in the airline sector, allowing airlines to modify ticket rates in response to changing market demand, rivalry, and various other influencing elements. This research investigates the use of Reinforcement Learning (RL) in dynamic pricing strategies, emphasizing its ability to boost revenue management and increase customer satisfaction. In contrast to conventional pricing strategies, RL allows airlines to adjust prices in real-time by continuously analyzing environmental data such as seat availability, departure time, and competitor pricing. This study explores current pricing models, the framework of RL-driven dynamic pricing, and a case analysis to showcase the real-world advantages and difficulties of RL. Core discoveries reveal that RL-driven dynamic pricing provides considerable benefits in responding to real-time demand fluctuations, thereby optimizing revenue opportunities. Nonetheless, obstacles like limited data, high computational demands, and striking a balance between exploration and exploitation still persist. The research ends with observations on how RL can further reshape airline revenue management and suggests future research avenues to improve its practical uses.

Resting metabolic rate and energy efficiency in response to an intensive 84-day combat-swimmer training in the German Armed Forces

Abstract Purpose According to the ‘constrained model’, there are compensations in resting metabolic rate (RMR) at high levels of physical activity (PA). Here, we have used a standardized combat-swimmer training protocol (CST) to investigate whether changes in RMR (i) confirm the ‘constraint model’, and (ii) differ between successful participants and dropouts. Methods Controlled 84d CST in 44 male soldiers with 13 finally successful. Fat mass (FM) and fat-free mass (FFM) were measured using Quantitative Magnetic Resonance. RMR was assessed by indirect calorimetry, VO2max, and work efficiency by treadmill spiroergometry. Plasma levels of thyroid hormones, testosterone, and cortisol were analysed by standard laboratory methods. Results CST increased VO2max (+ 6.9%) and exercise efficiency at low workloads of 10 and 12 km/h (+ 8.7 and + 6.5%; both p &lt; 0.05). As energy balance was moderately negative (−356 ± 383 kcal/d), FFM and FM decreased (−2 and −16%; both p &lt; 0.05). There was a considerable inter-individual variance but no change in in the mean values of RMR and RMRadjFFM. RMRadjFFM before CST had a negative association with its decrease with CST (p &lt; 0.005). Concomitantly, plasma hormone levels were unchanged. When compared with dropouts, successful participants had a higher VO2max at baseline (5.2 ± 0.6 vs. 4.9 ± 04 l/min; p &lt; 0.05) that increased with CST (+ 4.4 vs. −0.4%; p &lt; 0.05) at similar changes in body composition and energy balance. Conclusion While CST increased VO2max and exercise efficiency as a compensation, there was an inter-individual variance in exercise-related compensation of RMR with no differences between ‘completers’ and ‘non-completers’. Trial registration DRKS00018850, November 27, 2019.

Multiscale Responsive Kinetic Modeling: Quantifying Biomolecular Reaction Flux under Varying Electrochemical Conditions.

Attaining a complete thermodynamic and kinetic characterization for processes involving multiple interconnected rare-event transitions remains a central challenge in molecular biophysics. This challenge is amplified when the process must be understood under a range of reaction conditions. Herein, we present a novel condition-responsive kinetic modeling framework that can combine the strengths of bottom-up rate quantification from multiscale simulations with top-down solution refinement using both equilibrium and nonequilibrium experimental data. Although this framework can be applied to any process, we demonstrate its use for electrochemically driven transport through channels and transporters via the development of electrochemically responsive rates. Using the Cl-/H+ antiporter ClC-ec1 as a model system, we show how optimal and predictive kinetic solutions can be obtained when the solution space is grounded by thermodynamic constraints, seeded through multiscale rate quantification, and further refined with experimental data, such as electrophysiology assays. Turning to the Shaker K+ channel, we demonstrate that optimal solutions and biophysical insights can also be obtained with sufficient experimental data. This multi-pathway method also proves capable of identifying single-pathway dominant channel mechanisms but reveals that competing and off-pathway flux is still essential to replicate experimental findings and to describe concentration-dependent channel rectification.