Anemias are diverse and cause significant morbidity and mortality, but their mechanisms are not fully understood. To unravel this complexity requires understanding how hemoglobin and red blood cell function is regulated, and what goes wrong in each form of anemia. Anemias present puzzling imbalance between hemoglobin (Hb) and the main regulator of red blood cells - the hormone erythropoietin (EPO). In some anemias EPO is markedly elevated relative to the degree of anemia, whereas in others it is inappropriately low. This variability suggests that the feedback between oxygen delivery and erythropoietin production involves mechanisms beyond simple oxygen sensing. We developed a minimal mechanistic model of erythropoiesis composed of four coupled differential equations representing erythroid progenitors, marrow reticulocytes, circulating RBCs, and plasma EPO. Most parameters were derived from experimental measurements and correspond to physiological quantities. Data from ~1,830 adults across 36 published studies, encompassing healthy individuals and patients with major anemia types, were used to validate the model, along with blood-donor recovery cohorts. The model reproduces the near-exponential Hb–EPO relationship observed in reference populations, the characteristic trajectory of hemoglobin recovery after blood loss, and disease-specific deviations through physiologically plausible parameter changes, without ad hoc fitting. Elevated EPO in aplastic anemia emerges from reduced erythroid mass and diminished receptor-mediated clearance; chronic kidney disease is consistent with impaired EPO synthesis and marrow suppression; anemia of chronic disease arises from reduced progenitor differentiation without requiring primary EPO failure; and shortened RBC lifespan alone does not lower steady-state EPO in hemolysis. Of potential clinical significance is that steady-state erythropoietin levels provide a noninvasive indicator of bone marrow activity, with higher levels reflecting reduced erythroid mass and diminished receptor-mediated uptake.

High-spatiotemporal-resolution land surface temperature (LST) data are crucial for analyzing surface energy balance, modeling temperature-related processes, and monitoring thermal environments. However, despite advancements in multi-source fusion and reconstruction techniques, high-frequency LST data remain susceptible to anomalies such as abrupt changes and outliers due to retrieval uncertainties and varying observation conditions. Conventional statistical outlier detection methods risk misidentifying physically plausible rapid weather changes as data errors, introducing systematic biases. To address this, we propose a two-stage anomaly detection framework that follows a “temporal physical pre-screening first, spatial statistical verification later” logic. First, a piecewise empirical model, based on typical diurnal LST variation characteristics, is constructed to identify points violating physical patterns. Subsequently, a spatial consistency test using median absolute deviation (MAD) is introduced to distinguish real weather-driven fluctuations from genuine data anomalies from a spatial synergy perspective. This sequential design effectively reduces the risk of mis-correcting physically reasonable temperature variations. Validated using hourly seamless LST data (2016–2021) and ground observations in the Heihe River Basin, our method outperformed Seasonal-Trend decomposition using Loess (STL), double standardization methods, and robust Holt–Winters. For over 87% of the detected anomalies, the proposed method demonstrated positive improvement rates in RMSE, MAE, R, and R2. The overall average improvement rates reached 23.61%, 18.79%, 16.46%, and 61.33%, respectively, indicating robust performance. The results underscore that explicitly incorporating physical constraints enhances the reliability and interpretability of quality control for high-temporal-resolution remote sensing LST data.

Clinical evidence indicates that atraumatic needles (ATNs) versus conventional needles (CNs) reduce diagnostic lumbar puncture (DLP) complications. Despite this, the use of CNs in DLP remains widespread. This analysis estimates the cost-effectiveness of ATNs versus CNs in DLP. We constructed a model mapping DLP patient pathways and complications (limited to PDPH events and PDPH-related hospitalisations/epidural blood patches (EBP)). Model development was carried out in consultation with local clinical experts. Published data informed clinical data inputs (DLP characteristics and likelihood of PDPH) and resource estimates. Costs of PDPH management were estimated from UK NHS Reference Costs. Costs of LP were limited to needle costs. Model outputs included total PDPH, total costs, cost per PDPH avoided and numbers need to treat (NNT) to avoid one case of PDPH. Extensive one-way sensitivity analyses were conducted. Based on 100 patients undergoing DLP with CN (ATN), we estimated 31 (12) cases of PDPH with 7 (3) patients requiring EBP with total costs estimated at £9,469 (£4,257) i.e. 19 fewer cases of PDPH with ATN at a cost saving of £5,212. NNT to avoid one case of PDPH (hospitalised PDPH) was estimated at 5 (13). Clinical benefits and cost savings were robust to plausible input changes. Our model findings support an economic case for use of ATN in preference to CN in DLP, with improved outcomes achieved at a cost saving. Local data collection is recommended but is not expected to change the model findings.

In Russia, more than half of the population has no savings and that reduces household financial resilience, especially in the face of economic shocks. There is a question whether improving financial literacy can help address this problem. Using the data from four waves of the All-Russian Household Survey on Consumer Finances, a fixed-effects panel regression revealed that financial literacy is associated with both the availability and the amount of household savings. However, this relationship is heterogeneous across socio-demographic groups and savings forms. For example, research confirms a positive correlation between higher levels of financial literacy and specific demographics, including male-headed households, urban residency, and higher income levels. Financial literacy is positively associated with both availability and the size of bank deposits while being unrelated to stocks or cash. Robustness checks confirm that the main results remain stable despite plausible changes to model specifications and sample modifications.

Diabetes prevalence continues to rise in England, placing increasing pressure on primary and specialist healthcare services. This study examined how demographic, socioeconomic, and healthcare access factors influence Diabetes Mellitus register size across six Integrated Care Systems (ICSs) in the East of England and generated scenario based projections of future diabetes burden and specialist workforce requirements. A longitudinal panel design was applied using annual data (2012-2021) for six ICSs. Descriptive trend analysis summarised changes in diabetes registers, GP practice numbers, GP list size, deprivation (IMD scores), and population density. The association between these factors and Diabetes Mellitus register size was quantified using a fixed effects panel regression model, selected through F-tests, Breusch-Pagan LM tests, and Hausman specification testing. Future diabetes registers (2023-2027) were estimated using a regression based deterministic projection framework integrating: (i) model based forecasting, (ii) four scenario models based on plausible changes in population growth, deprivation, and GP capacity, and (iii) linear trend extrapolation of endocrinology consultant workforce numbers. Diabetes registers increased across all ICSs, with the region experiencing a 13% rise between 2012 and 2021. Regression findings showed that higher deprivation strongly predicted larger diabetes registers ([Formula: see text], [Formula: see text]), while increases in GP list size and GP practice numbers were also significant predictors. Under ScenarioI, projected diabetes registers for 2023 ranged from 60,603 (Cambridgeshire and Peterborough) to 85,574 (Hertfordshire and West Essex). ScenarioII, which incorporated greater increases in deprivation, produced larger projected registers across all ICSs, including 75,463 in Bedfordshire and 88,399 in Hertfordshire. Patient to consultant ratios were projected to increase in Bedfordshire and Mid and South Essex, suggesting potential specialist workforce shortages. Demographic growth, rising deprivation, and pressures in primary care are key drivers of the increasing diabetes burden in the East of England. Projection results indicate that several ICSs may face widening gaps between patient demand and specialist capacity. Strengthening consultant staffing, directing resources toward more deprived areas, and supporting primary care resilience will be essential to maintain equitable diabetes care in future years.

Abstract Sediment oxygen demand (SOD) rate measurements in Lake Erie and other lakes are complicated by the fact that SOD can show different degrees of dependence upon water temperature and dissolved oxygen (DO) concentration and different models have been used to describe this process. We incubated sediment cores from three locations within the basin, in factorial with temperature (8°C and 14°C) and time of year. We analyzed SOD kinetics using a phenomenological mixed‐order model where model order is an estimated parameter, a model based on Michaelis‐Menten (MM) kinetics, and a mechanistic model. The mixed‐order model showed that SOD was, on average, a 0.44‐order function of DO concentration, but model order declined from June (mean 0.74) to September (0.21). In the MM kinetics model, the half‐saturation constant decreased from 6.6 mg L −1 in June to 1.0 mg L −1 in September. The mechanistic SOD model indicated a shift from mostly DO diffusion into the sediment in June to mostly reduced substances release in September. Water column oxygen demand (WCOD) was similar across seasons, suggesting that sediment processes were responsible for the seasonal shift in SOD kinetics. All three models predicted plausible changes in DO compared to in situ observations. In addition to estimating rates and kinetics for future modeling studies in the lake, this study shows how the mixed‐order model approach can overcome limitations of using prescribed kinetics (i.e., zero‐ or first‐order) for empirical studies of biogeochemical fluxes that are controlled by a mix of different processes.

The sensitivity of hydroclimatic risk to plausible future hydroclimatic changes in the irrigated rice paddies of Malaysia

ABSTRACTLightning frequency in tropical forests has been increasing for decades and lightning is a major agent of forest biomass mortality, but the implications of increased lightning frequency are unclear. Here, we provide a species‐ and spatially explicit implementation of lightning in a mechanistic forest dynamics model. We evaluated the model's ability to reproduce current‐day observations in a Panamanian tropical forest, and the sensitivity of model outputs to plausible changes in lightning frequency. The lightning‐enabled model simulated aboveground biomass (AGB), carbon flux, and stem densities that were consistent with observations. As expected, AGB declined with increasing lightning frequency. However, the magnitude of AGB decline was greatly reduced when trees were assigned empirically derived, species‐specific lightning tolerances. Changes in species composition weakened the sensitivity of AGB to increasing lightning: the AGB of a small number of large‐statured, lightning‐tolerant species increased with increasing lightning frequency. In addition, the effect of lightning on AGB tended to saturate at high lightning frequencies because of the combined effect of changes in size structure and composition. Specifically, the number of large, lightning‐susceptible trees was relatively small at high lightning frequencies. Overall, this study shows that an empirically informed representation of lightning captures the contemporary effects of lightning on forests, indicates that changes in lightning frequency will change forest AGB, species composition, and size structure, and shows that forests can partially acclimate to higher lightning frequency through changes in composition. Thus, more widespread inclusion of the lightning into global ecosystem models would be an important step toward improving simulations of forest responses to global change.

Image by co-reasoning: A collaborative reasoning-based implicit data augmentation method for dual-view CEUS classification.

Abstract Changes in the properties of rainfall distributions at sub‐daily scales are key to assessing soil erosion rates under climate transition. However, such changes are difficult to detect and model, especially over landscape evolution timescales. In this contribution, we validate a new catchment‐scale landscape evolution model against event‐scale runoff and sediment records. Through multi‐century numerical experiments, we also show that changes in the sub‐daily rainfall distribution, like those observed under modern climate change, can increase soil erosion rates by 40% but cannot be accurately inferred from changes in the average event properties and total rainfall. We quantify erosion and topographic trajectories associated with plausible changes in the sub‐daily rainfall distribution, highlighting scenarios in which shifting tail properties impact landscape evolution, at times, contrary to expectations based on changes in total rainfall.

ObjectivesGallbladder polyps (GBPs) are commonly detected with trans-abdominal ultrasound (TAUS). Gallbladder cancer (GBC) is associated with GBPs but the risk of malignancy is low. International guidelines recommend ultrasound surveillance (USS) in selected cases of GBPs <10 mm, with cholecystectomy advised if the polyp size increases. USS (including potential cholecystectomies) is resource intense. We evaluated the costs and potential cost-effectiveness of USS in a theoretical UK patient cohort with GBPs.MethodsA health economic model mapped expected management pathways over 2 years for 1000 GBP patients with and without USS, stratified by the initial size of GBP (<6 mm and 6–9 mm). We estimated USS resource and costs under alternate referral thresholds for cholecystectomy. Clinical data were extracted from a large-scale cohort study. TAUS and cholecystectomy costs were based on NHS tariffs. GBC costs were estimated from the literature. Outcomes included USS costs, expected numbers of GBC, and incremental cost for each case of GBC avoided.ResultsThe 2-year additional cohort costs of USS (n = number of cholecystectomies) were estimated between £213 441 (n = 50) and £750 045 (n = 253) in GBPs <6 mm and between £420 275 (n = 165) and £531 297 (n = 207) in GBPs 6–9 mm, balanced against avoidance of 1.3 (<6 mm) and 8.7 (6–9 mm) cases of GBC. Model findings were robust to plausible changes in inputs.ConclusionsUsing published data, we demonstrated that, in patients with GBPs <10 mm, the costs of USS to avoid GBC outweigh potential GBC cost offsets and would result in high rates of cholecystectomy. Additional evidence is needed to establish the formal cost-effectiveness of GBP USS in the UK.Advances in knowledge• We developed a health economic model, based on published data, to evaluate the cost-effectiveness of guideline-recommended ultrasound surveillance (USS) in patients with gallbladder polyps measuring less than 10 mm in the UK.• The analysis provides a transparent platform to explore potential numbers of trans-abdominal ultrasound studies and cholecystectomies that might be expected if USS protocols are adhered to and discovers important gaps in current evidence that could be filled by additional targeted research.

The human voltage-gated proton channel (HV1) provides an efficient proton extrusion pathway from the cytoplasm contributing to the intracellular pH regulation and the oxidative burst. Although its pharmacological inhibition was previously shown to induce cell death in various cell types, no such effects have been examined in polarized macrophages albeit HV1 was suggested to play important roles in these cells. This study highlights that 5-chloro-2-guanidinobenzimidazole (ClGBI), the most widely applied HV1 inhibitor, reduces the viability of human THP-1-derived polarized macrophages at biologically relevant doses with M1 macrophages being the most, and M2 cells the least sensitive to this compound. ClGBI may exert this effect principally by blocking HV1 since the sensitivity of polarized macrophages correlates well with their HV1 expression levels; inhibitors of other macrophage ion channels that may be susceptible for off-target ClGBI effects cause no viability reductions; and Zn2+, another non-specific HV1 blocker, exerts similar effects. As a potential mechanism behind the ClGBI-induced cell death, we identify a complex pH dysregulation involving acidification of the cytoplasm and alkalinization of the lysosomes, which eventually result in membrane ceramide accumulation. Furthermore, ClGBI effects are alleviated by ARC39, a selective acid sphingomyelinase inhibitor supporting the unequivocal significance of ceramide accumulation in the process. Altogether, our results suggest that HV1 inhibition leads to cellular toxicity in polarized macrophages in a polarization-dependent manner, which occurs due to a pH dysregulation and concomitant ceramide overproduction mainly depending on the activity of acid sphingomyelinase. The reduced macrophage viability and plausible concomitant changes in homeostatic M1-M2 balance could contribute to both the therapeutic and potential side effects of HV1 inhibitors that show great promise in the treatment of neuroinflammation and malignant diseases.

Abstract The state of Colorado's West Slope Basins are critical headwaters of the Colorado River and play a vital role in supporting Colorado's local economy and natural environment. However, balancing the multi‐sectoral water demands in the West Slope Basins while maintaining crucial downstream deliveries to Lake Powell is an increasing challenge for water managers. Internal variability of the hydroclimatic system and climate change complicate future vulnerability assessments. This work contributes a detailed accounting of multi‐sectoral drought vulnerability in the West Slope Basins and the impacts of drought on downstream deliveries. We first introduce a novel multi‐site Hidden Markov Model (HMM)‐based synthetic streamflow generator to create an ensemble of streamflows for all West Slope basins that better characterizes the region's drought extremes. We capture the effects of climate change by perturbing the HMM to generate an ensemble of streamflows reflecting plausible changes in climate. We then route both ensembles through StateMod, Colorado's water allocation model, to evaluate spatially compounding drought impacts across the West Slope Basins. Our results illustrate how drought events emerging from the system's stationary internal variability in the absence of climate change can significantly impact local water uses and deliveries to Lake Powell, exceeding extreme conditions in the historical record. Further, we find that even modest climate change can cause a regime shift where historically low downstream delivery volumes and extreme drought impacts become routine. These results can inform future Colorado River planning efforts, and our methodology can be expanded to other snow‐dominated regions that face persistent droughts.

Introduction &amp; Purpose “Running technique is an important component of running economy and performance” (Folland et al., 2017). While economy and performance can directly be measured, no common measuring method exists for running technique. The aims of this study were twofold: (I) develop practice-informed running technique measures based on technique characterizations used by coaches (i.e. distinct variations of body segment movements instead of discrete kinematics); (II) investigate, how running technique changes with running speed. Methods Two independent kinematic data sets were recorded on a treadmill using a retro-reflective marker setup (“Plugin-Gait”) and a 10-camera system (Vicon Motion Systems Ltd., Oxford, UK). First, 20 experienced runners (age 25 ± 2 y; 10 females, 10 males) were tasked to vary their running according to 14 technique elements (vertical, horizontal, hip and upper body movement, foot strike, track width, ankle rotation, leg swing, back posture, elbow flexion/extension, arm swing amplitude and direction, gaze direction, cadence) into two opposing extreme forms per element. Measures for the 14 running technique elements were developed using principal component analyses (one PCA per two opposing technique element variations) and selecting principal components (PCs; Federolf, 2016) that aligned with the represented technique element. Second, an additional 19 experienced runners (age 30 ± 9 y, 3 females, 16 males) ran at different speeds (10-17 km/h with 1 km/h incremental steps) without any technique instructions. Their data were projected onto the selected PCs, resulting in averaged PC score waveforms of the different speeds along each technique element. Waveforms were analysed using statistical parametric mapping (SPM) with a repeated measures ANOVA design (Pataky et al., 2013). Results For all 14 technique elements, sections of significant differences between at least two different speeds were found within the cycle-normalized PC score waveforms. Figure 1 exemplifies the results for the foot track width, where the lateral range of motion of the feet decreased with speed. Post-hoc analyses revealed further differences, such as less vertical and greater horizontal movement, as well as smaller leg swing and greater arm swing amplitude at 17 km/h compared to 10 km/h. Discussion Firstly, practice-informed and data-driven running technique measures could be developed (I). Secondly, the measures could be applied on a group of runners and plausible changes in their technique due to running speed were identified (II). So far, the speed-dependent technique adaptations only reflect the specific techniques on a treadmill for a predominately male reference group, but the presented concept can be transferred to other runners and settings. Conclusion Running technique varies with speed, and the developed technique measures facilitate comparisons of these differences using practically relevant technique elements. Since the movement adaptations associated with running speed are directly quantifiable and visualizable, technique models for different speed ranges might be developed by researchers and then utilized by runners to train and assess their technique in alignment with these models.

Counterfactual Explanations (CEs) have emerged as a major paradigm in explainable AI research, providing recourse recommendations for users affected by the decisions of machine learning models. However, CEs found by existing methods often become invalid when slight changes occur in the parameters of the model they were generated for. The literature lacks a way to provide exhaustive robustness guarantees for CEs under model changes, in that existing methods to improve CEs' robustness are mostly heuristic, and the robustness performances are evaluated empirically using only a limited number of retrained models. To bridge this gap, we propose a novel interval abstraction technique for parametric machine learning models, which allows us to obtain provable robustness guarantees for CEs under a possibly infinite set of plausible model changes Δ. Based on this idea, we formalise a robustness notion for CEs, which we call Δ-robustness, in both binary and multi-class classification settings. We present procedures to verify Δ-robustness based on Mixed Integer Linear Programming, using which we further propose algorithms to generate CEs that are Δ-robust. In an extensive empirical study involving neural networks and logistic regression models, we demonstrate the practical applicability of our approach. We discuss two strategies for determining the appropriate hyperparameters in our method, and we quantitatively benchmark CEs generated by eleven methods, highlighting the effectiveness of our algorithms in finding robust CEs.

BackgroundSkin prick tests (SPTs), or intraepidermal tests, are often the first diagnostic approach for people with a suspected allergy. Together with the clinical history, SPTs allow doctors to draw conclusions on allergies based on the sensitization pattern. The purpose of this study is to investigate the potential cost consequences that would accrue to a Swiss University hospital after the adoption of computer vision-based SPTs.MethodsWe conducted a cost-consequence analysis from a hospital’s perspective to evaluate the potential cost consequences of using a computer vision-based system to read SPT results. The patient population consisted of individuals who were referred to the allergology department of one of the five university hospitals in Switzerland, Inselspital, whose allergology department averages 100 SPTs a week. We developed an early cost-consequence model comparing two SPT techniques; computer vision-based SPTs conducted with the aid of Nexkin DSPT and standard fully manual SPTs. Probabilistic sensitivity analysis and additional univariate sensitivity analyses were used to account for uncertainty.ResultsThe difference in average cost between the two alternatives from a hospital’s perspective was estimated to be CHF 7 per SPT, in favour of the computer vison-based SPTs. Monte Carlo probabilistic simulation also indicated that SPTs conducted using the computer vision-based system were cost saving compared to standard fully manual SPTs. Sensitivity analyses additionally demonstrated the robustness of the base case result subject to plausible changes in all the input parameters, with parameters representing the costs associated with both SPT techniques having the largest influence on the incremental cost. However, higher sensitization prevalence rates seemed to favour the more accurate standard fully manual SPTs.ConclusionAgainst the backdrop of rising healthcare costs especially in Switzerland, using computer-aided or (semi) automated diagnostic systems could play an important role in healthcare cost containment efforts. However, results should be taken with caution because of the uncertainty associated with the early nature of our analysis and the specific Swiss context adopted in this study.

Abstract Of concern to Colorado River management, as operating guidelines post-2026 are being considered, is whether water resource recovery from low flows during 2000–20 is possible. Here, we analyze new simulations from phase 6 of the Coupled Model Intercomparison Project (CMIP6) to determine plausible climate impacts on Colorado River flows for 2026–50 when revised guidelines would operate. We constrain projected flows for Lees Ferry, the gauge through which 85% of the river flow passes, using its estimated sensitivity to meteorological variability together with CMIP6-projected precipitation and temperature changes. The critical importance of precipitation, especially its natural variability, is emphasized. Model projections indicate increased precipitation in the upper Colorado River basin due to climate change, which alone increases river flows by 5%–7% (relative to a 2000–20 climatology). Depending on the river’s temperature sensitivity, this wet signal compensates for some, if not all, of the depleting effects of basin warming. Considerable internal decadal precipitation variability (∼5% of the climatological mean) is demonstrated, driving a greater range of plausible Colorado River flow changes for 2026–50 than previously surmised from treatment of temperature impacts alone: the overall precipitation-induced Lees Ferry flow changes span from −25% to +40%, contrasting with a range from −30% to −5% from expected warming effects only. Consequently, extreme low and high flows are more likely. Lees Ferry flow projections, conditioned on initial drought states akin to 2000–20, reveal substantial recovery odds for water resources, albeit with elevated risks of even further flow declines than in recent decades. Significance Statement Increasing temperatures have led to concerns that Colorado River flows will be permanently reduced due to global warming. Here, we analyze precipitation, surface temperature, and streamflow (at Lees Ferry) in the upper Colorado River basin since 1895 revealing precipitation to be the largest contributor to runoff variability while temperature variability has been a much smaller contributor. New climate model projections indicate increased precipitation in the upper basin due to global warming, acting to increase river flows by 5%–7% during 2026–50. This wet signal compensates for some of the depleting effects from further basinwide warming. Critically, the large intrinsic variability in precipitation is demonstrated to yield a wider range of future Colorado River flows than previously foreseen based solely on considering temperature effects.

Modified Newtonian dynamics (MOND), which postulates a breakdown of Newton's laws of gravity/dynamics below some critical acceleration threshold, can explain many otherwise puzzling observational phenomena on galactic scales. MOND competes with the hypothesis of dark matter, which successfully explains the cosmic microwave background and large-scale structure. Here we provide the first solar system test of MOND that probes the subcritical acceleration regime. Using the Bekenstein–Milgrom “aquadratic Lagrangian” (or AQUAL) formulation, we simulate the evolution of myriads of test particles (planetesimals or comets) born in the trans-Neptunian region and scattered by the giant planets over the lifetime of the Sun to heliocentric distances of 102–105 au. We include the effects of the Galactic tidal field and passing stars. While Newtonian simulations reproduce the distribution of binding energies of long-period and Oort-cloud comets detectable from Earth, MOND-based simulations do not. This conclusion is robust to plausible changes in the migration history of the planets, the migration history of the Sun, the MOND transition function, effects of the Sun's birth cluster, and the fading properties of long-period comets. For the most popular version of AQUAL, characterized by a gradual transition between the Newtonian and MOND regimes, our MOND-based simulations also fail to reproduce the orbital distribution of trans-Neptunian objects in the detached disk (perihelion q > 38 au). Our results do not rule out some MOND theories more elaborate than AQUAL, in which non-Newtonian effects are screened on small spatial scales, at small masses, or in external gravitational fields comparable in strength to the critical acceleration.

Research on human-animal chimeras have elicited alarms and prompted debates. Those involving the generation of chimeric brains, in which human brain cells become anatomically and functionally intertwined with their animal counterparts in varying ratios, either via xenografts or embryonic co-development, have been considered the most problematic. The moral issues stem from a potential for "humanization" of the animal brain, as well as speculative changes to the host animals' consciousness or sentience, with consequential alteration in the animal hosts' moral status. However, critical background knowledge appears to be missing to resolve these debates. Firstly, there is no consensus on animal sentience vis-à-vis that of humans, and no established methodology that would allow a wholesome and objective assessment of changes in animal sentience resulting from the introduction of human brain cells. Knowledge in interspecies comparative neuropsychology that could allow effective demarcation of a state of "humanization" is also lacking. Secondly, moral status as a philosophical construct has no scientific and objective points of reference. Either changes in sentience or humanization effects would remain unclear unless there are some neuroscientific research grounding. For a bioethical stance based on moral status of human-animal brain chimera to make meaningful contributions to regulatory policies, it might first need to be adequately informed by, and with its arguments constructed, in a manner that are factually in line with the science. In may be prudent for approved research projects involving the generation of human-animal brain chimera to have a mandatory component of assessing plausible changes in sentience.

The Causal Cognitive Architecture is a brain-inspired cognitive architecture developed from the hypothesis that the navigation circuits in the ancestors of mammals duplicated to eventually form the neocortex. Thus, millions of neocortical minicolumns are functionally modeled in the architecture as millions of "navigation maps." An investigation of a cognitive architecture based on these navigation maps has previously shown that modest changes in the architecture allow the ready emergence of human cognitive abilities such as grounded, full causal decision-making, full analogical reasoning, and near-full compositional language abilities. In this study, additional biologically plausible modest changes to the architecture are considered and show the emergence of super-human planning abilities. The architecture should be considered as a viable alternative pathway toward the development of more advanced artificial intelligence, as well as to give insight into the emergence of natural human intelligence.