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Human milk oligosaccharides (HMOs) are the third most abundant biomolecules in breast milk, with over 200 structural variants, mainly fucosylated, sialylated, and neutral core types. Key HMOs include 2′-fucosyllactose (2′-FL), and 3′/6′-sialyllactose (3′/6′-SL), which enhance brain development in animal models(1). Lactoferrin (Lf), a sialylated glycoprotein, also supports neurodevelopment by promoting neurogenesis and reducing neuroinflammation(2). However, the combined effects of HMOs and Lf on brain metabolism remain unknown. We therefore investigated their synergy on brain metabolites and neurotransmitters in neonatal piglets using in vivo ¹H-MRS. Three-day-old male domestic piglets (Sus scrofa – Large White × Duroc × Belgian Landrace) were randomly assigned to one of three groups and fed a standard pig milk replacer with the following supplements: control (methyl cellulose at 1.8 g/L; n = 14), combined HMOs (70% 2′-FL and 30% 3′-SL:6′-SL in a 1:2.5 ratio at 1.8 g/L; n = 16), or cHMOs + Lf (cHMOs at 1.8 g/L + lactoferrin at 0.5 g/L; n = 14). In vivo ¹H-MRS was performed on postnatal day 38/39 using a 3T scanner (TE = 30 ms) to assess regional brain metabolite profiles. The research protocol was approved by the ACECs of Charles Sturt University (A23566) and Monash University (38776). Our results demonstrated that the group received combined HMOs and Lf exhibited significantly higher absolute levels of total lipids and macromolecules, along with increased relative concentrations of glutathione (Glth), total creatine (TCr), total choline (TCh), and total lipids and macromolecules at 2.0 ppm (TLM20) (p < 0.05). In contrast, the cHMOs group were observed to have significantly increased levels of absolute total N-acetylaspartate (TNAA) (p < 0.05). Collectively, these findings suggest that combined HMOs and lactoferrin supplementation may synergistically support neurodevelopment by enhancing lipid mobilization, energy metabolism, and antioxidant capacity, while cHMOs alone promotes brain development by improving neuronal integrity and synaptic activity in piglets—a translational model for human infants. To our knowledge, these findings have not been previously reported.
Early brain growth demands essential precursors and nutrients. Lactoferrin (LF), a sialylated iron-binding glycoprotein rich in sialic acid (Sia) residues on its N-glycans, is significantly more abundant in human milk than in cow milk-based formulas. Sia forms polysialic acid (polySia), primarily attached to neural cell adhesion molecule (NCAM), producing polySia–NCAM, a key neuroplasticity marker involved in brain remodelling, neurogenesis, and cognition. Despite evidence linking LF to neurodevelopment and cognitive support(1), the specific effects of iron saturation and sialylation within LF on these outcomes remain unclear. Lactating Wistar rat dams were fed standard diets supplemented with native bovine LF (Native-bLF), iron-depleted LF (Apo-LF), or Sia-depleted LF (Desia-LF) at 0.60 g/kg throughout lactation. From postnatal day 22, dams and offspring received standard chow and water ad libitum. Offspring underwent the behavioural assessments between postnatal days 44 and 59. PolySia–NCAM expression(2) in the hippocampus was evaluated qualitatively by Western blot on day 63. The protocol was approved by the Xiamen University Animal Ethics Committee (AE1640102). Behavioural assessments demonstrated that offspring exposed to Apo-LF exhibited reduced anxiety-like behaviour in the open field test (p < 0.05). In the Morris water maze, Apo-LF offspring showed enhanced spatial learning, evidenced by significantly shorter escape latencies during the 9-day training period compared to both Native-LF and Desia-LF groups (p < 0.02). In contrast, Desia-LF offspring showed the poorest cognitive performance, although escape latency and anxiety-like behaviour did not differ significantly between Desia-LF and Native-LF groups (p > 0.05). Apo-LF supplementation also significantly increased polySia-NCAM expression in the hippocampus compared to the Native-LF group (p = 0.033), whereas no significant difference was observed between Desia-LF and Native-LF groups (p > 0.05). Maternal lactoferrin supplementation during lactation enhances cognitive development by modulating synaptic structure and plasticity, thereby shaping neurodevelopmental outcomes through distinct molecular mechanisms, with sialylation playing a crucial role in neuroplasticity.
In contrast to the “lazy prices” phenomenon in the stock market, more 10-K textual changes lead to larger increases in volatility smirks—consistent with options traders buying more out-of-the-money put options based on negative information disclosed in textual changes. Moreover, the lazy-prices effect is mainly driven by stocks with tradable options, suggesting that limits to arbitrage lead to a delayed response of stock prices. Finally, the return predictability of textual changes is stronger for stocks with larger option volatility smirk changes. Sophisticated options traders, therefore, demonstrate superior skills at extracting relevant information from public filings.
To reveal the influence laws of casing abradable coating wear on compressor aerodynamic performance, a numerical simulation study was conducted on the performance of Rotor 37 under high-speed scraping conditions with different hardness coating wear morphologies. The results show that compressor isentropic efficiency and outlet mass flow are sensitive to scraping-induced morphology changes. The medium-hardness coating causes the most significant performance degradation, with maximum reductions reaching 1.96% and 1.39%, respectively, while the pressure ratio shows little variation. Scraping grooves aggravate mixing losses between leading-edge (LE) leakage flow and mid-chord (MID) leakage flow. The tip leakage flow pushes suction-side separation vortices toward the main flow path. Under medium-hardness coating scraping conditions, the maximum entropy generation region affects up to 9.1% blade height and induces tip leakage vortex-shockwave interactions, resulting in substantial tip losses. The compressor aerodynamic performance is less affected by wear zone roughness, with the maximum isentropic efficiency reduction being only 0.31%. When wear zone roughness increases, near-wall turbulence fluctuations intensify and separation zones expand, causing flow structure changes in tip leakage paths and blade wake regions, which shifts the compressor aerodynamic characteristics toward lower flow rates. The study demonstrates that coating hardness alters leakage flow structures through wear morphology depth: medium-hardness coatings with the deepest wear grooves exhibit maximum performance deterioration, while high-hardness coatings show better wear resistance and performance maintenance.
Autonomous manoeuvre decision-making is essential for enhancing the survivability and operational effectiveness of unmanned aerial vehicles in high-risk and dynamic air combat scenarios. To address the limitations of traditional air combat decision-making methods in dealing with complex and rapidly changing environments, this paper proposes an autonomous air combat decision-making algorithm based on hybrid temporal difference error-reward prioritised experience replay with twin delayed deep deterministic policy gradient. This algorithm constructs a closed-loop learning system from environmental interaction to policy optimisation, addressing the key challenges of slow convergence and insufficient identification of critical tactical decisions in autonomous air combat. A hybrid priority metric leveraging reward backpropagation and temporal difference error filter is introduced to optimise the learning of high-value experiences while balancing sample diversity and the reuse of critical experiences. To reduce excessive trial and error in the initial phase, an integrated reward function combining task rewards and auxiliary guidance rewards is designed using the reward reshaping method to guide the agent on how to choose a manoeuvre strategy. Based on the established three-dimensional close-range air combat game model, simulation validations were conducted for both basic manoeuvre and expert system engagements. The results demonstrate that the proposed autonomous air combat manoeuvre decision-making algorithm exhibits higher learning efficiency and convergence stability. It can rapidly identify high-value manoeuvres and effectively formulate rational yet superior tactical strategies in the face of complex battlefield scenarios, demonstrating obvious benefits in enhancing combat effectiveness and tactical adaptability.
This paper studies a distributed fixed-time dynamic event-triggered formation control framework for a group of hypersonic gliding vehicles (GHGVs) suffering from internal uncertainties and non-affine properties. The main challenge is strong coupling of non-affine nonlinear dynamic with hypervelocity characteristics and multi-source uncertainties make it difficult to design the control protocol. Firstly, by integrating the distributed consensus control strategy, fractional order control theory and dynamic event-triggered mechanism, a framework of fixed-time formation control for GHGVs system is constructed. Secondly, to mitigate the issue of ‘explosion of complexity’ (EI), a fixed-time command filter (FCF) is proposed and a compensative strategy is formulated to tackle the impact of filtering errors. Thirdly, an additional auxiliary differential equation (ADE) is developed to decouple the control input from the status variable. Several radial base function neural networks (RBFNN) are utilised to handle the unknown internal uncertainties. Furthermore, a unique dynamic event-triggered mechanism (DTEM) is introduced for each follower, facilitating seamless transitions between two distinct dynamic threshold strategies. Analysis based on Lyapunov function illustrates that the output tracking error of followers exponentially converges to a small range within a fixed time, and Zeno behaviour is prevented. Finally, several numerical simulations are presented to demonstrate the practicability and meliority of the suggested approach.
Certain prescription drugs used during pregnancy are associated with offspring autism spectrum disorder (ASD). Nonetheless, ASD risk following prenatal exposure to most drugs remains unknown. Furthermore, methodological challenges and ethical concerns hinder the scope for causal inference.
Methods
We used a case-cohort study design of a nationally representative sample from Israel to examine the associations between maternal prescription drug use during pregnancy and offspring ASD. To scrutinize these associations, the analyses were (a) adjusted for indication proxy (level 2 Anatomical Therapeutic Chemical (ATC) codes), (b) repeated using shared pharmacological targets as exposures, and (c) inspected further through target-enrichment analysis.
Results
The sample included 1,400 individuals with and 94,713 without an ASD diagnosis. Among all drugs prescribed during pregnancy, five were statistically significantly associated with increased offspring ASD risk after adjustment for indication proxy (e.g., hazard ratio [95% confidence interval] cyproterone = 2.71 [1.17–6.25] and prednisolone = 2.10 [1.27–3.49]), and two with decreased risk (ferrous sulfate = 0.82 [0.68, 0.99] and lynestrenol = 0.43 [0.2, 0.93]). Further analysis revealed four pharmacological targets shared by these drugs, which were themselves associated with ASD (e.g., neuronal acetylcholine receptor α4β4 = 1.45 [1.05–1.99] and serotonin 2b receptor = 1.31 [1.04–1.61]). Enrichment analysis suggested the association between ASD and medications affecting cholinergic and serotonergic signaling.
Conclusions
Increased ASD risk followed prenatal exposure to five prescription drugs, and decreased risk followed exposure to two. Subsequent analyses suggested no confounding by indication in these associations, but further studies are warranted.
This paper studies the adaptive distributed consensus tracking control framework for hypersonic gliding vehicles (HGVs) flying in tight formation. The system investigated in this paper is non-affine and subjected to multisource disturbances and mismatched uncertainties caused by a dramatically changing environment. Firstly, by refining the primary factors in the three-dimensional cluster dynamics, a non-affine closed-loop control system is summarised. Note that actual control is coupled with states, an additional auxiliary differential equation is developed to introduce additional affine control inputs. Furthermore, by employing the hyperbolic tangent function and disturbance boundary estimator, time-varying multisource disturbances can be handled. Several radial base function neural networks (RBFNNs) are utilised to approximate unknown nonlinearities. Furthermore, a generalised equatorial coordinate system is proposed to convert the longitudinal, lateral and vertical relative distances in the desired formation configuration into first-order consensus tracking error, such as latitude, longitude and height deviations. Analysis based on the Lyapunov function illustrates that variables are globally uniformly bounded, and the output tracking error of followers exponentially converges to a small neighbourhood. Finally, numerical simulations of equilibrium glide and spiral diving manoeuvers are provided to demonstrate the validity and practicability of the proposed approach.
Haemonchus contortus is a parasitic nematode that causes significant economic losses in ruminant livestock worldwide. In this study, we assessed the global genetic diversity and population structure of H. contortus using mitochondrial COX1 and ribosomal ITS2 sequences retrieved from the NCBI GenBank database. In total, 324 haplotypes of the COX1 and 72 haplotypes of the ITS2 were identified. The haplotype diversity values were all higher than 0.5, and the nucleotide diversity values were higher than 0.005. The Tajima’s D value for COX1 (−1.65634) was higher than that for ITS2 (−2.60400). Fu’s Fs, Fu and Li’s D (FLD), and Fu and Li’s F (FLF) values also showed high negative values, indicating a high probability of future population growth. In addition, the high fixation index (FST) value suggests significant genetic differentiation among populations. The haplotype networks of H. contortus populations based on COX1 sequences revealed clear geographic clustering, whereas ITS2 sequences showed more haplotype admixture across regions. The results of phylogenetic analyses were consistent with the haplotype networks. These findings highlighted that H. contortus populations exhibit significant genetic variation and are undergoing rapid population expansion, with clear genetic differences across geographic regions. This study established critical baseline data for future molecular epidemiology studies, which could guide region-specific parasite surveillance and targeted control strategies, thus helping to mitigate the risk of cross-border parasite transmission and drug resistance.
There are multiple equilibrium points in the launching and unfolding process of the multi-body aircraft. Different equilibrium points exhibit different stability characteristics and change with parameters such as connection method. The changes in stability characteristics can also lead to the inability of multi-body aircraft to achieve stable deployment. To solve these problems, the dynamic stability of multi-body aircraft during falling is analysed based on bifurcation theory in this paper. In this paper, Lagrange multiplier method is used to establish the multi-body dynamics model of the multi-body aircraft, and the curly spring torque model is added. In order to consider the coupling effect between the wings and the influence of the relative motion between the flight units on the aerodynamic force, the reference angle-of-attack, the reference sideslip angle, the relative attitude angle and the relative attitude angular velocity between the flight units were introduced as new variables to establish the aerodynamic model of the multi-body aircraft. Based on the equilibrium equations, the equilibrium curve of the two-body aircraft is obtained by using the joint stiffness coefficient as the continuous variable parameter. The stability of the equilibrium point domain on each equilibrium curve was analysed by using linearised theory. The dynamic characteristics of the launching and unfolding process of the two-body aircraft were analysed using bifurcation theory, and the stable domain was obtained regarding the initial folding angle and connection stiffness coefficient. The influence of initial folding angle and connection stiffness coefficient on the dynamic characteristics of the launching and unfolding process and the meaning of the stability domain were analysed through numerical simulation calculations. Finally, the correctness of the analysis conclusion was verified through experiments on the two-body aircraft, accumulating the technical foundation for subsequent research on high-altitude deployment.
Background: TERT promoter mutation (TPM) is an established biomarker in meningiomas associated with aberrant TERT expression and reduced progression-free survival (PFS). TERT expression, however, has also been observed even in tumours with wildtype TERT promoters (TP-WT). This study aimed to examine TERT expression and clinical outcomes in meningiomas. Methods: TERT expression, TPM status, and TERT promoter methylation of a multi-institutional cohort of meningiomas (n=1241) was assessed through nulk RNA sequencing (n=604), Sanger sequencing of the promoter (n=1095), and methylation profiling (n=1218). 380 Toronto meningiomas were used for discovery, and 861 external institution samples were compiled as a validation cohort. Results: Both TPMs and TERTpromoter methylation were associated with increased TERT expression and may represent independent mechanisms of TERT reactivation. TERT expression was detected in 30.4% of meningiomas that lacked TPMs, was associated with higher WHO grades, and corresponded to shorter PFS, independent of grade and even among TP-WT tumours. TERT expression was associated with a shorter PFS equivalent to those of TERT-negative meningiomas of one higher grade. Conclusions: Our findings highlight the prognostic significance of TERT expression in meningiomas, even in the absence of TPMs. Its presence may identify patients who may progress earlier and should be considered in risk stratification models.
The frequency responses of circulation control and separation control using mini-spoilers for loads attenuation on plunging swept and unswept wings were compared in a water tunnel study. At the pre-stall angle-of-attack, the effectiveness of the spoilers significantly diminishes with increasing reduced frequency of the plunging motion. For the leading-edge spoiler, this happens because the roll-up of the vorticity promotes flow reattachment and reduces the effectiveness of loads attenuation. For the trailing-edge spoiler, the effectiveness of lift attenuation also decreases with increasing reduced frequency, due to the shedding of leading-edge vortices and immersion of the trailing-edge spoiler in the separated flow. The decay of the frequency response for both types of spoilers is similar, implying that it is dictated by the flow separation near the leading edge of the wing in both cases. With increasing sweep angle of the wings, the spoilers’ effectiveness decreases significantly in comparison to the unswept wing. Strong spanwise flow develops for the leading-edge spoiler, which sheds a streamwise vortex, with the same direction of rotation as the wing-tip trailing vortex. This causes partial reattachment of the flow and reduction of the separation area behind the spoiler. With increasing reduced frequency, strong leading-edge vortices dominate the flow over the wing. The leading-edge vortices generate additional vortex lift and also cause the trailing-edge spoiler to be immersed in the massively separated flows. Both factors reduce the effectiveness of the spoilers.
We report on an experience with impostor research participants, people who misrepresent themselves, and identify characteristics that can be used by investigators to screen out such participants. We compare the responses of impostor and valid participants, showing that impostors meaningfully change qualitative study findings with implications for policy interventions or follow-on research informed by the study. It is important for investigators to be alert to the potential for impostor participants and plan their research accordingly.
Lactoferrin (LF), a sialylated iron-binding glycoprotein consisting of multiple sialic acid (Sia) residues attached to N-linked glycan chains, and studies have shown that both the iron and Sia are crucial for early neurodevelopment and cognition.(1) However, there is limited knowledge of the impacts of the iron saturation and sialylation in LF molecule on the early neurodevelopment and cognition. Objectives of the study were to explore the impacts and mechanisms of iron saturation and sialylation in LF molecule on early neurodevelopment and cognition. Maternal dietary intervention with native bovine LF (Native-LF), iron-free bovine LF (Apo-LF), or Sia-free bovine LF (Desia-LF) at a dose of 0.60 g/kg body weight per day was administered throughout the lactation period. Offspring pups were assessed for anxiety, learning, and memory through behavioral tests before being euthanized on postnatal day 63. Brain hippocampal tissue was then analyzed for polysialic acid (polySia), a marker of neurodevelopment and neuroplasticity.(1) The study protocol was approved by the Xiamen University Animal Ethics Committee (AE1640102). Our results showed that Apo-LF pups exhibited a 1.32-fold increase in total distance travelled in the arena compared to both Native-LF and Desia-LF groups, with the overall difference among the groups being statistically significant in the open field test (p = 0.008). Additionally, the frequency of central area entries in the Apo-LF group was 2.00-fold higher than in Desia-LF pups (p = 0.038) and 1.3-fold higher than in Native-LF pups, with a significant overall difference (p = 0.042). No significant differences in total distance travelled or central area entries were observed between Native-LF and Desia-LF groups (p > 0.05). These results suggest that Apo-LF pups demonstrated better anti-anxiety behaviors than both Native-LF and Desia-LF pups. In the Morris water maze test, Apo-LF pups spent significantly more time in the target quadrant compared to both Desia-LF (p = 0.019) and Native-LF pups (p = 0.0009), indicating enhanced short-term memory. Additionally, Apo-LF pups exhibited greater polySia-NCAM expression (1.2.95 ± 0.048) in the hippocampus, a marker associated with neuroplasticity and neurogenesis compared to both Native-LF and Desia-LF pups. We conclude that maternal supplementation with different types of lactoferrin during lactation supports improved learning and memory in offspring through distinct mechanisms, with sialylation playing a crucial role in neurocognitive development.
Just as councils and assemblies were central to European polities for centuries, the Imperial Examination System (Keju) constituted the cornerstone of state institutions in China. This Element argues that Keju contributed to political stability, and its emergence was a process, not a shock, with consequences initially unanticipated by its contemporaries. The Element documents the emergence of Keju using evidence from early Chinese empires to the end of the Tang Dynasty in the 10th century, including epitaphs and government documents. It then traces the selection criteria of Keju and trends in social mobility over the second millennium, leveraging biographical information from over 70,000 examinees and 1,500 ministers and their descendants. The Element uses a panel of 112 historical polities to quantify Keju's association with country-level political indicators against the backdrop of global convergence in political stability and divergence in institutions. This title is also available as Open Access on Cambridge Core.
We present the first results from a new backend on the Australian Square Kilometre Array Pathfinder, the Commensal Realtime ASKAP Fast Transient COherent (CRACO) upgrade. CRACO records millisecond time resolution visibility data, and searches for dispersed fast transient signals including fast radio bursts (FRB), pulsars, and ultra-long period objects (ULPO). With the visibility data, CRACO can localise the transient events to arcsecond-level precision after the detection. Here, we describe the CRACO system and report the result from a sky survey carried out by CRACO at 110-ms resolution during its commissioning phase. During the survey, CRACO detected two FRBs (including one discovered solely with CRACO, FRB 20231027A), reported more precise localisations for four pulsars, discovered two new RRATs, and detected one known ULPO, GPM J1839 $-$10, through its sub-pulse structure. We present a sensitivity calibration of CRACO, finding that it achieves the expected sensitivity of 11.6 Jy ms to bursts of 110 ms duration or less. CRACO is currently running at a 13.8 ms time resolution and aims at a 1.7 ms time resolution before the end of 2024. The planned CRACO has an expected sensitivity of 1.5 Jy ms to bursts of 1.7 ms duration or less and can detect $10\times$ more FRBs than the current CRAFT incoherent sum system (i.e. 0.5 $-$2 localised FRBs per day), enabling us to better constrain the models for FRBs and use them as cosmological probes.
This paper develops a novel full-state-constrained intelligent adaptive control (FIAC) scheme for a class of uncertain nonlinear systems under full state constraints, unmodeled dynamics and external disturbances. The key point of the proposed scheme is to appropriately suppress and compensate for unmodeled dynamics that are coupled with other states of the system under the conditions of various disturbances and full state constraints. Firstly, to guarantee that the time-varying asymmetric full state constraints are obeyed, a simple and valid nonlinear error transformation method has been proposed, which can simplify the constrained control problem of the system states into a bounded control problem of the transformed states. Secondly, considering the coupling relationship between the unmodeled dynamics and other states of the controlled system such as system states and control inputs, a decoupling approach for coupling uncertainties is introduced. Thereafter, owing to the employed dynamic signal and bias radial basis function neural network (BIAS-RBFNN) improved on traditional RBFNN, the adverse effects of unmodeled dynamics on the controlled system can be suppressed appropriately. Furthermore, the matched and mismatched disturbances are reasonably estimated and circumvented by a mathematical inequality and a disturbance observer, respectively. Finally, numerical simulations are provided to demonstrate the effectiveness of the proposed FIAC strategy.
To investigate the flame acceleration to detonation in 2.0 and 0.5 mm planar glass combustion chambers, the experiments have been conducted utilising ethylene/oxygen mixtures at atmospheric pressure and temperature. The high-speed camera has been used to record the revolution of flame front and pressure inside the combustion chamber. Different equivalence ratios and ignition locations have been considered in the experiments. The results show that the detonation pressure in the 2 mm thick chamber is nearly three times of Chapman-Jouguet pressure, while detonation pressure in the 0.5 mm thick chamber is only 45.7% of the Chapman-Jouguet value at the stoichiometric mixture. This phenomenon is attributed to the larger pressure loss in the thinner chamber during the detonation propagation. As the value of equivalence ratio is 2.2, the detonation cannot be produced in the 2 mm thick chamber, while the detonation can be generated successfully in the 0.5 mm thick chamber. This phenomenon indicates that the deflagration is easily to be accelerated and transformed into the detonation, due to a larger wall friction and reflection. Besides, the micro-obstacle has been added into the combustor can shorten the detonation transition time and reduces the distance of the detonation transition.
The axisymmetric nozzle mechanism is the core part for thrust vectoring of aero engine, which contains complex rigid-flexible coupled multibody system with joints clearance and significantly reduces the efficiency in modeling and calculation, therefore the kinematics and dynamics analysis of axisymmetric vectoring nozzle mechanism based on deep neural network is proposed. The deep neural network model of the axisymmetric vector nozzle is established according to the limited training data from the physical dynamic model and then used to predict the kinematics and dynamics response of the axisymmetric vector nozzle. This study analyses the effects of joint clearance on the kinematics and dynamics of the axisymmetric vector nozzle mechanism by a data-driven model. It is found that the angular acceleration of the expanding blade and the driving force are mostly affected by joint clearance followed by the angle, angular velocity and position of the expanding blade. Larger joint clearance results in more pronounced fluctuations of the dynamic response of the mechanism, which is due to the greater relative velocity and contact force between the bushing and the pin. Since axisymmetric vector nozzles are highly complex nonlinear systems, traditional numerical methods of dynamics are extremely time-consuming. Our work indicates that the data-driven approach greatly reduces the computational cost while maintaining accuracy, and can be used for rapid evaluation and iterative computation of complex multibody dynamics of engine nozzle mechanism.