Dynamics of Center of Pressure Trajectory in Gait: Unilateral Transfemoral Amputees Versus Non-Disabled Individuals.

The primary goal of rehabilitation for individuals with lower limb amputation, particularly those with unilateral transfemoral amputation (uTFA), is to restore their ability to walk independently. Effective control of the center of pressure (COP) during gait is vital for maintaining balance and stability, yet it poses a significant challenge for individuals with uTFA. This study aims to study the COP during gait in individuals with uTFA and elucidate their unique compensatory strategies. This study involved 12 uTFA participants and age-matched non-disabled controls, with gait and COP trajectory data collected using an instrumented treadmill. Gait and COP parameters between the control limb (CL), prosthetic limb (PL), and intact limb (IL) were compared. Notably, the mediolateral displacement of COP in PL exhibited significant lateral displacement compared to the CL from 30% to 60% of the stance. In 20% to 45% of the stance, the COP forward speed of PL was significantly higher than that of the IL. Furthermore, during the initial 20% of the stance, the vertical ground reaction force of PL was significantly lower than that of IL. Additionally, individuals with uTFA exhibited a distinct gait pattern with altered duration of loading response, single limb support, pre-swing and swing phases, and step time. These findings indicate the adaptability of individuals with uTFA in weight transfer, balance control, and pressure distribution on gait stability. In conclusion, this study provides valuable insights into the unique gait dynamics and balance strategies of uTFA patients, highlighting the importance of optimizing prosthetic design, alignment procedures, and rehabilitation programs to enhance gait patterns and reduce the risk of injuries due to compensatory movements.

Transfemoral prosthetic simulators versus amputees: ground reaction forces and spatio-temporal parameters in gait.

This study aimed to compare the ground reaction forces (GRFs) and spatio-temporal parameters as well as their asymmetry ratios in gait between individuals wearing a transfemoral prosthetic simulator (TFSim) and individuals with unilateral transfemoral amputation (TFAmp) across a range of walking speeds (2.0-5.5 km h-1). The study recruited 10 non-disabled individuals using TFSim and 10 individuals with unilateral TFAmp using a transfemoral prosthesis. Data were collected using an instrumented treadmill with built-in force plates, and subsequently, the GRFs and spatio-temporal parameters, as well as their asymmetry ratios, were analysed. When comparing the TFSim and TFAmp groups, no significant differences were found among the gait parameters and asymmetry ratios of all tested metrics except the vertical GRFs. The TFSim may not realistically reproduce the vertical GRFs during the weight acceptance and push-off phases. The structural and functional variations in prosthetic limbs and components between the TFSim and TFAmp groups may be primary contributors to the difference in the vertical GRFs. These results suggest that TFSim might be able to emulate the gait of individuals with TFAmp regarding the majority of spatio-temporal and GRF parameters. However, the vertical GRFs of TFSim should be interpreted with caution.

Biomechanical effects of foot orthoses on jump landing performance: A systematic review.

Jumping is involved in a wide range of sports and activities, and foot orthoses (FO) are suggested to enhance performance and prevent injury. The aim of this systematic review was to investigate whether using FO with different modifications affects jump landing biomechanics and improves performance in healthy individuals. The search strategy included 7 databases that identified 19 studies. The study quality was evaluated using a modified Downs and Black index. The primary outcome measures were joint kinematics, kinetics, muscle activity, vertical jump height, and horizontal jump distance. Our findings indicated that incorporating arch support with a rearfoot post and softer forefoot region into FO may improve several biomechanical variables during jump landing activities. Improvements in vertical ground reaction force loading rates, knee and ankle kinematics, and muscle cocontraction during jumping with FO could enhance jumping performance. In addition, improvements in hip, knee, ankle, and tibial kinematics and vertical ground reaction force loading rates during landing could reduce impact forces and related injuries. Although a limited number of studies have addressed the effects of FO on vertical jump height and horizontal jump distance, inserting such FO inside shoes with optimum bending stiffness could facilitate jumping performance. A rigorous exploration of the effect and mechanism of FO designs on jumping performance could benefit jumping-related activities and prevent ankle and knee injuries.

Geochemical characteristics and ecological risks of rare earth elements in river sediments of coal-grain composite area in eastern China.

Coal and grain complex areas influence the geochemical characterization of REEs through coal mining activities and agricultural production. However, there is a lack of relevant studies. In this study, we investigated the geochemical characterization and risk assessment of REEs in river sediments of the northern Anhui plain, a typical coal-grain composite area. The results showed that the average concentrations of ∑REE in the sediments ranged from 134.7 to 220.3 µg/g, and LREE was significantly enriched. Among the 14 REEs, Gd and Eu were the most enriched, with enrichment factors of 1.792 and 1.764, respectively. In addition, the differences in REEs content and enrichment between different rivers were related to the location of coal mines and the degree of population concentration. The average values of δCe and δEu in the sediments were 0.990 and 1.080, respectively, and most of the sampling sites showed a weak positive Ce, Eu anomaly. The results of Pearson's correlation and RDA redundancy analyses showed that Fe, Al, Mn and sand contributed more to the enrichment of REEs. The river sediments in the whole area had a slight potential ecological risk, with Eu (Er=13.05) and Lu (Er=14.07) having the highest potential risk. The ADD results also showed that the average daily dose of REEs by children was around 2.000 (µg/(kg·day)), which was significantly higher than that of adults. The results of this study can be used as a basis for the prevention and control of REEs in rivers in northern Anhui Province.

Coordination of Lower Limb During Gait in Individuals With Unilateral Transfemoral Amputation.

Understanding the lower-limb coordination of individuals with unilateral transfemoral amputation (uTFA) while walking is essential to understand their gait mechanisms. Continuous relative phase (CRP) analysis provides insights into gait coordination patterns of the neuromusculoskeletal system based on movement kinematics. Fourteen individuals with uTFA and their age-matched non-disabled individuals participated in this study. Kinematic data of the lower limbs of the participants were collected during walking. The joint angles, segment angles, and CRP values of the thigh-shank and shank-foot couplings were investigated. The curves among the lower limbs of the participants were compared using a statistical parametric mapping test. Compensatory strategies were found in the lower limbs from coordination patterns. In thigh-shank coupling, although distinct coordination traits in stance and swing phases among the lower limbs were found, the lower limbs in both groups were discovered to remain in a similar coordination pattern during gait. For individuals with uTFA, in shank-foot coupling, intact limbs demonstrated a short period of foot-leading pattern which was significantly different from that of the other limbs during mid-stance to compensate for the weaker force generation by prosthetic limbs. The findings offer normative coordination patterns on the walking of individuals with uTFA, which could benefit prosthetic gait rehabilitation and development.

Accelerating the Discovery of Hybrid Perovskites with Targeted Band Gaps via Interpretable Machine Learning.

The band gap of hybrid organic-inorganic perovskites (HOIPs) is a key factor affecting the light absorption characteristics and thus the performance of perovskite solar cells (PSCs). However, band gap engineering, using experimental trial and error and high-throughput density functional theory calculations, is blind and costly. Therefore, it is critical to statistically identify the multiple factors influencing band gaps and to rationally design perovskites with targeted band gaps. This study combined feature engineering, the gradient-boosted regression tree (GBRT) algorithm, and the genetic algorithm-based symbolic regression (GASR) algorithm to develop an interpretable machine learning (ML) strategy for predicting the band gap of HOIPs accurately and quantitatively interpreting the factors affecting the band gap. Seven best physical features were selected to construct a GBRT model with a root-mean-square error of less than 0.060 eV, and the most important feature is the electronegativity difference between the B-site and the X-site (χB-X). Further, a mathematical formula (Eg = χB-X2 + 0.881χB-X) was constructed with GASR for a quantitative interpretation of the band gap influence patterns. According to the ML model, the HOIP MA0.23FA0.02Cs0.75Pb0.59Sn0.41Br0.24I2.76 was obtained, with a suitable band gap of 1.39 eV. Our proposed interpretable ML strategy provides an effective approach for developing HOIP structures with targeted band gaps, which can also be applied to other material fields.

A meta-analysis of the association between mindfulness and motivation.

Introduction: Mindfulness reflects attention to the present moment in a non-judgmental way and has been linked to individual autonomy and motivation, but conclusions are inconsistent. The purpose of this review was to summarize previous studies to explore the relationship between mindfulness and motivation and its intervention effects. Methods: Literature searches were conducted in five electronic databases. Both correlational studies assessing the association between motivation and mindfulness and experimental studies to verify the effect of intervention were included. Results: Six papers with seven intervention studies and twenty-three papers with twenty-seven correlational studies met the inclusion criteria. Meta-analysis showed that mindfulness was positively correlated with intrinsic motivation (r = 0.28, p < 0.0001) and total motivation (r = 0.37, p < 0.0001) but had no significant correlation with extrinsic motivation (r = 0.01, p = 0.93) or amotivation (r = -0.17, p = 0.14). Effect-size estimates suggested that mindfulness intervention was beneficial to motivation promotion, but the effect was at a low level (g = 0.12). Conclusion: We found consistent support for mindfulness practice relating to motivation promotion, especially on intrinsic motivation development. However, there was still a portion of heterogeneity that could not be explained and needed to be identified in future studies.

Effect of Boronizing on the Microstructure and Mechanical Properties of CoCrFeNiMn High-Entropy Alloy.

The CoCrFeNiMn high-entropy alloys were treated by powder-pack boriding to improve their surface hardness and wear resistance. The variation of boriding layer thickness with time and temperature was studied. Then, the frequency factor D0 and diffusion activation energy Q of element B in HEA are calculated to be 9.15 × 10-5 m2/s and 206.93 kJ/mol, respectively. The diffusion behavior of elements in the boronizing process was investigated and shows that the boride layer forms with the metal atoms diffusing outward and the diffusion layer forms with the B atoms diffusing inward by the Pt-labeling method. In addition, the surface microhardness of CoCrFeNiMn HEA was significantly improved to 23.8 ± 1.4 Gpa, and the friction coefficient was reduced from 0.86 to 0.48~0.61.

Sprinting performance of individuals with unilateral transfemoral amputation: compensation strategies for lower limb coordination.

Understanding the sprinting patterns of individuals with unilateral transfemoral amputation (uTFA) is important for designing improved running-specific prostheses and for prosthetic gait rehabilitation. Continuous relative phase (CRP) analysis acquires clues from movement kinematics and obtains insights into the sprinting coordination of individuals with uTFA. Seven individuals with uTFA sprinted on a 40 m runway. The spatio-temporal parameters, joint and segment angles of the lower limbs were obtained, and CRP analysis was performed on thigh-shank and shank-foot couplings. Subsequently, the asymmetry ratios of the parameters were calculated. Statistical analyses were performed between the lower limbs. Significant differences in the stance time, stance phase percentage, ankle joint angles and CRP of the shank-foot coupling (p < 0.05) were observed between the lower limbs. The primary contributor to these differences could be the structural differences between the lower limbs. Despite the presence of different coordination features in the stance and swing phases between the lower limbs, no significant difference in the coordination patterns of the thigh-shank coupling was observed. This may be a compensation strategy for achieving coordination patterns with improved symmetry between the lower limbs. The results of this study provide novel insights into the sprinting movement patterns of individuals with uTFA.

AMPK regulates homeostasis of invasion and viability in trophoblasts by redirecting glucose metabolism: Implications for pre-eclampsia.

Pre-eclampsia (PE) is deemed an ischemia-induced metabolic disorder of the placenta due to defective invasion of trophoblasts during placentation; thus, the driving role of metabolism in PE pathogenesis is largely ignored. Since trophoblasts undergo substantial glycolysis, this study aimed to investigate its function and regulatory mechanism by AMPK in PE development. Metabolomics analysis of PE placentas was performed by gas chromatography-mass spectrometry (GC-MS). Trophoblast-specific AMPKα1-deficient mouse placentas were generated to assess morphology. A mouse PE model was established by Reduced Uterine Perfusion Pressure, and placental AMPK was modulated by nanoparticle-delivered A769662. Trophoblast glucose uptake was measured by 2-NBDG and 2-deoxy-d-[3 H] glucose uptake assays. Cellular metabolism was investigated by the Seahorse assay and GC-MS.PE complicated trophoblasts are associated with AMPK hyperactivation due not to energy deficiency. Thereafter, AMPK activation during placentation exacerbated PE manifestations but alleviated cell death in the placenta. AMPK activation in trophoblasts contributed to GLUT3 translocation and subsequent glucose metabolism, which were redirected into gluconeogenesis, resulting in deposition of glycogen and accumulation of phosphoenolpyruvate; the latter enhanced viability but compromised trophoblast invasion. However, ablation of AMPK in the mouse placenta resulted in decreased glycogen deposition and structural malformation. These data reveal a novel homeostasis between invasiveness and viability in trophoblasts, which is mechanistically relevant for switching between the 'go' and 'grow' cellular programs.

miR21 modulates the Hippo signaling pathway via interference with PP2A Bß to inhibit trophoblast invasion and cause preeclampsia.

Preeclampsia (PE) is a pregnancy-specific disorder attributed to deficient extravillous trophoblast (EVT) invasion into the uterus, but the mechanism of EVT invasion remains unclear. In this study, we found significantly elevated expression of microRNA 21 (miR21), which negatively regulates trophoblast invasion and migration, in preeclamptic placentae. Whole-genome RNA sequencing revealed that PPP2R2B, which encodes PP2A Bß, and the Hippo pathway are downstream targets of miR21. The effects of miR21 on trophoblast mobility were abolished in LATS1T1079A/S909A and YAP-5SA mutants. Moreover, we found that PP2A Bß dephosphorylates LATS1 via direct protein-protein interactions and thus modulates the phosphorylation and subcellular distribution of YAP. PPP2R2B overexpression ameliorated the miR21-induced LATS1-YAP phosphorylation and cytoplasmic sequestration of YAP, which resulted in the rescue of compromised trophoblast invasion and migration. The upregulation of placental miR21 abundance by placenta-specific nanoparticles loaded with agomir-miR21 during placentation interfered with PPP2R2B and activated the Hippo pathway in the placenta, leading to a PE-like phenotype. Thus, aberrant elevation of miR21 impairs EVT mobility by modulating the PP2A Bß/Hippo axis, which is one of the causes of PE.

The effects of the tension of figure-8 straps of a soft ankle orthosis on the ankle joint kinematics while walking in healthy young adults: A pilot study.

BACKGROUND: Figure-8 straps are commonly used in ankle orthoses, which are provided to reduce the risks of primary and recurrent sprain by providing functional support. Functional treatment with ankle orthoses can provide better rehabilitation than immobilization for a mild ankle sprain. However, it is not known how much tension should be applied to the straps while donning the orthosis to optimize its effectiveness. RESEARCH QUESTION: The aim of this study was to investigate the effects of figure-8 strap tension of a soft ankle orthosis on ankle joint kinematics in the sagittal, coronal, and transverse planes during gait in healthy young adults. METHODS: Ten healthy adults (five males and five females) were enrolled in this study. The 3-dimensional motion analysis system was used to evaluate the ankle kinematics of the participants during gait under five conditions: no soft ankle orthosis, soft ankle orthosis with no figure-8 straps tension (lace-up only), 50 N, 80 N, and 110 N tension of the figure-8 straps, respectively. All participants walked in a straight path at a comfortable speed. RESULTS: Plantarflexion angles were significantly reduced with 110 N of tension in the figure-8 straps when compared to the lace-up only and a moderate correlation with r = 0.34 (p = 0.03) was observed between the tensions of figure-8 straps and maximum plantarflexion angles at pre-swing of a gait cycle. No significant effects on ankle joint angles were demonstrated in the coronal and transverse planes. SIGNIFICANCE: This study showed that increasing the tension of the figure-8 straps could restrict the ankle joint plantarflexion angle during pre-swing in gait. However, it might not affect inversion/eversion or internal/external rotation angles of the ankle joint in individuals without ankle pathologies.

Maturation of subtilisin-like protease NbSLP1 from microsporidia Nosema bombycis.

Microsporidia are obligate intracellular parasites and possess a unique way of invading hosts, namely germination. Microsporidia are able to infect almost all animal cells by germination. During the process, the polar tube extrudes from the spores within, thus injecting infectious sporoplasm into the host cells. Previous studies indicated that subtilisin-like protease 1 (NbSLP1) of microsporidia Nosema bombycis were located at the polar cap of germinated spores where the polar tube extrusion. We hypothesized that NbSLP1 is an essential player in the germination process. Normally, SLP need to be activated by autoproteolysis under conditions. In this study, we found that the signal peptide of NbSLP1 affected the activation of protease, two self-cleavage sites were involved in NbSLP1 maturation between Ala104Asp105 and Ala124Asp125 respectively. Mutants at catalytic triad of NbSLP1 confirmed the decreasing of autoproteolysis. This study demonstrates that intramolecular proteolysis is required for NbSLP1 maturation. The protease undergoes a series of sequential N-terminal cleavage events to generate the mature enzyme. Like other subtilisin-like enzymes, catalytic triad of NbSLP1 are significant for the self-activation of NbSLP1. In conclusion, clarifying the maturation of NbSLP1 will be valuable for understanding the polar tube ejection mechanism of germination.

Surface Re-Engineering of Perovskites with Buckybowls to Boost the Inverted-Type Photovoltaics.

Despite their multifaceted advantages, inverted perovskite solar cells (PSCs) still suffer from lower power conversion efficiencies (PCEs) than their regular counterparts, which is largely due to recombination energy losses (Eloss) that arise from the chemical, physical, and energy level mismatches, especially at the interfaces between perovskites and fullerene electron transport layers (ETLs). To address this problem, we herein introduce an aminium iodide derivative of a buckybowl (aminocorannulene) that is molecularly layered at the perovskite-ETL interface. Strikingly, besides passivating the PbI2-rich perovskite surface, the aminocorannulene enforces a vertical dipole and enhances the surface n-type character that is more compatible with the ETL, thus boosting the electron extraction and transport dynamics and suppressing interfacial Eloss. As a result, the champion PSC achieves an excellent PCE of over 22%, which is superior compared to that of the control device (∼20%). Furthermore, the device stability is significantly enhanced, owing to a lock-and-key-like grip on the mobile iodides by the buckybowls and the resultant increase of the interfacial ion-migration barrier. This work highlights the potential of buckybowls for the multifunctional surface engineering of perovskite toward high-performance and stable PSCs.

Effects of step frequency during running on the magnitude and symmetry of ground reaction forces in individuals with a transfemoral amputation.

BACKGROUND: Individuals with unilateral transfemoral amputation are prone to developing health conditions such as knee osteoarthritis, caused by additional loading on the intact limb. Such individuals who can run again may be at higher risk due to higher ground reaction forces (GRFs) as well as asymmetric gait patterns. The two aims of this study were to investigate manipulating step frequency as a method to reduce GRFs and its effect on asymmetric gait patterns in individuals with unilateral transfemoral amputation while running. METHODS: This is a cross-sectional study. Nine experienced track and field athletes with unilateral transfemoral amputation were recruited for this study. After calculation of each participant's preferred step frequency, each individual ran on an instrumented treadmill for 20 s at nine different metronome frequencies ranging from - 20% to + 20% of the preferred frequency in increments of 5% with the help of a metronome. From the data collected, spatiotemporal parameters, three components of peak GRFs, and the components of GRF impulses were computed. The asymmetry ratio of all parameters was also calculated. Statistical analyses of all data were conducted with appropriate tools based on normality analysis to investigate the main effects of step frequency. For parameters with significant main effects, linear regression analyses were further conducted for each limb. RESULTS: Significant main effects of step frequency were found in multiple parameters (P < 0.01). Both peak GRF and GRF impulse parameters that demonstrated significant main effects tended towards decreasing magnitude with increasing step frequency. Peak vertical GRF in particular demonstrated the most symmetric values between the limbs from - 5% to 0% metronome frequency. All parameters that demonstrated significant effects in asymmetry ratio became more asymmetric with increasing step frequency. CONCLUSIONS: For runners with a unilateral transfemoral amputation, increasing step frequency is a viable method to decrease the magnitude of GRFs. However, with the increase of step frequency, further asymmetry in gait is observed. The relationships between step frequency, GRFs, and the asymmetry ratio in gait may provide insight into the training of runners with unilateral transfemoral amputation for the prevention of injury.

Claudin 19 inhibits the malignant potential of breast cancer cells by modulating extracellular matrix-associated UBE2C/Wnt signaling.

Claudin proteins are a major component of the tight junctions between cells, which are involved in a variety of human diseases, including cancer. This study aimed to investigate the functional role of claudin 19 (CLDN19) in human breast cancer progression. Here, we firstly found that CLDN19 was downregulated in breast tumor tissues than normal control, and loss of CLDN19 predicted poor patient survival in patients with breast cancer, by utilizing the Cancer Genome Atlas Program (TCGA) dataset analysis. To further validate the tumor suppressive effects of CLDN19, we established CLDN19 overexpressed MDA-MB-231 and T47D cells. And overexpression of CLDN19 resulted in suppression of cell growth/migration in breast cancer cells cultured in 3D environment or in vivo. Mechanistically, we demonstrated that CLDN19 downregulated ubiquitin conjugating enzyme E2 C (UBE2C) expression, which further suppressed Wnt/ß-catenin pro-survival signaling pathway activation induced by extracellular matrix (ECM), in 3D environment or in vivo. Altogether, our study revealed a tumor suppressive role of CLDN19, which hindered ECM/UBE2C/Wnt signaling activation in breast cancer, and offered novel insight for tumor diagnosis and targeted therapy.

Effects of walking speed on magnitude and symmetry of ground reaction forces in individuals with transfemoral prosthesis.

Individuals with unilateral transfemoral amputation (uTFA) walk asymmetrically. Investigating gait symmetry in ground reaction force (GRF) is critical because asymmetric loading on the residual limb can result in injury. The aim of this study was to investigate the GRF of individuals with uTFA by systematically controlling their walking at eight speeds(2.0-5.5 km/h with increments of 0.5 km/h) on a treadmill. Forty-eight individuals participated in this study, which included 24 individuals with uTFA (K3 and K4) and 24 individuals without amputation. GRFs (anteroposterior, mediolateral, and vertical) of the prosthetic and intact limb steps were collected for the individuals with uTFA and those of the right limb were collected for the control group. Peak force values of the GRF components, temporal parameters, impulses, and their asymmetry ratios were investigated and statistically analyzed. With an increasing walking speed, the magnitude of GRF changed gradually; individuals with uTFA exhibited increased GRF asymmetry in the vertical and mediolateral components, while that of the anteroposterior component remained constant. uTFA individuals typically maintained a constant asymmetry ratio in the mediolateral and anteroposterior (braking and propulsive) GRF impulses across a wide range of walking speeds. This result suggests that individuals with uTFA may cope with various walking speeds by maintaining symmetric mediolateral and anteroposterior impulses. The data provided in this study can serve as normative data for the GRF and its symmetry across a range of walking speeds in individuals with uTFA.

Impaired Sphingosine-1-Phosphate Synthesis Induces Preeclampsia by Deactivating Trophoblastic YAP (Yes-Associated Protein) Through S1PR2 (Sphingosine-1-Phosphate Receptor-2)-Induced Actin Polymerizations.

Incomplete spiral artery remodeling, caused by impaired extravillous trophoblast invasion, is a fundamental pathogenic process associated with malplacentation and the development of preeclampsia. Nevertheless, the mechanisms controlling this regulation of trophoblast invasion are largely unknown. We report that sphingosine-1-phosphate synthesis and expression is abundant in healthy trophoblast, whereas in pregnancies complicated by preeclampsia the placentae are associated with reduced sphingosine-1-phosphate and lower SPHK1 (sphingosine kinase 1) expression and activity. In vivo inhibition of sphingosine kinase 1 activity during placentation in pregnant mice led to decreased placental sphingosine-1-phosphate production and defective placentation, resulting in a preeclampsia phenotype. Moreover, sphingosine-1-phosphate increased HTR8/SVneo (immortalized human trophoblst cells) cell invasion in a Hippo-signaling-dependent transcriptional coactivator YAP (Yes-associated protein) dependent manner, which is activated by S1PR2 (sphingosine-1-phosphate receptor-2) and downstream RhoA (Ras homolog gene family, member A)/ROCK (Rho-associated protein kinase) induced actin polymerization. Mutation-based YAP-5SA (S61A, S109A, S127A, S164A, S381A) demonstrated that sphingosine-1-phosphate activation of YAP could be either dependent or independent of Hippo signaling. Together, these findings suggest a novel pathogenic pathway of preeclampsia via disrupted sphingosine-1-phosphate metabolism and signaling-induced, interrupted actin dynamics and YAP deactivation; this may lead to potential novel intervention targets for the prevention and management of preeclampsia.

Revisiting preeclampsia: a metabolic disorder of the placenta.

Preeclampsia (PE) is a leading cause of maternal and neonatal mortality and morbidity worldwide, impacting the long-term health of both mother and offspring. PE has long been characterized by deficient trophoblast invasion into the uterus and consequent placental hypoperfusion, yet the upstream causative factors and effective interventional targets for PE remain unknown. Alterations in the metabolism of preeclamptic placentas are thought to result from placental ischemia, while disturbances of the metabolism and of metabolites in PE pathogenesis are largely ignored. In fact, as one of the largest fetal organs at birth, the placenta consumes a considerable amount of glucose and fatty acid. Increasing evidence suggests glucose and fatty acid exist as energy substrates and regulate placental development through bioactive derivates. Moreover, recent findings have revealed that the placental metabolism adapts readily to environmental changes, altering its response to nutrients and endocrine signals; this adaptability optimizes pregnancy outcomes by diversifying available carbon sources for energy production, hormone synthesis, angiogenesis, immune activation, and tolerance, and fetoplacental growth. These observations raise the possibility that carbohydrate and lipid metabolism abnormalities play a role in both the etiology and clinical progression of PE, sparking a renewed interest in the interrelationship between PE and metabolic dysregulation. This review will focus on key metabolic substrates and regulatory molecules in the placenta and aim to provide novel insights with respect to the metabolism's role in modulating placental development and functions. Further investigations from this perspective are poised to decipher the etiology of PE and suggest potential therapies.

Gestational Diabetes Mellitus-Associated Hyperglycemia Impairs Glucose Transporter 3 Trafficking in Trophoblasts Through the Downregulation of AMP-Activated Protein Kinase.

AMP-activated protein kinase (AMPK) is an important regulator of glucose metabolism, and glucose transporter 3 (GLUT3) is an efficient glucose transporter in trophoblasts. Whether placental AMPK and GLUT3 respond accordingly to gestational diabetes mellitus (GDM) remains uncertain. Here, we explored the regulatory role of AMPK in the GLUT3-dependent uptake of glucose by placental trophoblasts and the viability of the cells. In this study, the level of glycolysis in normal and GDM-complicated placentas was assessed by LC-MS/MS. The trophoblast hyperglycemia model was induced by the incubation of HTR8/SVneo cells with a high glucose concentration. GDM animal models were generated with db/ + mice and C57BL/6J mice fed a high-fat diet, and AMPK was manipulated by the oral administration of metformin. The uptake of glucose by trophoblasts was assessed using 2-NBDG or 2-deoxy-D-[3H] glucose. The results showed that GDM is associated with impaired glycolysis, AMPK activity, GLUT3 expression in the plasma membrane (PM) and cell survival in the placenta. Hyperglycemia induced similar changes in trophoblasts, and these changes were rescued by AMPK activation. Both hyperglycemic db/ + and high-fat diet-induced GDM mice exhibited a compromised AMPK-GLUT3 axis and suppressed cell viability in the placenta as well as excessive fetal growth, and all of these effects were partially alleviated by metformin. Taken together, our findings support the notion that AMPK activation upregulates trophoblast glucose uptake by stimulating GLUT3 translocation, which is beneficial for viability. Thus, the modulation of glucose metabolism in trophoblasts by targeting AMPK might ameliorate the adverse intrauterine environment caused by GDM.