Increased serum interleukin-41 correlates with disease severity in myasthenia gravis.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disease mediated by pathogenic antibodies produced by abnormally activated B cells, resulting in neuromuscular junction transmission dysfunction. Interleukin-41 (IL-41) is a novel immunomodulatory cytokine that has been implicated in various metabolic, inflammatory, and autoimmune diseases. The role of IL-41 in MG is still unclear up to now, our study aimed to investigate the level of IL-41 in MG patients and its correlation with clinical features and inflammatory indicators. METHODS: Totally, 60 MG patients and 30 healthy controls (HC) were recruited. Baseline data and laboratory parameters were routinely recorded through electronic medical systems. IL-41 levels were measured by enzyme-linked immunosorbent assay. Proportions of T-cell and B-cell subsets and natural killer cells were analyzed by flow cytometry. The correlation between serum IL-41 and MG related parameters was investigated, and the clinical value of IL-41 in the diagnosis of MG was evaluated by receiver operator characteristic curve (ROC) analysis. RESULTS: Serum IL-41 levels in MG patients were higher than in HC, and were higher in Myasthenia Gravis Foundation of America (MGFA) III + IV group than that in MGFA I + II group. Serum IL-41 was positively correlated with MG-specific activities of daily living scale (MG-ADL), MGFA classification, platelet to lymphocyte ratio (PLR), and proportion of CD19+ B cells, while it was negatively correlated with high-sensitive C-reactive protein (hs-CRP) and circulatory plasma cells in MG patients. Serum IL-41 levels increased in patients who were treated with efgartigimod during the first cycle of therapy. However, compared to disease initiation, serum IL-41 levels decreased when clinical features steadily improved. ROC analysis showed that IL-41 had a diagnostic value for MG. CONCLUSION: The present findings suggested that serum IL-41 was increased in MG patients and was positively associated with the severity of the disease. IL-41 may be essential to the immunopathological mechanism of MG and a potential biomarker for MG.

Device for Measuring Contact Reaction Forces during Animal Adhesion Landing/Takeoff from Leaf-like Compliant Substrates.

A precise measurement of animal behavior and reaction forces from their surroundings can help elucidate the fundamental principle of animal locomotion, such as landing and takeoff. Compared with stiff substrates, compliant substrates, like leaves, readily yield to loads, presenting grand challenges in measuring the reaction forces on the substrates involving compliance. To gain insight into the kinematic mechanisms and structural-functional evolution associated with arboreal animal locomotion, this study introduces an innovative device that facilitates the quantification of the reaction forces on compliant substrates, like leaves. By utilizing the stiffness-damping characteristics of servomotors and the adjustable length of a cantilever structure, the substrate compliance of the device can be accurately controlled. The substrate was further connected to a force sensor and an acceleration sensor. With the cooperation of these sensors, the measured interaction force between the animal and the compliant substrate prevented the effects of inertial force coupling. The device was calibrated under preset conditions, and its force measurement accuracy was validated, with the error between the actual measured and theoretical values being no greater than 10%. Force curves were measured, and frictional adhesion coefficients were calculated from comparative experiments on the landing/takeoff of adherent animals (tree frogs and geckos) on this device. Analysis revealed that the adhesion force limits were significantly lower than previously reported values (0.2~0.4 times those estimated in previous research). This apparatus provides mechanical evidence for elucidating structural-functional relationships exhibited by animals during locomotion and can serve as an experimental platform for optimizing the locomotion of bioinspired robots on compliant substrates.

High-Frequency Local Field Potential Oscillations for Pigeons in Effective Turning.

Flexible turning behavior endows Homing Pigeons (Columba livia domestica) with high adaptability and intelligence in long-distance flight, foraging, hazard avoidance, and social interactions. The present study recorded the activity pattern of their local field potential (LFP) oscillations and explored the relationship between different bands of oscillations and turning behaviors in the formatio reticularis medialis mesencephali (FRM). The results showed that the C (13-60 Hz) and D (61-130 Hz) bands derived from FRM nuclei oscillated significantly in active turning, while the D and E (131-200 Hz) bands oscillated significantly in passive turning. Additionally, compared with lower-frequency stimulation (40 Hz and 60 Hz), 80 Hz stimulation can effectively activate the turning function of FRM nuclei. Electrical stimulation elicited stronger oscillations of neural activity, which strengthened the pigeons' turning locomotion willingness, showing an enhanced neural activation effect. These findings suggest that different band oscillations play different roles in the turning behavior; in particular, higher-frequency oscillations (D and E bands) enhance the turning behavior. These findings will help us decode the complex relationship between bird brains and behaviors and are expected to facilitate the development of neuromodulation techniques for animal robotics.

Macrophage migration inhibitory factor: A noval biomarker upregulates in myasthenia gravis and correlates with disease severity and relapse.

OBJECTIVE: To explore the relationship between macrophage migration inhibitory factor (MIF) and disease severity and relapse in patients with myasthenia gravis (MG). METHODS: 145 MG patients including 79 new-onset patients, 30 remission patients and 36 relapse patients were enrolled in this study. The detailed characteristics of all enrolled MG patients were routinely recorded, including gender, age, type, MGFA classification, antibody, thymic status, clinical score, treatment, MGFA-PIS and B cell subsets (memory B cells, plasmablast cells and plasma cells) detected by flow cytometry. Serum MIF levels were measured by enzyme-linked immunosorbent assay (ELISA) kit. The correlation of MIF levels with clinical subtypes, disease severity and B cell subsets were investigated. Moreover, logistic regression analysis was applied to assess the factors affecting relapse of generalized MG (GMG). RESULTS: Serum MIF levels were higher in new-onset MG patients than those in controls and were positively associated with QMG score, MGFA classification and memory B cells. Subgroup analysis revealed that MIF levels were increased in GMG patients than in ocular MG (OMG), as well as elevated in MGFA III/IV compared with MGFA I/II. With the remission of the disease, the expression of serum MIF decreased. The multivariate logistic regression models indicated that high MIF and thymoma was a risk factor for relapse of GMG, and rituximab could prevent disease relapse. CONCLUSIONS: MIF can be used as a novel biomarker to reflect disease severity and predict disease relapse in MG patients.

Association between questionnaire-based and accelerometer-based physical activity and the incidence of chronic kidney disease using data from UK Biobank: a prospective cohort study.

Background: Prior studies on the relationship between chronic kidney disease (CKD) and physical activity (PA) mainly relied on subjective PA data and rarely considered the genetic risk. This study aims to thoroughly investigate this relationship by utilizing both accelerometer-measured and questionnaire-measured PA data. Methods: This prospective cohort study encompasses two cohorts from the UK Biobank. The questionnaire-based cohort involves 448,444 CKD-free participants who completed an International Physical Activity Questionnaire between 2006 and 2010 and had genetic data. PA was categorized into distinct activities: leisure, housework, job-related, and transportation. The accelerometer-based cohort involves 89,296 CKD-free participants who provided a full week of accelerometer-based physical activity data between 2013 and 2015 and had genetic data. PA was classified as light-intensity, moderate-intensity, vigorous-intensity, moderate to vigorous-intensity PA (LPA, MPA, VPA, MVPA), and total PA. Incident CKD was ascertained from linked hospital inpatient and death records. Genetic risk was assessed using polygenic risk scores. Cox proportional hazard models with restricted cubic splines were used for the analysis. Findings: In the questionnaire-based cohort, 18,184 (4.05%) participants developed CKD during 13.6 years of follow-up. Engaging in strenuous sports, other exercises, walking for pleasure, stair climbing, and heavy DIY were associated with a reduced risk of CKD. In the accelerometer-based cohort, 2297 (2.57%) participants developed CKD during 7.9 years of follow-up. Higher levels [highest quartile vs lowest quartile] of MPA (HR 0.639, 95% CI 0.554-0.737), VPA (HR 0.639, 95% CI 0.549-0.745), MVPA (HR 0.630, 95% CI 0.545-0.729), and total PA (HR 0.649, 95% CI 0.563-0.750) were associated with a lower CKD risk. There were significant interactions between MPA and genetic risk on the risk of CKD incidence (P for interaction = 0.025). A linear dose-response relationship was observed between MPA, total PA, and the risk of CKD incidence with no minimal or maximal threshold. These associations are robust in different subgroups and a series of sensitivity analyses. Interpretation: Engaging in multiple types of PA and higher levels of total PA, MPA, VPA, and MVPA may be associated with a lower risk of developing CKD, regardless of genetic risk. This finding holds substantial implications for clinical approaches to CKD prevention and provides evidence to inform future PA guideline development. Funding: Medical Science Advancement Program of Wuhan University, and the National Science Foundation of China.

Plasma C18:0-ceramide is a novel potential biomarker for disease severity in myasthenia gravis.

Myasthenia gravis (MG) is an antibody-mediated autoimmune disorder characterized by fluctuation of fatigue and weakness of muscle. Due to the heterogeneity of the course of MG, available biomarkers for prognostic prediction are urgently needed. Ceramide (Cer) was reported to participate in immune regulation and many autoimmune diseases, but its effects on MG remain undefined. This study aimed to investigate the ceramides expression levels in MG patients and their potential as novel biomarkers of disease severity. Levels of plasma ceramides were determined by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Severity of disease was assessed by quantitative MG scores (QMGs), MG-specific activities of daily living scale (MG-ADLs) and 15-item MG quality of Life (MG-QOL15). The concentrations of serum interleukin-1ß (IL-1ß), IL-6, IL-17A, and IL-21 were determined by enzyme-linked immunosorbent assay (ELISA), and the proportions of circulating memory B cells and plasmablasts were detected by flow-cytometry assay. Four plasma ceramides levels we studied were detected higher in MG patients. And three of them (C16:0-Cer, C18:0-Cer, and C24:0-Cer) were positively associated with QMGs. In addition, receiver operating characteristic (ROC) analysis suggested that plasma ceramides have a good ability of differentiating MG from HCs. Importantly, only C18:0-Cer was shown to be positively associated with the concentration of serum IL and circulating memory B cells, and the decrease in plasma C18:0-Cer paralleled the clinical improvement of patients with MG. All together, our data suggest that ceramides may play an important role in the immunopathological mechanism of MG, and C18:0-Cer has the potential to be a novel biomarker for disease severity in MG.

Grade-control outdoor turning flight of robo-pigeon with quantitative stimulus parameters.

Introduction: The robo-pigeon using homing pigeons as a motion carrier has great potential in search and rescue operations due to its superior weight-bearing capacity and sustained flight capabilities. However, before deploying such robo-pigeons, it is necessary to establish a safe, stable, and long-term effective neuro-electrical stimulation interface and quantify the motion responses to various stimuli. Methods: In this study, we investigated the effects of stimulation variables such as stimulation frequency (SF), stimulation duration (SD), and inter-stimulus interval (ISI) on the turning flight control of robo-pigeons outdoors, and evaluated the efficiency and accuracy of turning flight behavior accordingly. Results: The results showed that the turning angle can be significantly controlled by appropriately increasing SF and SD. Increasing ISI can significantly control the turning radius of robotic pigeons. The success rate of turning flight control decreases significantly when the stimulation parameters exceed SF > 100 Hz or SD > 5 s. Thus, the robo-pigeon's turning angle from 15 to 55° and turning radius from 25 to 135 m could be controlled in a graded manner by selecting varying stimulus variables. Discussion: These findings can be used to optimize the stimulation strategy of robo-pigeons to achieve precise control of their turning flight behavior outdoors. The results also suggest that robo-pigeons have potential for use in search and rescue operations where precise control of flight behavior is required.

A Neural Coordination Strategy for Attachment and Detachment of a Climbing Robot Inspired by Gecko Locomotion.

Climbing behavior is a superior motion skill that animals have evolved to obtain a more beneficial position in complex natural environments. Compared to animals, current bionic climbing robots are less agile, stable, and energy-efficient. Further, they locomote at a low speed and have poor adaptation to the substrate. One of the key elements that can improve their locomotion efficiency is the active and flexible feet or toes observed in climbing animals. Inspired by the active attachment-detachment behavior of geckos, a hybrid pneumatic-electric-driven climbing robot with active attachment-detachment bionic flexible feet (toes) was developed. Although the introduction of bionic flexible toes can effectively improve the robot's adaptability to the environment, it also poses control challenges, specifically, the realization of attachment-detachment behavior by the mechanics of the feet, the realization of hybrid drive control with different response characteristics, and the interlimb collaboration and limb-foot coordination with a hysteresis effect. Through the analysis of geckos' limbs and foot kinematic behavior during climbing, rhythmic attachment-detachment strategies and coordination behavior between toes and limbs at different inclines were identified. To enable the robot to achieve similar foot attachment-detachment behavior for climbing ability enhancement, we propose a modular neural control framework comprising a central pattern generator module, a post-processing central pattern generation module, a hysteresis delay line module, and an actuator signal conditioning module. Among them, the hysteresis adaptation module helps the bionic flexible toes to achieve variable phase relationships with the motorized joint, thus enabling proper limb-to-foot coordination and interlimb collaboration. The experiments demonstrated that the robot with neural control achieved proper coordination, resulting in a foot with a 285% larger adhesion area than that of a conventional algorithm. In addition, in the plane/arc climbing scenario, the robot with coordination behavior increased by as much as 150%, compared to the incoordinated one owing to its higher adhesion reliability.

Reversible Adhesive Bio-Toe with Hierarchical Structure Inspired by Gecko.

The agile locomotion of adhesive animals is mainly attributed to their sophisticated hierarchical feet and reversible adhesion motility. Their structure-function relationship is an urgent issue to be solved to understand biologic adhesive systems and the design of bionic applications. In this study, the reversible adhesion/release behavior and structural properties of gecko toes were investigated, and a hierarchical adhesive bionic toe (bio-toe) consisting of an upper elastic actuator as the supporting/driving layer and lower bionic lamellae (bio-lamellae) as the adhesive layer was designed, which can adhere to and release from targets reversibly when driven by bi-directional pressure. A mathematical model of the nonlinear deformation and a finite element model of the adhesive contact of the bio-toe were developed. Meanwhile, combined with experimental tests, the effects of the structure and actuation on the adhesive behavior and mechanical properties of the bio-toe were investigated. The research found that (1) the bending curvature of the bio-toe, which is approximately linear with pressure, enables the bio-toe to adapt to a wide range of objects controllably; (2) the tabular bio-lamella could achieve a contact rate of 60% with a low squeeze contact of less than 0.5 N despite a ±10° tilt in contact posture; (3) the upward bending of the bio-toe under negative pressure provided sufficient rebounding force for a 100% success rate of release; (4) the ratio of shear adhesion force to preload of the bio-toe with tabular bio-lamellae reaches approximately 12, which is higher than that of most existing adhesion units and frictional gripping units. The bio-toe shows good adaptability, load capacity, and reversibility of adhesion when applied as the basic adhesive unit in a robot gripper and wall-climbing robot. Finally, the proposed reversible adhesive bio-toe with a hierarchical structure has great potential for application in space, defense, industry, and daily life.

Biomimetic Patch with Wicking-Breathable and Multi-mechanism Adhesion for Bioelectrical Signal Monitoring.

Wearable bioelectrical monitoring devices can provide long-term human health information such as electrocardiogram and other physiological signals. It is a crucial part of the remote medical system. These can provide prediction for the diagnosis and treatment of cardiovascular disease and access to timely treatment. However, the patch comfort of the wearable monitoring devices in long-term contact with the skin have been a technical bottleneck of the hardware. In this study, the biomimetic patch with wicking-breathable and multi-mechanism adhesion performance to achieve adaptability and comfortability to human skin has been reported. The patch was designed based on a conical through-hole and hexagonal microgroove to directionally transport sweat from skin to air which gives the patch the breathable performance. The breathable and drainage capability of the biomimetic patch was experimentally verified by analyzing the conical through-hole and hexagonal microgroove with the structural mechanism of wicking. Multi-mechanism adhesion of the Ag/Ni microneedle array and PDMS-t adhesion material ensures the stability of patch signal acquisition. This study provides a new way for enhancing the breathability and adaptability of the patch to realize accurate bioelectrical signal monitoring under sweat conditions on human skin.

Effect of the Structural Characteristics on Attachment-Detachment Mechanics of a Rigid-Flexible Coupling Adhesive Unit.

The terminal toes of adhesive animals are characterized by rigid-flexible coupling, and their structure-function relationship is an urgent problem to be solved in understanding bioinspired adhesive systems and the design of biomimetic adhesive units. In this paper, inspired by the rigid-flexible coupling adhesive system of the gecko toe, a rigid-flexible coupling adhesive unit was designed, the interface strength of the adhesives under different preloads was tested, and the model and analysis method of the compression and peeling process of the rigid-flexible coupling adhesive unit was established. Meanwhile, combined with the experimental test, the effect of the coupling mechanism of the rigid-flexible structure on the interfacial stress and the final peeling force during the compression and peeling process of the adhesive unit was studied. The research found that the length of the adhesive unit L has no apparent effect on the normal peel force of the system within a specific range, and the normal peeling force increases linearly with the increase in the compression force P; while the influence of the inclination angle θ0 of the adhesive unit and the thickness of the rigid backing layer hb on the final normal peeling force of the system presents nonlinear characteristics, when the inclination angle θ0 of the adhesive unit is 5°, and the thickness of the rigid backing layer hb is 0.2 mm or 0.3 mm, the normal peel force and the ratio of adhesion force to preload the system reaches its maximum value. Compared with the flexible adhesive unit, the compressed zone formed by the rigid-flexible coupling adhesive unit during the same compression process increased by 6.7 times, while under the same peeling force, the peel zone increased by 8 times, and the maximum normal tensile stress at the peeling end decreased by 20 times. The rigid-flexible coupling mechanics improves the uniformity of the contact stress during the compression and peeling process. The research results provide guidelines for the design of the rigid-flexible coupling adhesive unit, further providing the end effector of the bionic wall-climbing robot with a rigid-flexible coupled bionic design.

Peking geckos (Gekko swinhonis) traversing upward steps: the effect of step height on the transition from horizontal to vertical locomotion.

The ability to transition between surfaces (e.g., from the ground to vertical barriers, such as walls, tree trunks, or rock surfaces) is important for the Peking gecko's (Gekko swinhonis Günther 1864) survival. However, quantitative research on gecko's kinematic performance and the effect of obstacle height during transitional locomotion remains scarce. In this study, the transitional locomotion of geckos facing different obstacle heights was assessed. Remarkably, geckos demonstrated a bimodal locomotion ability, as they could climb and jump. Climbing was more common on smaller obstacles and took longer than jumping. The jumping type depended on the obstacle height: when geckos could jump onto the obstacle, the vertical velocity increased with obstacle height; however, geckos jumped from a closer position when the obstacle height exceeded this range and would get attached to the vertical surface. A stability analysis of vertical surface landing using a collision model revealed that geckos can reduce their restraint impulse by increasing the landing angle through limb extension close to the body, consequently dissipating collision energy and reducing their horizontal and vertical velocities. The findings of this study reveal the adaptations evolved by geckos to move in their environments and may have applicability in the robotics field.

Incline-dependent adjustments of toes in geckos inspire functional strategies for biomimetic manipulators.

Geckos show versatility by rapidly maneuvering on diverse complex terrain because they benefit from their distributed, setae-covered toes and thus have the ability to generate reliable and adaptive attachment. Significant attention has been paid to their adhesive microstructures (setae), but the effectiveness of the gecko's adaptive attachment at the level of toes and feet remains unclear. In order to better understand the geckos' attachment, we first focused on the deployment of toes while challenging geckos to locomote on varying inclines. When the slope angle was less than 30°, their feet mainly interacted with the substrate using the bases of the toes and generated anisotropic frictional forces. As the slope angle increased to 90°, the participation of the toe bases was reduced. Instead, the setae contribution increased for the middle three toes of the front feet and for the first three toes of the hind feet. As the incline changed from vertical to inverted, the adhesive contribution of the toes of the front feet became more equal, whereas the effective adhesion contact of the hind feet gradually shifted to the toes oriented rearwards. Second, a mathematical model was established and then suggested the potential advantages of distributed control among the toes to regulate foot force. Finally, a physical foot model containing five compliant, adjustable toes was constructed and validated the discoveries with regard to the animals. Using the gecko toes' control strategies, the artificial foot demonstrated diverse behavior regulating attachment forces. The success of the foot prototype not only tested our understanding of the mechanism of biological attachment, but also provided a demonstration for the design and control of gecko-inspired attachment devices, grippers and other manipulators.

A gecko-inspired robot with CPG-based neural control for locomotion and body height adaptation.

Today's gecko-inspired robots have shown the ability of omnidirectional climbing on slopes with a low centre of mass. However, such an ability cannot efficiently cope with bumpy terrains or terrains with obstacles. In this study, we developed a gecko-inspired robot (Nyxbot) with an adaptable body height to overcome this limitation. Based on an analysis of the skeletal system and kinematics of real geckos, the adhesive mechanism and leg structure design of the robot were designed to endow it with adhesion and adjustable body height capabilities. Neural control with exteroceptive sensory feedback is utilised to realise body height adaptability while climbing on a slope. The locomotion performance and body adaptability of the robot were tested by conducting slope climbing and obstacle crossing experiments. The gecko robot can climb a 30° slope with spontaneous obstacle crossing (maximum obstacle height of 38% of the body height) and can climb even steeper slopes (up to 60°) without an obstacle or bump. Using 3D force measuring platforms for ground reaction force analysis of geckos and the robot, we show that the motions of the developed robot driven by neural control and the motions of geckos are dynamically comparable. To this end, this study provides a basis for developing climbing robots with adaptive bump/obstacle crossing on slopes towards more agile and versatile gecko-like locomotion.

Synergetic adhesion in highly adaptable bio-inspired adhesive.

Biologically inspired adhesives microstructure requires enough flexibility to make a conformal attachment to the surface as well as high rigidity to maintain the mechanical stability of structure against buckling. To tackle these conflicting factors for the synthetic adhesives is a challenge towards large-scale production and utilizing in practical applications. Addressing this problem, we have fabricated a honeycomb structure with a soft elastic film, partially covering the cavity of the honeycomb pattern. Honeycomb structure provides enough support to maintain the structural stability of the microstructure and soft PDMS film over the pattern provides sufficient flexibility to form a strong attachment with the target surface. Meanwhile, the resemblance of the designed structure to the octopi's sucker generates a negative pressure resulting in suction forces. To justify this suction effect, we compared our results with other controlled honeycomb microstructures (1) without any elastic film (2) with elastic film covering the whole cavity of the honeycomb pattern. Experimental results and theoretical prediction demonstrate the synergistic role of van der Waals and suction forces in the proposed partial-film honeycomb microstructure. The synergistic role of adhesive forces makes this structure a stronger, durable, and surface adaptable adhesive. We also investigated the critical role of the viscous forces for our proposed microstructure in water and silicon oil wetting conditions which signify the contribution of capillary forces.

Role of multiple, adjustable toes in distributed control shown by sideways wall-running in geckos.

Remarkable progress has been made characterizing one of nature's most integrated, hierarchical structures--the fibrillar adhesive system of geckos. Nonetheless, we lack an understanding of how multiple toes coordinate to facilitate geckos' acrobatic locomotion. Here, we tested the control function of gecko toes by running them on vertical substrates varying in orientation, friction and roughness. Sideways wall-running geckos realigned the toes of their top feet upward to resist gravity. Toe contact area was not compromised, but redistributed. Geckos aligned all toes upward to resist slipping when encountering low-friction patches during sideways wall-running. Negotiation of intermittent slippery strips showed an increased contribution of particular toes to compensate for toes that lost adhesion. Increasing substrate roughness using discrete rods perpendicular to sideways locomotion resulted in geckos bending and/or rotating toes to conform to and even grasp the rods, with potential forces more than five times body weight. Geckos increase their effectiveness of manoeuvrability in demanding environments by taking advantage of the distributed control afforded by multiple toes. Our findings provide insight on biological attachment and offer inspiration to advance gecko-inspired robotics and other biomimetic applications.

Elevation of pS262-Tau and Demethylated PP2A in Retina Occurs Earlier than in Hippocampus During Hyperhomocysteinemia.

Hyperhomocysteinemia is an independent risk factor of Alzheimer's disease (AD), which is not diagnosed for many years before onset due to lack of peripherally detectable early biomarkers. Visual dysfunction is prevalent in AD patients and correlates with the severity of cognitive defects. Importantly, alterations in eyes can be non-invasively detected. To search for early biomarkers in eyes from high risk factors of AD, we injected homocysteine (Hcy) into the rats via vena caudalis for 3, 7, and 14 days, respectively, and characterized the chronological order of the AD-like pathologies appearing in retina and the hippocampus during the progression of hyperhomocysteinemia, and their correlations with cognitive impairment. We found that administration of Hcy for 14 days, but not 3 or 7 days, induced hyperhomocysteinemia, although a gradually increased blood Hcy level was detected. In retina and/or the hippocampus, significant loss of retinal ganglion cells and stenosis of retinal arteries with the AD-like tau and amyloid-ß (Aß) pathologies and memory deficit were shown only in the 14-day Hcy group. Interestingly, accumulation of Ser262 hyperphosphorylated tau (pS262-tau) but not Aß with decreased methylation of protein phosphatase-2A catalytic subunit (M-PP2Ac) and increased de-methylated PP2Ac (DM-PP2Ac) was detected in retina of the 3-day Hcy group, in which the retinal pathologies were preceded by those of the hippocampus. These findings suggest that elevated pS262-tau and DM-PP2Ac and reduced M-PP2Ac in retina may serve as surveillance biomarkers for diagnosis of the hyperhomocysteinemia-induced AD in the early stage.

Paternal spatial training enhances offspring's cognitive performance and synaptic plasticity in wild-type but not improve memory deficit in Alzheimer's mice.

Recent studies suggest that spatial training can maintain associative memory capacity in Tg2576 mice, but it is not known whether the beneficial effects can be inherited from the trained fathers to their offspring. Here, we exposed male wild-type and male 3XTg Alzheimer disease (AD) mice (3-m old) respectively to spatial training for one week and assessed the transgenerational effects in the F1 offspring when they were grown to 7-m old. We found that the paternal spatial training significantly enhanced progeny's spatial cognitive performance and synaptic transmission in wild-type mice. Among several synapse- or memory-associated proteins, we observed that the expression level of synaptotagmin 1 (SYT1) was significantly increased in the hippocampus of the paternally trained-offspring. Paternal training increased histone acetylation at the promoter of SYT1 in both fathers' and the offspring's hippocampus, and as well as in the fathers' sperm. Finally, paternal spatial training for one week did not improve memory and synaptic plasticity in 3XTg AD F1 offspring. Our findings suggest paternal spatial training for one week benefits the offspring's cognitive performance in wild-type mice with the mechanisms involving an enhanced transgenerational histone acetylation at SYT1 promoter.