Multi-Proteomic Analysis Reveals the Effect of Protein Lactylation on Matrix and Cholesterol Metabolism in Tendinopathy.

Tendinopathy is a disease with surging prevalence. Lacking understanding of molecular mechanisms impedes the development of therapeutic approaches and agents. Lysine lactylation (Kla) is a newly discovered post-translational modification related to glycolysis. It has long been noted that manipulation of glycolysis metabolism could affect tendon cell function, tendon homeostasis, and healing process of tendon. However, protein lactylation sites in tendinopathy remain unexplored. Here, we conducted the first proteome-wide Kla analysis in tendon samples harvested from patients with rotator cuff tendinopathy (RCT), which identified 872 Kla sites across 284 proteins. Compared with normal counterparts, 136 Kla sites on 77 proteins were identified as upregulated in the pathological tendon, while 56 sites on 32 proteins were downregulated. Function enrichment analysis demonstrated that the majority of proteins with upregulated Kla levels functioned in organization of the tendon matrix and cholesterol metabolism, accompanied by lower expression levels which meant impaired cholesterol metabolism and degeneration of the tendon matrix, indicating potential cross-talk between protein lactylation and expression levels. At last, by western blotting and immunofluorescence, we verified the correlation between high lactylation and the downregulation of matrix and cholesterol-related proteins including BGN, MYL3, TPM3, and APOC3. ProteomeXchange: PXD033146.

Long-range functional connections mirror and link microarchitectural and cognitive hierarchies in the human brain.

BACKGROUND: Higher-order cognition is hypothesized to be implemented via distributed cortical networks that are linked via long-range connections. However, it is unknown how computational advantages of long-range connections reflect cortical microstructure and microcircuitry. METHODS: We investigated this question by (i) profiling long-range cortical connectivity using resting-state functional magnetic resonance imaging (MRI) and cortico-cortical geodesic distance mapping, (ii) assessing how long-range connections reflect local brain microarchitecture, and (iii) examining the microarchitectural similarity of regions connected through long-range connections. RESULTS: Analysis of 2 independent datasets indicated that sensory/motor areas had more clustered short-range connections, while transmodal association systems hosted distributed, long-range connections. Meta-analytical decoding suggested that this topographical difference mirrored shifts in cognitive function, from perception/action towards emotional/social processing. Analysis of myelin-sensitive in vivo MRI as well as postmortem histology and transcriptomics datasets established that gradients in functional connectivity distance are paralleled by those present in cortical microarchitecture. Notably, long-range connections were found to link spatially remote regions of association cortex with an unexpectedly similar microarchitecture. CONCLUSIONS: By mapping covarying topographies of long-range functional connections and cortical microcircuits, the current work provides insights into structure-function relations in human neocortex.

Improved Energy Storage Property of Sandwich-Structured Poly(vinylidene fluoride)-Based Composites by Introducing Na0.5Bi0.5TiO3@TiO2 Whiskers.

In recent years, high-energy-density polymer-based capacitors have received extensive attention because of their potential applications in advanced power systems and electronic equipment. However, their development is severely hampered by the inherent features of polymers such as low polarization and low charge-discharge efficiency (η). In this study, a new strategy for core-shell Na0.5Bi0.5TiO3(NBT)@TiO2(TO) whiskers combined with sandwich-structured poly(vinylidene fluoride) (PVDF)-based dielectric composites is proposed, in which the middle layer is the PVDF-based composites filled with different fractions of NBT@TO whiskers and the outer layers are pristine PVDF. The experimental results show that the loading of NBT@TO whiskers can simultaneously optimize electrical displacement and breakdown strength of the sandwich-structured composite due to the additional interfacial polarization and the contribution of the barrier effect between adjacent layers. Thus, a significantly improved electric displacement of ∼13.99 µC cm-2, a maximum discharge energy density (Ud) of ∼15.42 J cm-3 at a low electric field of 314 MV m-1, and a high charging-discharging efficiency (η ∼ 66.12%) can be obtained from the composite with the middle layer containing 6 wt % NBT@TO whiskers. This research provides a strategy for the preparation of advanced polymer-based composites with a superior discharge energy density in the future.

The effect of talus osteochondral defects of different area size on ankle joint stability: a finite element analysis.

BACKGROUND: Osteochondral lesion of the talus (OLT) is one of the most common ankle injuries, which will lead to biomechanical changes in the ankle joint and ultimately affect ankle function. Finite element analysis (FEA) is used to clarify the effect of talus osteochondral defects on the stability of the ankle joint at different depths. However, no research has been conducted on talus osteochondral defect areas that require prompt intervention. In this research, FEA was used to simulate the effect of the area size of talus osteochondral defect on the stress and stability of the ankle joint under a specific depth defect. METHODS: Different area sizes (normal, 2 mm* 2 mm, 4 mm* 4 mm, 6 mm* 6 mm, 8 mm* 8 mm, 10 mm* 10 mm, and 12 mm* 12 mm) of the three-dimensional finite element model of osteochondral defects were established. The model was used to simulate and calculate joint stress and displacement of the articular surface of the distal tibia and the proximal talus when the ankle joint was in the heel-strike, midstance, and push-off phases. RESULTS: When OLT occurred, the contact pressure of the articular surface, the equivalent stress of the proximal talus, the tibial cartilage, and the talus cartilage did not change significantly with an increase in the size of the osteochondral defect area when the heel-strike phase was below 6 mm * 6 mm. Gradual increases started at 6 mm * 6 mm in the midstance and push-off phases. Maximum changes were reached when the defect area size was 12 mm * 12 mm. The same patterns were observed in the talus displacement. CONCLUSIONS: The effect of the defect area of the ankle talus cartilage on the ankle biomechanics is evident in the midstance and push-off phases. When the size of the defect reaches 6 mm * 6 mm, the most apparent change in the stability of the ankle joint occurs, and the effect does not increase linearly with the increase in the size of the defect.

Topographic divergence of atypical cortical asymmetry and atrophy patterns in temporal lobe epilepsy.

Temporal lobe epilepsy, a common drug-resistant epilepsy in adults, is primarily a limbic network disorder associated with predominant unilateral hippocampal pathology. Structural MRI has provided an in vivo window into whole-brain grey matter structural alterations in temporal lobe epilepsy relative to controls, by either mapping (i) atypical inter-hemispheric asymmetry; or (ii) regional atrophy. However, similarities and differences of both atypical asymmetry and regional atrophy measures have not been systematically investigated. Here, we addressed this gap using the multisite ENIGMA-Epilepsy dataset comprising MRI brain morphological measures in 732 temporal lobe epilepsy patients and 1418 healthy controls. We compared spatial distributions of grey matter asymmetry and atrophy in temporal lobe epilepsy, contextualized their topographies relative to spatial gradients in cortical microstructure and functional connectivity calculated using 207 healthy controls obtained from Human Connectome Project and an independent dataset containing 23 temporal lobe epilepsy patients and 53 healthy controls and examined clinical associations using machine learning. We identified a marked divergence in the spatial distribution of atypical inter-hemispheric asymmetry and regional atrophy mapping. The former revealed a temporo-limbic disease signature while the latter showed diffuse and bilateral patterns. Our findings were robust across individual sites and patients. Cortical atrophy was significantly correlated with disease duration and age at seizure onset, while degrees of asymmetry did not show a significant relationship to these clinical variables. Our findings highlight that the mapping of atypical inter-hemispheric asymmetry and regional atrophy tap into two complementary aspects of temporal lobe epilepsy-related pathology, with the former revealing primary substrates in ipsilateral limbic circuits and the latter capturing bilateral disease effects. These findings refine our notion of the neuropathology of temporal lobe epilepsy and may inform future discovery and validation of complementary MRI biomarkers in temporal lobe epilepsy.

Structural Connectivity Gradients of the Temporal Lobe Serve as Multiscale Axes of Brain Organization and Cortical Evolution.

The temporal lobe is implicated in higher cognitive processes and is one of the regions that underwent substantial reorganization during primate evolution. Its functions are instantiated, in part, by the complex layout of its structural connections. Here, we identified low-dimensional representations of structural connectivity variations in human temporal cortex and explored their microstructural underpinnings and associations to macroscale function. We identified three eigenmodes which described gradients in structural connectivity. These gradients reflected inter-regional variations in cortical microstructure derived from quantitative magnetic resonance imaging and postmortem histology. Gradient-informed models accurately predicted macroscale measures of temporal lobe function. Furthermore, the identified gradients aligned closely with established measures of functional reconfiguration and areal expansion between macaques and humans, highlighting their potential role in shaping temporal lobe function throughout primate evolution. Findings were replicated in several datasets. Our results provide robust evidence for three axes of structural connectivity in human temporal cortex with consistent microstructural underpinnings and contributions to large-scale brain network function.

A Global Phosphorylation Atlas of Proteins Within Pathological Site of Rotator Cuff Tendinopathy.

Rotator cuff tendinopathy (RCT) is the most common cause of shoulder pain, therefore posing an important clinical problem. Understanding the mechanism and biochemical changes of RCT would be of crucial importance and pave the path to targeting novel and effective therapeutic strategies in translational perspectives and clinical practices. Phosphorylation, as one of the most important and well-studied post-translational modifications, is tightly associated with protein activity and protein functional regulation. Here in this study, we generated a global protein phosphorylation atlas within the pathological site of human RCT patients. By using Tandem Mass Tag (TMT) labeling combined with mass spectrometry, an average of 7,741 phosphorylation sites (p-sites) and 3,026 proteins were identified. Compared with their normal counterparts, 1,668 p-sites in 706 proteins were identified as upregulated, while 73 p-sites in 57 proteins were downregulated. GO enrichment analyses have shown that majority of proteins with upregulated p-sites functioned in neutrophil-mediated immunity whereas downregulated p-sites are mainly involved in muscle development. Furthermore, pathway analysis identified NF-κB-related TNF signaling pathway and protein kinase C alpha type (PKCα)-related Wnt signaling pathway were associated with RCT pathology. At last, a weighted kinase-site phosphorylation network was built to identify potentially core kinase, from which serine/threonine-protein kinase 39 (STLK3) and mammalian STE20-like protein kinase 1 (MST1) were proposed to be positively correlated with the activation of Wnt pathway.

Relationship between the disrupted topological efficiency of the structural brain connectome and glucose hypometabolism in normal aging.

Normal aging is accompanied by structural degeneration and glucose hypometabolism in the human brain. However, the relationship between structural network disconnections and hypometabolism in normal aging remains largely unknown. In the present study, by combining MRI and PET techniques, we investigated the metabolic mechanism of the structural brain connectome and its relationship with normal aging in a cross-sectional, community-based cohort of 42 cognitively normal elderly individuals aged 57-84 years. The structural connectome was constructed based on diffusion MRI tractography, and the network efficiency metrics were quantified using graph theory analyses. FDG-PET scanning was performed to evaluate the glucose metabolic level in the cortical regions of the individuals. The results of this study demonstrated that both network efficiency and cortical metabolism decrease with age (both p < 0.05). In the subregions of the bilateral thalamus, significant correlations between nodal efficiency and cortical metabolism could be observed across subjects. Individual-level analyses indicated that brain regions with higher nodal efficiency tend to exhibit higher metabolic levels, implying a tight coupling between nodal efficiency and glucose metabolism (r = 0.56, p = 1.15 × 10-21). Moreover, efficiency-metabolism coupling coefficient significantly increased with age (r = 0.44, p = 0.0046). Finally, the main findings were also reproducible in the ADNI dataset. Together, our results demonstrate a close coupling between structural brain connectivity and cortical metabolism in normal elderly individuals and provide new insight that improve the present understanding of the metabolic mechanisms of structural brain disconnections in normal aging.

Age-Related Decline in the Topological Efficiency of the Brain Structural Connectome and Cognitive Aging.

Brain disconnection model has been proposed as a possible neural mechanism for cognitive aging. However, the relationship between structural connectivity degeneration and cognitive decline with normal aging remains unclear. In the present study, using diffusion MRI and tractography techniques, we report graph theory-based analyses of the brain structural connectome in a cross-sectional, community-based cohort of 633 cognitively healthy elderly individuals. Comprehensive neuropsychological assessment of the elderly subjects was performed. The association between age, brain structural connectome, and cognition across elderly individuals was examined. We found that the topological efficiency, modularity, and hub integration of the brain structural connectome exhibited a significant decline with normal aging, especially in the frontal, parietal, and superior temporal regions. Importantly, network efficiency was positively correlated with attention and executive function in elderly subjects and had a significant mediation effect on the age-related decline in these cognitive functions. Moreover, nodal efficiency of the brain structural connectome showed good performance for the prediction of attention and executive function in elderly individuals. Together, our findings revealed topological alterations of the brain structural connectome with normal aging, which provides possible structural substrates underlying cognitive aging and sensitive imaging markers for the individual prediction of cognitive functions in elderly subjects.

An injectable extracellular matrix derived hydrogel for meniscus repair and regeneration.

Tissue-derived extracellular matrix (ECM) biomaterials to regenerate the meniscus have gained increasing attention in treating meniscus injuries and diseases, particularly for aged persons and athletes. However, ECM scaffold has poor cell infiltration and can only be implanted using surgical procedures. To overcome these limitations, we developed an injectable ECM hydrogel material from porcine meniscus via modified decellularization and enzymatic digestion. This meniscus-derived ECM hydrogel exhibited a fibrous morphology with tunable compression and initial modulus. It had a good injectability evidenced by syringe injection into mouse subcutaneous tissue. The hydrogel showed good cellular compatibility by promoting the growth of both bovine chondrocytes and mouse 3T3 fibroblasts encapsulated in the hydrogel for 2 weeks. It also promoted cell infiltration as shown in both in vitro cell culture and in vivo mouse subcutaneous implantation. The in vivo study revealed that the ECM hydrogel possessed good tissue compatibility after 7 days of implantation. The results support the great potential of the newly produced injectable meniscus-derived ECM hydrogel specifically for meniscus repair and regeneration.

Microfluidic serpentine antennas with designed mechanical tunability.

This paper describes the design and characterization of microfluidic serpentine antennas with reversible stretchability and designed mechanical frequency modulation (FM). The microfluidic antennas are designed based on the Poisson's ratio of the elastomer in which the liquid alloy antenna is embedded, to controllably decrease, stabilize or increase its resonance frequency when being stretched. Finite element modelling was used in combination with experimental verification to investigate the effects of substrate dimensions and antenna aspect ratios on the FM sensitivity to uniaxial stretching. It could be designed within the range of -1.2 to 0.6 GHz per 100% stretch. When the aspect ratio of the serpentine antenna is between 1.0 and 1.5, the resonance frequency is stable under stretching, bending, and twisting. The presented microfluidic serpentine antenna design could be utilized in the field of wireless mobile communication for the design of wearable electronics, with a stable resonance frequency under dynamic applied strain up to 50%.