A Self-Delivery Nanodrug Simultaneously Inhibits COX-2/PGE2 Mediated Inflammation and Downregulates PD-L1 to Boost Photoimmunotherapy.

Phototherapy promotes anti-tumor immunity by inducing immunogenic cell death (ICD), However, the accompanying inflammatory responses also trigger immunosuppression, attenuating the efficacy of photo-immunotherapy. Herein, they co-assembled a cell-membrane targeting chimeric peptide C16-Cypate-RRKK-PEG8-COOH (CCP) and anti-inflammatory diclofenac (DA) to develop a nanodrug (CCP@DA) that both enhances the immune effect of phototherapy and weakens the inflammation-mediated immunosuppression. CCP@DA achieves cell membrane-targeting photodynamic and photothermal synergistic therapies to damage programmed death ligand 1 (PD-L1) and induce a strong ICD to activate anti-tumor response. Simultaneously, the released DA inhibits the cycoperoxidase-2 (COX-2)/prostaglandin E2 (PGE2) pathway in tumor cells to inhibit pro-tumor inflammation and further down-regulate PD-L1 expression to relieve the immunosuppressive microenvironment. CCP@DA significantly inhibited tumor growth and inflammation both in vitro and in vivo, while maintaining a potent anti-tumor immune response. Additionally, it exhibits excellent anti-metastatic capabilities and prolongs mouse survival time with a single dose and low levels of near-infrared (NIR) light exposure. This work provides a valuable strategy to control the therapy-induced inflammation for high-efficiency photoimmunotherapy.

Self-Delivery Nanomedicines Reverse Thermal Resistance to Enhance Tumor Mild-Temperature Photothermal Therapy.

Tumoral thermal defense mechanisms considerably attenuate the therapeutic outcomes of mild-temperature photothermal therapy (PTT). Thus, developing a simple, efficient, and universal therapeutic strategy to sensitize mild-temperature PTT is desirable. Herein, we report self-delivery nanomedicines ACy NPs comprising a near-infrared (NIR) photothermal agent (Cypate), mitochondrial oxidative phosphorylation inhibitor (ATO), and distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-PEG2000), which have a high drug-loading efficiency that can reverse tumoral thermal resistance, thereby increasing mild-temperature PTT efficacy. ACy NPs achieved targeted tumor accumulation and performed NIR fluorescence imaging capability in vivo to guide tumor PTT for optimized therapeutic outcomes. The released ATO reduced intracellular ATP levels to downregulate multiple heat shock proteins (including HSP70 and HSP90) before PTT, which reversed the thermal resistance of tumor cells, contributing to the excellent results of mild-temperature PTT in vitro and in vivo. Therefore, this study provides a simple, biosafe, advanced, and universal heat shock protein-blocking strategy for tumor PTT.

Changes in respiratory structure and function after traumatic cervical spinal cord injury: observations from spinal cord and brain.

Respiratory difficulties and mortality following severe cervical spinal cord injury (CSCI) result primarily from malfunctions of respiratory pathways and the paralyzed diaphragm. Nonetheless, individuals with CSCI can experience partial recovery of respiratory function through respiratory neuroplasticity. For decades, researchers have revealed the potential mechanism of respiratory nerve plasticity after CSCI, and have made progress in tissue healing and functional recovery. While most existing studies on respiratory plasticity after spinal cord injuries have focused on the cervical spinal cord, there is a paucity of research on respiratory-related brain structures following such injuries. Given the interconnectedness of the spinal cord and the brain, traumatic changes to the former can also impact the latter. Consequently, are there other potential therapeutic targets to consider? This review introduces the anatomy and physiology of typical respiratory centers, explores alterations in respiratory function following spinal cord injuries, and delves into the structural foundations of modified respiratory function in patients with CSCI. Additionally, we propose that magnetic resonance neuroimaging holds promise in the study of respiratory function post-CSCI. By studying respiratory plasticity in the brain and spinal cord after CSCI, we hope to guide future clinical work.

Clinical characteristics and proposed mechanism of pediatric spinal cord injury resulting from backbend practice.

Objective: Pediatric spinal cord injury without radiographic abnormality (SCIWORA) caused by backbend practice is increasing. This study proposed an underlying 'combined injury mechanism' related to the spinal cord and femoral nerve overstretching. Methods: Pediatric patients diagnosed with backbend-associated SCIWORA at the China Rehabilitation Research Center during 2017-2021 were recruited. Clinical and imaging data were collected, and each patient's clinical course and prognosis were determined. Healthy dancers were recruited to simulate the backbend, obtain images, and estimate the spinal cord and femoral nerve stretch ratio. A model for the 'combined injury mechanism' was established using 4-week-old SD rats. Results: Forty-two SCIWORA female patients with an average age of 6 (SD 1) years and an average hospitalization time of 91 (SD 43) days were assessed. The primary initial symptom was pain in the back and/or lower extremities (33, 79%). The average time from injury onset to severe paralysis was 2.0 (SD 0.6) hours. Most patients had complete paraplegia (32, 76%), and neurological levels were distributed mainly in thoracic segments (38, 91%). Patients with elicited tendon reflexes on admission tended to have an incomplete spinal cord injury (p = 0.001) and improved motor recovery (p = 0.018). After one year, the most common complications were scoliosis (31, 74%) and abnormal hips (14, 33%). Injury of the caudal spinal cord torn by nerve roots was confirmed by surgical exploration in a case. The thoracic spinal cord and femoral nerves were overstretched by 148.8 ± 3.6% and111.7 ± 4.0%, respectively, in a full backbend posture. The 'combined injury mechanism' was partially replicated in the animal model. Conclusion: Spinal overstretch and transient dislocation are considered the primary mechanisms by which SCIWORA occurs in children. Overstretching the femoral nerve aggravates spinal cord injuries caused by backbend practice.

Effects of microplastic combined with Cr(III) on apoptosis and energy pathway of coral endosymbiont.

The combined effect of polyethylene (PE) microplastics and chromium (Cr(III)) on the scleractinian coral Acropora pruinosa (A. pruinosa) was investigated. The endpoints analysed in this study included the endosymbiont density, the chlorophyll a + c content, and the activity of enzymes involved in apoptosis (caspase-1, caspase-3), glycolysis (lactate dehydrogenase, LDH), the pentose phosphate pathway (glucose-6-phosphate dehydrogenase, G6PDH) and electron transfer coenzyme (nicotinamide adenine dinucleotide, NAD+/NADH). During the 7-day exposure to PE and Cr(III) stress, the endosymbiont density and chlorophyll content decreased gradually. The caspase-1 and caspase-3 activities increased in the high-concentration Cr(III) exposure group. Furthermore, the LDH and G6PDH activities decreased significantly, and the NAD+/NADH was decreased significantly. In summary, the results showed that PE and Cr(III) stress inhibited the endosymbiont energy metabolism enzymes and further led to endosymbiont apoptosis in coral. In addition, under exposure to the combination of stressors, when the concentration of Cr(III) remained at 1 × 10-2 mg/L, the toxic effects of heavy metals on the endosymbiont were temporarily relieved with elevated PE concentrations. In contrast, when coral polyps were exposed to 5 mg/L PE and increasing Cr(III) concentrations, their metabolic activities were seriously disturbed, which increased the burden of energy consumption. In the short term, the toxic effect of Cr(III) was more obvious than that of PE because Cr(III) exposure leads to endosymbiont apoptosis and irreversible damage. This is the first study to provide insights into the combined effect of microplastic and Cr(III) stress on the apoptosis and energy pathways of coral endosymbionts. This study suggested that microplastics combined with Cr(III) are an important factor affecting the apoptosis and energy metabolism of endosymbionts, accelerating the collapse of the balance between the coral host and symbiotic endosymbiont.

Effects of Microplastics Exposure on the Acropora sp. Antioxidant, Immunization and Energy Metabolism Enzyme Activities.

Microplastic pollution in marine environments has increased rapidly in recent years, with negative influences on the health of marine organisms. Scleractinian coral, one of the most important species in the coral ecosystems, is highly sensitive to microplastic. However, whether microplastic causes physiological disruption of the coral, via oxidative stress, immunity, and energy metabolism, is unclear. In the present study, the physiological responses of the coral Acropora sp. were determined after exposure to polyethylene terephthalate (PET), polyamide 66 (PA66), and polyethylene (PE) microplastic for 96 h. The results showed that there were approximately 4-22 items/nubbin on the surface of the coral skeleton and 2-10 items/nubbin on the inside of the skeleton in the MPs exposure groups. The density of endosymbiont decreased (1.12 × 105-1.24 × 105 cell/cm2) in MPs exposure groups compared with the control group. Meanwhile, the chlorophyll content was reduced (0.11-0.76 µg/cm2) after MPs exposure. Further analysis revealed that the antioxidant enzymes in coral tissues were up-regulated (Total antioxidant capacity T-AOC 2.35 × 10-3-1.05 × 10-2 mmol/mg prot, Total superoxide dismutase T-SOD 3.71-28.67 U/mg prot, glutathione GSH 10.21-10.51 U/mg prot). The alkaline phosphatase (AKP) was inhibited (1.44-4.29 U/mg prot), while nitric oxide (NO) increased (0.69-2.26 µmol/g prot) for cell signal. Moreover, lactate dehydrogenase (LDH) was down-regulated in the whole experiment period (0.19-0.22 U/mg prot), and Glucose-6-phosphate dehydrogenase (G6PDH) for cell the phosphate pentoses pathway was also reduced (0.01-0.04 U/mg port). Results showed that the endosymbiont was released and chlorophyll was decreased. In addition, a disruption could occur under MPs exposure, which was related to anti-oxidant, immune, and energy metabolism.

Structural Covariance Changes of Anterior and Posterior Hippocampus During Musical Training in Young Adults.

Musical training can induce the functional and structural changes of the hippocampus. The hippocampus is not a homogeneous structure which can be divided into anterior and posterior parts along its longitudinal axis, and the whole-brain structural covariances of anterior (aHC) and posterior hippocampus (pHC) show distinct patterns in young adults. However, little is known about whether the anterior and posterior hippocampal structural covariances change after long-term musical training. Here, we investigated the musical training-induced changes of the whole-brain structural covariances of bilateral aHC and pHC in a longitudinal designed experiment with two groups (training group and control group) across three time points [the beginning (TP1) and the end (TP2) of 24 weeks of training, and 12 weeks after training (TP3)]. Using seed partial least square, we identified two significant patterns of structural covariance of the aHC and pHC. The first showed common structural covariance of the aHC and pHC. The second pattern revealed distinct structural covariance of the two regions and reflected the changes of structural covariance of the left pHC in the training group across three time points: the left pHC showed significant structural covariance with bilateral hippocampus and parahippocampal gyrus, left calcarine sulcus only at TP1 and TP3. Furthermore, the integrity of distinct structural networks of aHC and pHC in the second pattern significantly increased in the training group. Our findings suggest that musical training could change the organization of structural whole-brain covariance for left pHC and enhance the degree of the structural covariance network differentiation of the aHC and pHC in young adults.

More Flexible Integration of Functional Systems After Musical Training in Young Adults.

Musical training, because it involves the interaction and integration of diverse functional systems, is an excellent model to investigate training-induced brain plasticity. The human brain functions in a network architecture in which dynamic modules and subgraphs are considered to enable efficient information communication. However, it remains largely unknown how the dynamic integration of functional systems changes with musical training, which may provide new insight into musical training-induced brain plasticity and further the use of music therapy for neuropsychiatric disease and brain injury. Here, 29 healthy young adult novices who received 24 weeks of piano training, and another 27 novices without any intervention were scanned at three time points-before and after musical training and 12 weeks after training. We used nonnegative matrix factorization to identify a set of subgraphs and their corresponding time-dependent coefficients from a concatenated functional network of all the subjects in sliding time windows. The energy and entropy of the time-dependent coefficients were computed to quantify the subgraph's dynamic changes in expression. The training group showed a significantly increased energy of the time-dependent coefficients of 3 subgraphs after training. Furthermore, one of the subgraphs, comprised of primary functional systems and cingulo-opercular task control and salience systems, showed significantly changed entropy in the training group after training. Our results suggest that the integration of functional systems undergoes increased flexibility in fine-scale dynamics after musical training, which reveals how brain functional systems engage in musical performance. The efficacy of musical training induced brain plasticity may provide new therapeutic strategies for brain injury and neuropsychiatric disorders.

Dynamic reconfiguration of the functional brain network after musical training in young adults.

Musical performance strongly depends on continuous and dynamic information integration from the motor, sensory and cognitive systems. Musical training is an excellent model to investigate the plasticity of the dynamics in functional brain networks. Here, we compared the dynamics of the resting-state functional brain network in 29 healthy, young adults (13 males) before and after 24 weeks of piano training (all participants had been novices) with the functional brain network of 27 matched participants (13 males) who were also evaluated longitudinally but without any training. The sliding window approach was used to construct the time-varying functional networks, and the dynamics of 13 well-known functional systems were evaluated. The mean nodal flexibility of each functional system, which is a measure that captures changes in the local properties of the network, was calculated. In addition, the intrasystem connections, intersystem connections and their ratio for each functional system were also calculated. We found increased flexibility of the visual and auditory systems in participants after musical training when compared with the controls. Moreover, the visual system showed increased intrasystem and intersystem connections, and the auditory system showed increased intersystem connections and a decreased ratio of the intrasystem and intersystem connections in the training group after musical training. Furthermore, regression analysis revealed a positive correlation between the increased intersystem connections of the visual system and practice time in the training group. Our results indicated that the dynamics of the functional brain network can be changed by musical training, which provided new insights into the brain plasticity and functional architecture of the brain network.

Musical training induces functional and structural auditory-motor network plasticity in young adults.

Playing music requires a strong coupling of perception and action mediated by multimodal integration of brain regions, which can be described as network connections measured by anatomical and functional correlations between regions. However, the structural and functional connectivities within and between the auditory and sensorimotor networks after long-term musical training remain largely uninvestigated. Here, we compared the structural connectivity (SC) and resting-state functional connectivity (rs-FC) within and between the two networks in 29 novice healthy young adults before and after musical training (piano) with those of another 27 novice participants who were evaluated longitudinally but with no intervention. In addition, a correlation analysis was performed between the changes in FC or SC with practice time in the training group. As expected, participants in the training group showed increased FC within the sensorimotor network and increased FC and SC of the auditory-motor network after musical training. Interestingly, we further found that the changes in FC within the sensorimotor network and SC of the auditory-motor network were positively correlated with practice time. Our results indicate that musical training could induce enhanced local interaction and global integration between musical performance-related regions, which provides insights into the mechanism of brain plasticity in young adults.

Morphological Changes of Amygdala in Turner Syndrome Patients.

AIMS: Turner's syndrome (TS) losts one of the X chromosomes and exhibits social cognition deficits. Previous studies have reported that women with TS demonstrated structural and functional abnormalities in brain, including increased volume in amygdala. However, most studies regarded the amygdala as a whole, and the abnormalities in the specific subregions of amygdala in TS have not been studied. Here, we aimed to investigate the local morphological changes of amygdala in TS using the surface morphology analysis method. METHODS: A total of 19 adolescents with 45XO TS and 20 matched adolescents with typical development were evaluated using magnetic resonance imaging. The amygdalae of all participants were manually delineated. 3D surface remodeling and parameterization were performed based on the outlined boundaries of amygdalae. We extracted two surface metrics, namely direct Euclidean displacement and normal projection that were used to represent the morphology of amygdala. RESULTS: Statistical analysis showed significant outward deformation in the laterobasal subregion of left amygdala in patients with TS, compared with the controls using either direct Euclidean displacement or normal displacement. CONCLUSIONS: Our findings provide novel insight into the pathological changes in the amygdala of patients with TS.