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Abstract Objective Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by proximal muscle weakness and atrophy. The increasing availability of disease-modifying therapies has prompted the development of biomarkers to facilitate clinical assessments. We explored the association between disease severity and serum creatinine (Crn) levels in SMA patients undergoing up to two years of treatment with nusinersen. Methods We measured serum Crn levels and assessed function performance using the Hammersmith Functional Motor Scale-Expanded (HFMSE), Medical Research Council Scale (MRC), 6-Minute Walk Test (6MWT), ulnar Compound Muscle Action Potential (CMAP), and forced vital capacity (FVC) in a cohort comprising 28 adolescent and adult patients with SMA. The association between Crn and disease severity was investigated through partial rank correlation analysis and linear mixed models while accounting for age, gender, and BMI. Linear models were employed to predict functional performance. Results 28 SMA patients and 28 gender- and age-matched healthy controls (HCs) were included, resulting in a dataset of 185 visits. Compared to HCs, SMA patients exhibited significantly lower Crn values ​​(67.4 ± 14 vs. 23.7 ± 14.8 umol/L, p

The research aimed to investigate effects of the addition of Clitocybe squamulosa and Auricularia heimuer powders on processing properties of doughs and quality of dried noodles. For this purpose, wheat flour was mixed uniformly with C. squamulosa and A. heimuer powders at different ratios (100:0, 99:1, 97:3, 95:5, 90:10) respectively, the processing properties of mixed flour doughs were preliminarily determined by texture analyzer, viscometer and rheometer, and then the edible quality of prepared dried noodles were systematically analyzed. The results showed that compared with the pure wheat flour dough, the hardness of doughs increased significantly (P

Metastasis is the leading cause of cancer-related death in cancer patients. Tumor cells primarily spread through the hematogenous and lymphatic system. The underlying mechanisms of hematogenous metastasis have been well described over the past few decades. However, the understanding of the molecular mechanisms involved in lymphatic metastasis is still at an early stage. Tumor microenvironment (TME), primarily consisting of T cells, B cells, tumor-associated macrophages, neutrophils, and cancer-associated fibroblasts, has been implicated in the development of lymphatic metastasis. Recent studies have been reported that the dynamic and complex interplay between these cellular components of TME has great effects on lymphatic metastasis. Here, we discussed the paradoxical roles of these cellular component within the TME during lymphatic metastasis, as well as potential therapeutic opportunities to re-educate these cells within the TME to have anti-tumorigenic effects.

Porcine deltacoronavirus (PDCoV) is an emerging porcine enteropathogenic coronavirus that causes acute watery diarrhoea in piglets, resulting in significant economic losses to the global swine industry. However, the underlying mechanism of PDCoV infection is not well defined, which seriously hinders the development of effective drugs and vaccines. Integrins (ITG) are heterodimeric transmembrane glycoproteins that play important roles in the life cycle of many viruses. In the current study, the viral entry pathways of PDCoV were explored and the role of ITGαVβ3 was investigated during PDCoV infection. Our results showed that the lysosomal acidification inhibitor bafilomycin-A1 (Baf-A1) significantly reduced PDCoV infection, while exogenous protease facilitated PDCoV infection and even allowed PDCoV entry to bypass the endosomal pathway, suggesting PDCoV entry into cells via the endocytic pathway and the exogenous protease-mediated pathway simultaneously. Furthermore, ITGαVβ3 was identified to be involved in PDCoV infection, especially during viral entry stages. PDCoV infection triggers the activation of the focal adhesion kinase (FAK)-phosphatidylinositol 3-kinase (PI3K)-serine/threonine-specific protein kinase (AKT) signalling pathway, and this activation is ITGαVβ3-dependent, suggesting that the activation of the FAK-PI3K-AKT signalling pathway during PDCoV infection is mediated by ITGαVβ3. Our results further demonstrated that PDCoV infection induced the expression of inflammatory cytokines, which was mediated by activation of the ITGαVβ3-FAK-PI3K-AKT-nuclear transcription factor-κB (NF-κB) signalling pathway. Overall, the results revealed that ITGαVβ3 is an essential host factor for PDCoV infection and can serve as a supplementary receptor to facilitate PDCoV infection, which can help us to explore the molecular mechanism of PDCoV infection.

Abstract Background As a common disabling disease, irreversible neuronal death due to spinal cord injury (SCI) is the root cause of functional impairment; however, the capacity for neuronal regeneration in the developing spinal cord tissue is limited. Therefore, there is an urgent need to investigate how defective neurons can be replenished and functionally integrated by neural regeneration; the reprogramming of intrinsic cells into functional neurons may represent an ideal solution. Methods A mouse model of transection SCI was prepared by forceps clamping, and an adeno-associated virus (AAV) carrying the transcription factors NeuroD1 and Neurogenin-2(Ngn2) was injected in situ into the spinal cord to specifically overexpress these transcription factors in astrocytes close to the injury site. 5-bromo-2´-deoxyuridine (BrdU) was subsequently injected intraperitoneally to continuously track cell regeneration, neuroblasts and immature neurons marker expression, neuronal regeneration, and glial scar regeneration. In addition, immunoprotein blotting was used to measure the levels of transforming growth factor-β (TGF-β) pathway-related protein expression. We also evaluated motor function, sensory function, and the integrity of the blood-spinal cord barrier(BSCB). Results The in situ overexpression of NeuroD1 and Ngn2 in the spinal cord was achieved by specific AAV vectors. This intervention led to a significant increase in cell regeneration and the proportion of cells with neuroblasts and immature neurons cell properties at the injury site(p 0.05), although the treated mice had more sensory sensitivity and greater voluntary motor ability in open field than the non-intervention mice. We observed significant repair of the BSCB at the center of the injury site (p

With the rapid development of Industrial Internet of Things (IIoT) technology, various IIoT devices are generating large amounts of industrial sensor data that are spatiotemporally correlated and heterogeneous from multi-source and multi-domain. This poses a challenge to current detection algorithms. Therefore, this paper proposes an improved long short-term memory (LSTM) neural network model based on the genetic algorithm, attention mechanism and edge-cloud collaboration (GA-Att-LSTM) framework is proposed to detect anomalies of IIoT facilities. Firstly, an edge-cloud collaboration framework is established to real-time process a large amount of sensor data at the edge node in real time, which reduces the time of uploading sensor data to the cloud platform. Secondly, to overcome the problem of insufficient attention to important features in the input sequence in traditional LSTM algorithms, we introduce an attention mechanism to adaptively adjust the weights of important features in the model. Meanwhile, a genetic algorithm optimized hyperparameters of the LSTM neural network is proposed to transform anomaly detection into a classification problem and effectively extract the correlation of time-series data, which improves the recognition rate of fault detection. Finally, the proposed method has been evaluated on a publicly available fault database. The results indicate an accuracy of 99.6%, an F1-score of 84.2%, a precision of 89.8%, and a recall of 77.6%, all of which exceed the performance of five traditional machine learning methods.

Abstract The prosperous evolution of conductive hydrogel‐based skin sensors is attracting tremendous attention nowadays. Nevertheless, it remains a great challenge to simultaneously integrate excellent mechanical strength, desirable electrical conductivity, admirable sensing performance, and brilliant healability in hydrogel‐based skin sensors for high‐performance diagnostic healthcare sensing and wearable human‐machine interface, as well as robust photothermal performance for promptly intelligent photothermal therapy followed by the medical diagnosis and superior electromagnetic interference (EMI) shielding performance for personal protection. Herein, a flexible healable MXene hydrogel‐based skin sensor is prepared through a delicate combination of MXene (Ti3C2Tx) nanosheets network with the polymeric network. The as‐prepared skin sensor is featured with significantly enhanced mechanical, conducting, and sensing performances, along with robust self‐healability, good biocompatibility, and reliable injectability, enabling ultrasensitive human motion monitoring and teeny electrophysiological signals sensing. As a frontier technology in artificial intelligence, machine learning can facilitate to efficiently and precisely identify the electromyography signals produced by various human motions (such as variable finger gestures) with up to 99.5% accuracy, affirming the reliability of the machine learning‐assisted gesture identification with great potential in smart personalized healthcare and human‐machine interaction. Moreover, the MXene hydrogel‐based skin sensor displays prominent EMI shielding performance, demonstrating the great promise of effective personal protection.

BackgroundThe aldehyde dehydrogenase 2 (ALDH2) rs671 (A) allele has been implicated in neurodegeneration, potentially through oxidative and inflammatory pathways. The study aims to investigate the effects of the ALDH2 rs671 (A) allele and high sensitivity C-reactive protein (hs-CRP) on the clinical phenotypes of amyotrophic lateral sclerosis (ALS) in male and female patients.MethodsClinical data and ALDH2 rs671 genotype of 143 ALS patients, including 85 males and 58 females, were collected from January 2018 to December 2022. All patients underwent assessment using the Chinese version of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). Complete blood count and metabolic profiles were measured. Clinical and laboratory parameters were compared between carriers and non-carriers of the rs671 (A) allele in males and females, respectively. The significant parameters and rs671 (A) Allele were included in multivariate linear regression models to identify potential contributors to motor and cognitive impairment. Mediation analysis was employed to evaluate any mediation effects.ResultsMale patients carrying rs671 (A) allele exhibited higher levels of hs-CRP than non-carriers (1.70 mg/L vs. 0.50 mg/L, p = 0.006). The rs671 (A) allele was identified as an independent risk factor for faster disease progression only in male patients (β = 0.274, 95% CI = 0.048−0.499, p = 0.018). The effect of the rs671 (A) allele on the executive function in male patients was fully mediated by hs-CRP (Indirect effect = −1.790, 95% CI = −4.555−−0.225). No effects of the rs671 (A) allele or hs-CRP were observed in female ALS patients. The effects of the ALDH2 rs671 (A) allele and the mediating role of hs-CRP in male patients remained significant in the sensitivity analyses.ConclusionThe ALDH2 rs671 (A) allele contributed to faster disease progression and hs-CRP mediated cognitive impairment in male ALS patients.

Objectives To investigate the relationship among patients’ apathy, cognitive impairment, depression, anxiety, and caregiver burden in amyotrophic lateral sclerosis (ALS).Design A cross-sectional study design was used.Setting The study was conducted at a tertiary hospital in Wuhan, Hubei, China.Participants A total of 109 patients with ALS and their caregivers were included.Outcome measures Patients with ALS were screened using the Edinburgh Cognitive and Behavioural Screen, Beck Depression Inventory-II, Generalised Anxiety Disorder-7 and Apathy Scale to assess their cognition, depression, anxiety and apathy, respectively. The primary caregivers completed the Zarit Burden Interview. The association between apathy, cognitive impairment, depression, anxiety and caregiver burden was analysed using logistic regression. Mediation models were employed to investigate the mediating effect of patients’ apathy on the relationship between depression/anxiety and caregiver burden.Results Patients in the high caregiver burden group exhibited significantly higher levels of depression, anxiety and apathy compared with those in the low caregiver burden group (p

Background Periodontal ligament cells (PDLCs) are a major component of the periodontal ligament and have an important role in the regeneration of periodontal tissue and maintenance of homeostasis. High glucose can affect the activity and function of PDLCs in a variety of ways; therefore, it is particularly important to find ways to alleviate the effects of high glucose on PDLCs. Annexin A2 (ANXA2) is a calcium- and phospholipid-binding protein involved in a variety of cellular functions and processes, including cellular cytokinesis, cytophagy, migration, and proliferation. Aim The aim of this study was to exploring whether ANXA2 attenuates the deleterious effects of high glucose on PDLCs and promotes osteogenic differentiation capacity. Methods and results Osteogenic differentiation potential, cellular senescence, oxidative stress, and cellular autophagy were detected. Culturing PDLCs with medium containing different glucose concentrations (CTRL, 8 mM, 10 mM, 25 mM, and 40 mM) revealed that high glucose decreased the protein expression of ANXA2 (p

Background: This study aimed to explore the longitudinal associations of rumination with suicidal ideation and suicide attempts in individuals with major depressive disorder (MDD). Methods: Participants were derived from the Depression Cohort in China study (DCC). Those who completed at least one follow-up visit during the 12 months were included in the analysis. Dimensions of rumination including brooding and reflection were each measured using five items of the Ruminative Responses Scale. Suicidal ideation was assessed using the Beck Scale for Suicide Ideation. Suicide attempts were also assessed and all were analyzed with generalized estimating equations. Results: Our final sample included 532 participants aged 18 to 59 years (mean [SD], 26.91 [6.94] years) consisting of 148 (27.8%) males and 384 (72.2%) females. After adjusting for temporal trend and potential confounders, individuals with higher levels of reflection were more likely to report suicidal ideation (AOR =1.11, 95% CI:1.01–1.22). However, no statistically significant association was found between brooding and suicidal ideation (AOR =1.06, 95% CI:0.96–1.17). Conversely, individuals with higher levels of brooding were more likely to report suicide attempts (AOR =1.13, 95% CI:1.02–1.24), while no statistically significant association was observed between reflection and suicide attempts (AOR =0.91, 95% CI:0.82–1.01). Conclusion: Rumination reflects a disturbance in cognitive emotional processing and manifests in different dimensions. Our findings suggest that high levels of reflection and brooding may be associated with a higher likelihood of having suicidal ideation and suicide attempts, respectively. However, it should be interpreted with caution, given that effect sizes are small.

Abstract Flexible wearables have attracted extensive interests for personal human motion sensing, intelligent disease diagnosis, and multifunctional electronic skins. However, the reported flexible sensors, mostly exhibited narrow detection range, low sensitivity, limited degradability to aggravate environmental pollution from vast electronic wastes, and poor antibacterial performance to hardly improve skin discomfort and skin inflammation from bacterial growth under long‐term wearing. Herein, bioinspired from human skin featuring highly sensitive tactile sensation with spinous microstructures for amplifying sensing sensitivity between epidermis and dermis, a wearable antibacterial degradable electronics is prepared from degradable elastomeric substrate with MXene‐coated spinous microstructures templated from lotus leaf assembled with the interdigitated electrode. The degradable elastomer is facilely obtained with tunable modulus to match the modulus of human skin with improved hydrophilicity for rapid degradation. The as‐obtained sensor displays ultra‐low detection limit (0.2 Pa), higher sensitivity (up to 540.2 kPa−1), outstanding cycling stability (>23,000 cycles), a wide detection range, robust degradability, and excellent antibacterial capability. Facilitated by machine learning, the collected sensing signals from the integrated sensors on volunteer's fingers to the related American Sign Language are effectively recognized with an accuracy up to 99%, showing excellent potential in wireless human movement sensing and smart machine learning‐enabled human–machine interaction.

Esophageal squamous cell carcinoma (ESCC) is a malignancy with high incidence in China. Due to the lack of effective molecular targets, the prognosis of ESCC patients is poor. It is urgent to explore the pathogenesis of ESCC to identify promising therapeutic targets. Metabolic reprogramming is an emerging hallmark of ESCC, providing a novel perspective for revealing the biological features of ESCC. In the hypoxic and nutrient-limited tumor microenvironment, ESCC cells have to reprogram their metabolic phenotypes to fulfill the demands of bioenergetics, biosynthesis and redox homostasis of ESCC cells. In this review, we summarized the metabolic reprogramming of ESCC cells that involves glucose metabolism, lipid metabolism, and amino acid metabolism and explore how reprogrammed metabolism provokes novel opportunities for biomarkers and potential therapeutic targets of ESCC.

Metal–organic frameworks (MOFs), a new class of porous organic–organic hybrid materials controlled by self-assembly of metal atoms and organic pillars, are attracting considerable interest because of their specific properties. More recently, the advantages of different types of nanoscale metal–organic frameworks for the use of MOF nanoparticles in stomatology have been reported in the literature. This article covers the treatment of oral cancer, surface modification of implants, antibacterial dressings, and treatment of periodontitis and periodontal regeneration. It presents recent applications, future challenges, and prospects for MOFs in stomatology in four areas. It provides an overview of recent advances in the design and application of MOFs in stomatology from their intrinsic properties to different syntheses and their use as smart drug delivery systems or a combination of these.

In this work, a two-parameter inversion problem is analyzed, related to surface crack widths for measuring depths of normal surface notches, based on a laser-based ultrasonic measurement method in the time domain. In determining the depth measurement formulas, the main technique is the time delay between reflected and scattered waves. Scattered waves are generated by two reflections along the bottom and three mode transformations at the surface of the crack tips. Moreover, the scattering angle of the mode-conversion waves is 30°. These two key factors lead to corrected item “2wβ” in the depth measurement formula. A laser-based ultrasonic experimental platform is built to generate and receive surface waves in a non-contact manner on aluminum and steel specimens with surface cracks. The depth measurement method proposed in this paper has been validated through theoretical, simulation, and experimental methods. Finally, in this paper, an effective approach for quantitatively measuring crack depths, based on laser ultrasound, using the time-domain properties of surface wave propagation is provided.

Spinal cord injury is a severe neurological trauma that can frequently lead to neuropathic pain. During the initial stages following spinal cord injury, inflammation plays a critical role; however, excessive inflammation can exacerbate pain. Regulatory T cells (Treg cells) have a crucial function in regulating inflammation and alleviating neuropathic pain. Treg cells release suppressor cytokines and modulate the function of other immune cells to suppress the inflammatory response. Simultaneously, inflammation impedes Treg cell activity, further intensifying neuropathic pain. Therefore, suppressing the inflammatory response while enhancing Treg cell regulatory function may provide novel therapeutic avenues for treating neuropathic pain resulting from spinal cord injury. This review comprehensively describes the mechanisms underlying the inflammatory response and Treg cell regulation subsequent to spinal cord injury, with a specific focus on exploring the potential mechanisms through which Treg cells regulate neuropathic pain following spinal cord injury. The insights gained from this review aim to provide new concepts and a rationale for the therapeutic prospects and direction of cell therapy in spinal cord injury-related conditions.

BackgroundNicotinamide mononucleotide (NMN), an important transforming precursor of nicotinamide adenine dinucleotide (NAD+). Numerous studies have confirmed the neuroprotective effects of NMN in nervous system diseases. However, its role in spinal cord injury (SCI) and the molecular mechanisms involved have yet to be fully elucidated.MethodsWe established a moderate-to-severe model of SCI by contusion (70 kdyn) using a spinal cord impactor. The drug was administered immediately after surgery, and mice were intraperitoneally injected with either NMN (500 mg NMN/kg body weight per day) or an equivalent volume of saline for seven days. The central area of the spinal cord was harvested seven days after injury for the systematic analysis of global gene expression by RNA Sequencing (RNA-seq) and finally validated using qRT-PCR.ResultsNMN supplementation restored NAD+ levels after SCI, promoted motor function recovery, and alleviated pain. This could potentially be associated with alterations in NAD+ dependent enzyme levels. RNA sequencing (RNA-seq) revealed that NMN can inhibit inflammation and potentially regulate signaling pathways, including interleukin-17 (IL-17), tumor necrosis factor (TNF), toll-like receptor, nod-like receptor, and chemokine signaling pathways. In addition, the construction of a protein-protein interaction (PPI) network and the screening of core genes showed that interleukin 1β (IL-1β), interferon regulatory factor 7 (IRF 7), C-X-C motif chemokine ligand 10 (Cxcl10), and other inflammationrelated factors, changed significantly after NMN treatment. qRT-PCR confirmed the inhibitory effect of NMN on inflammatory factors (IL-1β, TNF-α, IL-17A, IRF7) and chemokines (chemokine ligand 3, Cxcl10) in mice following SCI.ConclusionThe reduction of NAD+ levels after SCI can be compensated by NMN supplementation, which can significantly restore motor function and relieve pain in a mouse model. RNA-seq and qRT-PCR systematically revealed that NMN affected inflammation-related signaling pathways, including the IL-17, TNF, Toll-like receptor, NOD-like receptor and chemokine signaling pathways, by down-regulating the expression of inflammatory factors and chemokines.

Abstract Background Osteoarthritis (OA) is a chronic degenerative joint disease characterized by loss of joint function, which seriously reduces the quality of life of the elderly and imposes a heavy socioeconomic burden worldwide. Monotropein (MON), the main active ingredient of Morinda officinalis F.C. How, has exhibited therapeutic effects in different disease models. However, its potential effects on chondrocytes in an arthritic model remain unclear. This study aimed to evaluate the effects of MON in chondrocytes and a mouse model of OA, and explore the potential mechanisms. Materials and methods Murine primary chondrocytes were pretreated with 10 ng/ml interleukin (IL)-1β for 24 h to establish an in vitro model of OA, and then treated with different concentrations of MON (0, 25, 50 and 100 μM) for 24 h. The proliferation of the chondrocytes was assayed using ethynyl-deoxyuridine (EdU) staining. Immunofluorescence staining, western blotting and TUNEL staining were performed to assess the effects of MON on cartilage matrix degradation, apoptosis and pyroptosis. The mouse model of OA was constructed by surgical destabilization of the medial meniscus (DMM), and the animals were randomly divided into the sham-operated, OA and OA + MON groups. Following OA induction, the mice were given intraarticular injection of 100 μM MON or equal volume of normal saline twice a week for 8 weeks. The effects of MON on cartilage matrix degradation, apoptosis and pyroptosis were assessed as indicated. Results MON significantly accelerated the proliferation of chondrocytes, and inhibited cartilage matrix degradation, apoptosis and pyroptosis in the IL-1β-stimulated cells by blocking the nuclear factor-kappa B (NF-κB) signaling pathway. In the mouse model as well, MON treatment alleviated OA progression and promoted cartilage repair by inhibiting cartilage matrix degradation, and chondrocyte apoptosis and pyroptosis through the inactivation of the NF-κB signaling pathway. Furthermore, the MON-treated arthritic mice exhibited better articular tissue morphology and lower OARSI scores. Conclusions MON alleviated OA progression by inhibiting cartilage matrix degradation, and the apoptosis and pyroptosis of chondrocytes via NF-κB pathway inactivation, and is a promising alternative for the treatment of OA.

Epilepsy is one of the most common and oldest neurological disorders, characterized by periodic seizures that affect millions globally. Despite its long history, its pathophysiology is not fully understood. Additionally, the current treatment methods have their limitations. Finding a new alternative is necessary. Activated Protein C (APC) has been proven to have neurological protection in other neurological disorders; however, there is no study that focuses on the role of APC in seizures. We propose that APC's protective effect could be associated with seizures through inflammation and apoptosis regulation. The results demonstrated that APC's pathway proteins are involved in neuroprotection mechanisms in seizure-induced models by acting on certain inflammatory factors, such as NF-κB and apoptosis proteins.

Abstract Enzymatic sensors have inherent problems such as the low stability and limited pH range in industrial and biomedical applications and therefore, more efficient nonenzymatic sensors are highly desirable. Herein, plasma‐functionalized defective MoSe2 is prepared and studied as a highly efficient catalyst for electrochemical sensing of H2O2. Experiments and theoretical computations show that the plasma‐induced Se multi‐vacancies and nitrogen dopants generate new active sites, expose more edge active surfaces, narrow the bandgap, and strengthen binding with the ·OH intermediate, which imparts new fundamental knowledge about the roles of defects in catalysis. The defective MoSe2‐catalyzed sensor delivers competitive performance in hydrogen peroxide detection such as a low detection limit of 12.6 nmol/L, wide operational pH range of 1−13, good long‐term stability, and high selectivity. The portable sensor produced by screen printing confirms the excellent commercial potential and in addition, the results not only reveal a novel concept to design and fabricate high‐performance sensors for H2O2 but also provide insights into the effectiveness of surface modification of diverse catalytic materials.

Summary: Peritoneal metastasis is a challenging aspect of clinical practice for gastric cancer. Animal models are crucial in understanding molecular mechanisms, assessing drug efficacy, and conducting clinical intervention studies, including those related to gastric cancer peritoneal metastasis. Unlike other xenograft models, peritoneal metastasis models should not only present tumor growth at the transplant site, but also recapitulate tumor cell metastasis in the abdominal cavity. Developing a reliable model of gastric cancer peritoneal metastasis involves several technical aspects, such as the selection of model animals, source of xenograft tumors, technology of transplantation, and dynamic monitoring of the tumor progression. To date, challenges remain in developing a reliable model that can completely recapitulate peritoneal metastasis. Thus, this review aims to summarize the techniques and strategies used to establish animal models of gastric cancer peritoneal metastasis, providing a reference for future model establishment.

Abstract Objective To determine the efficacy of distal femur condyle locking plate (DFCLP) alone or in combination with cannulated screws for Hoffa fractures. Methods In this study, between May 2014 and February 2019, 13 patients between 26 and 64 years with isolated Hoffa fractures were enrolled during the study period and retrospectively analyzed. All patients underwent open reduction and internal fixation by DFCLP alone or in combination with cannulated screws followed by early active rehabilitation postoperatively. The primary outcome was evaluated using range of movement (ROM), Knee Society Score (KSS), International Knee Documentation Committee (IKDC) scoring system, and the fracture healing time of the patients during the 24‐month follow‐up period. Postoperative complications were also used to assess the patients’ conditions. Results A total of 13 patients completed the 24‐month follow‐up assessment and achieved bone re‐union at Hoffa fracture sites. The average follow‐up period was 24.5 months (ranging from 24 to 28 months). Six patients were treated by DFCLP in combination with cannulated screws and the remaining seven patients were treated by DFCLP alone. The mean ROM was determined as 119° (ranging from 100° to 130°). The mean KSS score was 87.9 (ranging from 80 to 92 points), with 11 patients evaluated as excellent, two as good, and zero bad cases. The mean IKDC score was 84.2 (ranging from 74.7 to 89.7 points), with 10 evaluated as excellent, three as good, and zero bad cases. The mean IKDC score was 83.3 for patients with medial Hoffa fractures and 84.4 for those with lateral Hoffa fractures. The average time to healing was 3.5 months (ranging from 3 to 4 months), and at month 3, the fracture healing was evident in seven patients (54%), and at month 4, fracture healing was seen in six patients (46%). It is worth mentioning that two patients suffered from knee joint stiffness and osteoarthritis during the 24 months follow‐up. Eleven patients (84.6%) achieved satisfactory knee joint function through early postoperative rehabilitation. Conclusion In patients with Hoffa fractures, treatment with DFCLP alone or in combination with cannulated screws followed by early active rehabilitation resulted in great stability and satisfactory functional outcomes after 24 months. Our findings may provide surgeons with a new way to treat Hoffa fractures.

Alzheimer’s disease (AD) is the most common neurodegenerative disease. There are many studies targeting extracellular deposits of amyloid β-peptide (Aβ) and intracellular neurofibrillary tangles (NFTs), however, there are no effective treatments to halt the progression. Mitochondria-associated endoplasmic reticulum membranes (MAMs) have long been found to be associated with various pathogenesis hypotheses of AD, such as Aβ deposition, mitochondrial dysfunction, and calcium homeostasis. However, there is a lack of literature summarizing recent advances in the mechanism and treatment studies. Accordingly, this article reviews the latest research involving the roles of MAM structure and tethering proteins in the pathogenesis of AD and summarizes potential strategies targeting MAMs to dissect treatment perspectives for AD.

Aiming at people cannot provide enough strength in lifting heavy objects， an urgent need of power supporting devices attached to the human body， a wearable elbow joint power mechanism with rigid and flexible coupling is proposed to provide assistance for the human body in the lifting process. It solves the problems that the traditional rigid mechanism is bulky and inflexible， and that flexible mechanisms have difficulty in supporting the weight of the human body. The configuration and characteristics of the mechanism are analyzed. The degree of freedom is calculated based on the screw theory， the closed vector method is used for position analysis. The Matlab is used to draw the change curve of flexible cable length and flexible cable tension to obtain the flexible cable length and tension at different angles. The workspace diagram is drawn， and the internal continuity of the workspace is obtained， which verify the correctness of the kinematics theory. The rigid flexible coupling elbow joint power assisted mechanism has good motion performance and can assist the elbow joint.

A 2-CRR/UPU parallel mechanism is proposed for apple sorting and packing. A kinematic spiral matrix of 2-CRR/UPU parallel mechanism is established，its degree of freedom is analyzed by the spiral theory，and a modified Kutzbach-Grübler formula is used for verification. Through the geometric relations of the mechanism，the inverse solution of the position of the mechanism is solved，and then the Jacobian matrix of the mechanism is derived and its velocity is analyzed. The workspace of the mechanism is solved by 3D dynamic search method. The singularity of the mechanism is analyzed by Jacobian matrix，and the distribution law of the dexterity index in the workspace is obtained. The 2-CRR/UPU parallel mechanism can carry out three translational motions，and the motion is stable，which can meet the action requirements of apple sorting and packing.

A kind of corn hill-seeder based on 4-CRR parallel mechanism is presented. The degree of freedom of the 4-CRR parallel mechanism is solved by using screw theory，and verified by using the modified Kutzbach-Grübler formula. The inverse position solution of the mechanism is solved by using equivalent plane projection method，and the Jacobian matrix of the mechanism is derived to analyze its velocity. The value range of rod length of 4-CRR parallel mechanism applied to hill-seeder is analyzed. The workspace of the mechanism with a rod length of 250 mm is solved by the limit boundary search method. The moving platform of the mechanism can realize translation movements along the three coordinate axis directions. The interior of the workspace is continuous，and a 300 mm×300 mm adjustable seeding area can be formed below the hill-seeder. The hill-seeder based on 4-CRR parallel mechanism can flexibly adjust the sowing position and change the planting density according to the different soil conditions in the field to achieve the effect of increasing yield and income of corn.

Spinal cord injury (SCI) is a global medical problem with high disability and mortality rates. At present, the diagnosis and treatment of SCI are still lacking. Spinal cord injury has a complex etiology, lack of diagnostic methods, poor treatment effect and other problems, which lead to the difficulty of spinal cord regeneration and repair, and poor functional recovery. Recent studies have shown that gene expression plays an important role in the regulation of SCI repair. MicroRNAs (miRNAs) are non-coding RNA molecules that target mRNA expression in order to silence, translate, or interfere with protein synthesis. Secondary damage, such as oxidative stress, apoptosis, autophagy, and inflammation, occurs after SCI, and differentially expressed miRNAs contribute to these events. This article reviews the pathophysiological mechanism of miRNAs in secondary injury after SCI, focusing on the mechanism of miRNAs in secondary neuroinflammation after SCI, so as to provide new ideas and basis for the clinical diagnosis and treatment of miRNAs in SCI. The mechanisms of miRNAs in neurological diseases may also make them potential biomarkers and therapeutic targets for spinal cord injuries.

Background. The clinical outcomes of low-grade glioma (LGG) are associated with T cell infiltration, but the specific contribution of heterogeneous T cell types remains unclear. Method. To study the different functions of T cells in LGG, we mapped the single-cell RNA sequencing results of 10 LGG samples to obtain T cell marker genes. In addition, bulk RNA data of 975 LGG samples were collected for model construction. Algorithms such as TIMER, CIBERSORT, QUANTISEQ, MCPCOUTER, XCELL, and EPIC were used to depict the tumor microenvironment landscape. Subsequently, three immunotherapy cohorts, PRJEB23709, GSE78820, and IMvigor210, were used to explore the efficacy of immunotherapy. Results. The Human Primary Cell Atlas was used as a reference dataset to identify each cell cluster; a total of 15 cell clusters were defined and cells in cluster 12 were defined as T cells. According to the distribution of T cell subsets (CD4+ T cell, CD8+ T cell, Naïve T cell, and Treg cell), we selected the differentially expressed genes. Among the CD4+ T cell subsets, we screened 3 T cell-related genes, and the rest were 28, 4, and 13, respectively. Subsequently, according to the T cell marker genes, we screened six genes for constructing the model, namely, RTN1, HERPUD1, MX1, SEC61G, HOPX, and CHI3L1. The ROC curve showed that the predictive ability of the prognostic model for 1, 3, and 5 years was 0.881, 0.817, and 0.749 in the TCGA cohort, respectively. In addition, we found that risk scores were positively correlated with immune infiltration and immune checkpoints. To this end, we obtained three immunotherapy cohorts to verify their predictive ability of immunotherapy effects and found that high-risk patients had better clinical effects of immunotherapy. Conclusion. This single-cell RNA sequencing combined with bulk RNA sequencing may elucidate the composition of the tumor microenvironment and pave the way for the treatment of low-grade gliomas.

Abstract Background The use of Oxford uni-compartmental knee arthroplasty (UKA) has rapidly increased worldwide,however,the relevance of younger patients for postoperative function after Oxford UKA remains unclear. The main purpose of our study is to clarify the effectivemess of Oxford UKA in the younger Chinese patients with anteromedial osteoarthritis (AMOA). Methods We retrospectively enrolled 252 consecutive patients who underwent Oxford UKA for AMOA with a minimum follow-up of 5 years between March 2013 and December 2016. The patients were divided into the younger (≤60 years) and elderly (> 60 years) age groups. The demographic data and surgery variables were recorded and compared. Patient satisfaction grade, range of motion (ROM), Oxford knee score (OKS), Hospital for Special Surgery (HSS) score, Western Ontario and McMaster (WOMAC) Universities Osteoarthritis Index score and postoperative complications were recorded. The 5-year survival of the implants were also compared with TKA revision as the endpoint. Results A total of 252 consecutive patients were recruited, including 96 aged 60 years or less and 156 aged over 60 years. The mean follow-up duration in the younger and elderly groups were 73.6 months (SD,standard deviation, 4.1) and 74.7 months (SD 6.2) respectively. Patient satisfaction rate was high in both groups (P = 0.805). Furthermore, no significant differences were observed in postoperative ROM(P = 0.299), OKS(P = 0.117), HSS(P = 0.357) and WOMAC scores(P = 0.151) between the younger and elderly groups (P>0.05). However, the incidence of joint stiffness (P = 0.033) and delayed wound dehiscence (P = 0.026) were significantly different between both groups. Five-year implant survival without revision were also similar in both groups (96.9% vs 97.4%, P = 0.871), and that for the entire cohort was 97.2% (95% CI 95.4–99.6). Conclusion Oxford UKA for AMOA demonstrated favorable results in younger patients aged ≤60 years at a minimum 5-year follow-up in terms of patient satisfaction, functional outcomes, implant survival and postoperative complications. Therefore, younger patients might not be considered as an absolute contraindication to Oxford UKA.

Quantifying the aggregation patterns of urban population, economic activities, and land use are essential for understanding compact development, but little is known about the difference among the distribution characteristics and how the built environment influences urban aggregation. In this study, five elements are collected in Wuhan, China, namely population density, floor area ratio, business POIs, road network and built-up area as the representative of urban population, economic activities and land use. An inverse S-shape function is employed to fit the elements’ macro distribution. An aggregation degree index is proposed to measure the aggregation level of urban elements. The kernel density estimation is used to identify the aggregation patterns. The spatial regression model is used to identify the built environment factors influencing the spatial distribution of urban elements. Results indicates that all urban elements decay outward from the city center in an inverse S-shape manner. The business Point-of-Interest (POI) density and population density are highly aggregated; floor area ratio and road density are moderately aggregated, whereas the built-up density is poorly aggregated. Three types of spatial aggregation patterns are identified: a point-shaped pattern, an axial pattern and a planar pattern. The spatial regression modeling shows that the built environment is associated with the distribution of the urban population, economic activities and land use. Destination accessibility factors, transit accessibility factors and land use diversity factors shape the distribution of the business POI density, floor area ratio and road density. Design factors are positively associated with population density, floor area ratio and built-up density. Future planning should consider the varying spatial concentration of urban population, economic activities and land use as well as their relationships with built environment attributes. Results of this study will provide a systematic understanding of aggregation of urban land use, population, and economic activities in megacities as well as some suggestions for planning and compact development.

Brachial plexus avulsion (BPA), which commonly occurs in neonatal birth injuries and car accidents, severely disrupts spinal cord segments and nerve roots. Avulsion is usually located in the transitional zone at the junction of spinal nerve roots and starting point of the spinal cord, which places heavy disability burdens on patients due to sensory and motor function loss in the innervated areas. Primary mechanical injuries and secondary pathogenesis, such as inflammatory infiltration and oxidative stress, lead to inefficient management and poor prognosis. Astaxanthin (AST) has a strong ability to bleach singlet oxygen and capture free radicals, quench singlet oxygen and trap free radicals, and folic acid (FC) can effectively inhibit the inflammatory response. This study aimed to investigate the therapeutic effects of AST and FC on BPA. The 24 h after BPA was considered the acute phase of the injury, and the combination of AST and FC had the best therapeutic effect due to the synergistic effect of AST’s antioxidant and FC’s anti-inflammatory properties. At 6 weeks after BPA, AST-FC promoted the recovery of biceps motor functions, increased myofiber diameter, enlarged the amplitude of musculocutaneous nerve-biceps compound action potential, and improved Terzis grooming test (TGT) scores. Meanwhile, more functional ventral horn motor neurons in the spinal cord were maintained. In conclusion, AST-FC combined therapy has a potential role in the clinical management of BPA since it can effectively alleviate oxidative stress and the inflammatory response in the acute phase of BPA, increase the survival rate of neurons, and promote neuronal regeneration and recovery of motor functions in the late stage of BPA.

Background: Spinal cord injury (SCI) is a common disorder of the central nervous system with considerable socio-economic burden. Andrographolide (Andro), the main active component of Andrographis paniculata, has exhibited neuroprotective effects in different models of neurological diseases. The aim of this study was to evaluate the neuroprotective effects of Andro against SCI and explore the related mechanisms.Methods: SCI was induced in rats by the Allen method, and the modeled animals were randomly divided into sham-operated, SCI, SCI + normal saline (NS) and SCI + Andro groups. The rats were injected intraperitoneally with Andro (1 mg/kg) or the same volume of NS starting day one after the establishment of the SCI model for 28 consecutive days. Post-SCI tissue repair and functional recovery were evaluated by measuring the spinal cord water content, footprint tests, Basso-Beattie-Bresnahan (BBB) scores, hematoxylin-eosin (HE) staining and Nissl staining. Apoptosis, oxidative stress and inflammation, as well as axonal regeneration and remyelination were analyzed using suitable markers. The in vitro model of SCI was established by treating cortical neurons with H2O2. The effects of Andro on apoptosis, oxidative stress and inflammation were evaluated as indicated.Results: Andro treatment significantly improved tissue repair and functional recovery after SCI by reducing apoptosis, oxidative stress and inflammation through the nuclear factor E2-related factor 2/heme oxygenase-1 (Nrf-2/HO-1) and nuclear factor-kappa B (NF-κB) signaling pathways. Furthermore, Andro treatment promoted M2 polarization of the microglial cells and contributed to axonal regeneration and remyelination to improve functional recovery after SCI. In addition, Andro also attenuated apoptosis, oxidative stress and inflammation in H2O2-stimulated cortical neurons in vitro.Conclusion: Andro treatment alleviated SCI by reducing apoptosis, oxidative stress and inflammation in the injured tissues and cortical neurons, and promoted axonal regeneration and remyelination for functional recovery.

Location information is the core data in IoT applications, which is the essential foundation for scene interpretation and interconnection of everything, and thus high-precision positioning is becoming an immediate need. However, the non-line-of-sight (NLOS) effect of indoor complex environment on UWB signal occlusion has been a major factor limiting the improvement in ultra-wideband (UWB) positioning accuracy, and the optimization of NLOS error has not yet been studied in a targeted manner. To this end, this paper deeply analyzes indoor scenes, divides NLOS into two forms of spatial occlusion and human occlusion, and proposes a particle filtering algorithm based on LOS/NLOS mapping and NLOS error optimization. This algorithm is targeted to optimize the influence of two different forms of NLOS, using spatial a priori information to accurately judge the LOS/NLOS situation of the anchor, optimizing the NLOS anchor ranging using IMU to project the virtual position, judging whether the LOS anchor is affected by human occlusion, and correcting the affected LOS anchor using the established human occlusion error model. Through experimental verification, the algorithm can effectively suppress two different NLOS errors of spatial structure and human occlusion and can achieve continuous and reliable high-precision positioning and tracking in complex indoor environments.

Abstract Background ALS patients have changed peripheral immunity. It is unknown whether peripheral immunity is related to cognitive dysfunction in ALS patients. Objective To explore the relationship between the peripheral blood lymphocyte subsets and the cognitive status in ALS patients. Methods Among 81 ALS patients, we compared the demographic, clinical, and peripheral levels of total T lymphocyte, CD4+ T lymphocyte, CD8+ T lymphocyte, B lymphocyte, and NK cell between those with cognitive impairment (ALS-ci) and those without (ALS-nci). The cognitive status was evaluated via the Chinese version of the Edinburgh cognitive and behavioral screen (ECAS). Significant predictors of cognitive impairment in univariate logistic regression analysis were further examined using multivariate logistic regression analysis. Results 39.5% of all ALS patients had cognitive impairment. The ALS-ci group had shorter education time, older age at both symptom onset and testing, longer disease duration, and lower levels of peripheral total, CD4+, and CD8+ T lymphocyte and B lymphocyte than the ALS-nci group. Frequency of behavioral impairment did not differ between the two groups. While parameters with significant differences identified by group comparison were also significant predictors of cognitive impairment in univariate logistic regression analysis except the level of B lymphocyte, only older age at testing, education time less than 9 years, and lower level of CD4+ T lymphocyte remained significant in multivariate logistic regression analysis. The predictive model combining these three parameters had an area under the receiver operating characteristic curve value of 0.842 with a sensitivity of 90.6% and a specificity of 67.3%. Conclusion In Chinese ALS patients, blood CD4+ T lymphocyte might help evaluate cognitive impairment along with age and education level.

Synaptic dysfunction is closely related to Alzheimer’s disease (AD) which is also recognized as synaptic disorder. β-amyloid (Aβ) is one of the main pathogenic factors in AD, which disrupts synaptic plasticity and mediates the synaptic toxicity through different mechanisms. Aβ disrupts glutamate receptors, such as NMDA and AMPA receptors, which mediates calcium dyshomeostasis and damages synapse plasticity characterized by long-term potentiation (LTP) suppression and long-term depression (LTD) enhancement. As Aβ stimulates and Ca2+ influx, microglial cells and astrocyte can be activated and release cytokines, which reduces glutamate uptake and further impair synapse function. Besides, extracellular glutamate accumulation induced by Aβ mediates synapse toxicity resulting from reduced glutamate receptors and glutamate spillovers. Aβ also mediates synaptic dysfunction by acting on various signaling pathways and molecular targets, disrupting mitochondria and energy metabolism. In addition, Aβ overdeposition aggravates the toxic damage of hyperphosphorylated tau to synapses. Synaptic dysfunction plays a critical role in cognitive impairment of AD. The review addresses the possible mechanisms by which Aβ mediates AD-related synaptic impairment from distant perspectives.

Purpose: Currently, the early diagnosis and treatment of osteoarthritis (OA) remain a challenge. In the present study, we attempted to explore potential biomarkers for the diagnosis and treatment of OA.Methods: The differentially expressed genes (DEGs) were identified based on three mRNA datasets of synovial tissues for OA patients and normal controls downloaded from the Gene Expression Omnibus (GEO) database. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were used for evaluating gene function related categories. Then, miRNA sequencing was performed for differentially expressed miRNAs’ identification. Finally, weighted gene co-expression network analysis (WGCNA) was performed for genes detected by the three mRNA datasets and a competing endogenous RNA (ceRNA) network with DEGs and differentially expressed microRNAs (miRNAs) was constructed for central genes identification. In addition, the relationship between central gene expression and immune infiltration was analyzed, and the candidate agents for OA were predicted based on the Connectivity Map database. Quantitative RT-PCR (qRT-PCR), Western blotting analysis, and immunofluorescent staining were performed to validate the expression levels of differentially expressed miRNAs and differentially expressed target genes in normal and OA tissues and chondrocytes. MiRNA–mRNA network was also validated in chondrocytes in vitro.Results: A total of 259 DEGs and 26 differentially expressed miRNAs were identified, among which 94 miRNA–mRNA interactions were predicted. The brown module in WGCNA was most closely correlated with the clinical traits of OA. After overlapping the brown module genes with miRNA–mRNA pairs, 27 miRNA–mRNA pairs were obtained. A ceRNA network was constructed with 5505 lncRNA–miRNA–mRNA interactions. B-cell translocation gene 2(BTG2), Abelson-related gene (ABL2), and vascular endothelial growth factor A (VEGFA) were identified to be the central genes with good predictive performance, which were significantly correlated with immune cell infiltration in OA, reflected by declined activated dendritic cells (aDCs), and elevated contents of B cells, macrophages, neutrophils, and T helper cells. Anisomycin, MG-132, thapsigargin, and lycorine were predicted to be the potential candidate agents for OA intervention. In vitro, the expression levels of differentially expressed miRNAs and biomarkers identified in the present study were consistent with the results obtained in normal or OA knee cartilage tissues and chondrocytes. Furthermore, BTG2 was identified to be negatively regulated by miR-125a-5p.Conclusion: BTG2, ABL2, and VEGFA can be regarded as potential predictive and treatment biomarkers for OA, which might guide the clinical therapy of OA.

Abstract Background Femoral neck fractures are common fractures in the elderly. Common treatment options include internal fixation (IF) and hemiarthroplasty (HA). However, the clinical application of these two options is always controversial due to the potential clinical trauma, postoperative function, early complications, and other factors. Materials and methods Randomized controlled trials and cohort studies comparing screw fixation and hemiarthroplasty in elderly patients with displaced femoral neck fractures were extracted from databases such as PubMed, Web of Science, EMBASE, and Cochrane. The revised Jadad scale or NOS treatment evaluation form was used to evaluate the quality of the included studies. After extracting the data, the standard deviation of continuous data and the relative risk of binary data were used. The operation time, blood loss during operation, EQ-5D (EuroQol-5 Dimension) score, mortality rate, reoperation rate, and postoperative common complications were reviewed using Review Manager software (RevMan 5.3) were compared. Results There were 7 randomized controlled trials and 5 cohort studies. The results showed that the operation time, intraoperative blood loss, and short-term EQ-5D score of the internal fixation group were lower than those of the hemi-hip replacement group, but the reoperation rate was higher. There was no statistically significant difference in mortality and common complications such as deep vein thrombosis, pulmonary embolism, infection, and pressure sores during short-term follow-up. Conclusions In the treatment of elderly femoral neck fractures, the screw internal fixation group has shorter operation time and less intraoperative bleeding, and the perioperative advantage is more obvious. However, the hemi-hip replacement group had more advantages in postoperative functional scoring and reoperation.

Acute kidney injury (AKI) leads to acute cardiac injury and dysfunction in cardiorenal syndrome Type 3 (CRS3) through oxidative stress (OS). The stress-inducible Sestrin2 (Sesn2) protein reduces reactive oxygen species (ROS) accumulation and activates AMP-dependent protein kinase (AMPK) to regulate cellular metabolism and energetics during OS. Sesn2 levels and its protective effects decline in the aged heart. Antidiabetic drug metformin upregulates Sesn2 levels in response to ischemia–reperfusion (IR) stress. However, the role of metformin in CRS3 remains unknown. This study seeks to explore how the age-related decrease in cardiac Sesn2 levels contributes to cardiac intolerance to AKI-induced insults, and how metformin ameliorates CRS3 through Sesn2. Young (3–5 months) and aged (21–23 months) C57BL/6J wild-type mice along with cardiomyocyte-specific knockout (cSesn2−/−) and their wild type of littermate (Sesn2f/f) C57BL/6J mice were subjected to AKI for 15 min followed by 24 h of reperfusion. Cardiac and mitochondrial functions were evaluated through echocardiograms and seahorse mitochondria respirational analysis. Renal and cardiac tissue was collected for histological analysis and immunoblotting. The results indicate that metformin could significantly rescue AKI-induced cardiac dysfunction and injury via Sesn2 through an improvement in systolic and diastolic function, fibrotic and cellular damage, and mitochondrial function in young, Sesn2f/f, and especially aged mice. Metformin significantly increased Sesn2 expression under AKI stress in the aged left-ventricular tissue. Thus, this study suggests that Sesn2 mediates the cardioprotective effects of metformin during post-AKI.

Ecosystems conservation is vital to social-economic and environmental sustainability. The relationship between ecosystems preservation and economic growth has been a popular topic worldwide. However, the economic effects of ecosystems preservation across multiple levels are unclear. This study analyzes the spatiotemporal characteristics of different ecosystems preservation, analyzing the correlations between ecosystem preservation and economic growth based on the method of “trading space for time”, extending a multilevel modeling to explore the overall and the regional differentiation in economic effects of ecosystems preservation at multi-levels in the coastal region in China during the period 2000–2015. Results show an overall decline in different ecosystems and an increase in green coverage rate and urban green space across the coastal region. With the same type of growth speed, the higher the economic output, the smaller the forest, wetland, and other ecosystems, and the larger the urban green space. Multilevel modeling regression revealed that economic growth is influenced by ecosystems preservation and effects of ecosystems preservation differentials vary substantially across regions. Wetland and forest ecosystems preservation played a negative role, whereas urban greening in cities played a positive role in overall urban economic growth and economic growth of surrounding or non-surrounding cities of the provincial capital. Furthermore, nature reserves preservation presented a negative association with economic growth at the provincial level. The heterogeneities of ecosystems along with economic growth stages is imperative, as is differentiating ecosystem preservation objectives across coastal regions. This study might help to develop theories of ecosystems preservation in economic growth and may fill the gap in which previous research ignored the multilevel effects of ecosystems preservation. Therefore, it provides good strategies to implement effective sustainable ecosystems management and sustainable regional economic growth.

Objective: Uric acid as an antioxidant plays an important role in neurodegenerative disease. Our objective is to investigate the relationship between plasma uric acid and cognitive impairment in patients with amyotrophic lateral sclerosis (ALS).Methods: In this cross-sectional study, 124 ALS patients were screened by the Edinburgh Cognitive and Behavioral Screen (ECAS) and classified according to the revised Strong's criteria. Additionally, based on total ECAS cut-off score patients were categorized into those with cognitive impairment (ALS-cie) and those without cognitive impairment (ALS-ncie), and clinical data and uric acid level were compared between the two groups. Parameters with significant differences were further included in a multivariate linear regression analysis with ECAS score as a dependent variable. Hold-out validation was performed to evaluate the fitness of regression model.Results: Up to 60% of ALS patients showed cognitive or/and behavioral impairment. The ALS-cie group had lower education level (p < 0.001), older age at symptom onset (p = 0.001), older age at testing (p = 0.001), and lower plasma uric acid (p = 0.01). Multivariate analysis showed increased uric acid (β = 0.214, p = 0.01), lower age at testing (β = −0.378, p < 0.001), and higher education level (β = 0.424, p < 0.001) could predict higher ECAS score (F = 19.104, R2 = 0.381, p < 0.0001). Validation analysis showed that predicted ECAS score was significantly correlated with raw ECAS score in both the training set (rs = 0.621, p < 0.001) and the testing set (rs = 0.666, p < 0.001).Conclusions: Cognitive impairment was a common feature in our Chinese ALS patients. Plasma uric acid might help evaluate the risk of cognitive impairment in ALS patients when combined with education level and age at testing.

Adult brachial plexus root avulsion can cause serious damage to nerve tissue and impair axonal regeneration, making the recovery of nerve function difficult. Nogo-A extracellular peptide residues 1-40 (NEP1-40) promote axonal regeneration by inhibiting the Nogo-66 receptor (NgR1), and poly (D, L-lactide-co-glycolide)-poly (ethylene glycol)-poly (D, L-lactide-co-glycolide) (PLGA-PEG-PLGA) hydrogel can be used to fill in tissue defects and concurrently function to sustain the release of NEP1-40. In this study, we established an adult rat model of brachial plexus nerve root avulsion injury and conducted nerve root replantation. PLGA-PEG-PLGA hydrogel combined with NEP1-40 was used to promote nerve regeneration and functional recovery in this rat model. Our results demonstrated that functional recovery was enhanced, and the survival rate of spinal anterior horn motoneurons was higher in rats that received a combination of PLGA-PEG-PLGA hydrogel and NEP1-40 than in those receiving other treatments. The combined therapy also significantly increased the number of fluorescent retrogradely labeled neurons, muscle fiber diameter, and motor endplate area of the biceps brachii. In conclusion, this study demonstrates that the effects of PLGA-PEG-PLGA hydrogel combined with NEP1-40 are superior to those of other therapies used to treat brachial plexus nerve root avulsion injury. Therefore, future studies should investigate the potential of PLGA-PEG-PLGA hydrogel as a primary treatment for brachial plexus root avulsion.

Obesity is of concern to the population because it is known to cause inflammation and oxidative stress throughout the body, leading to patient predisposition for health conditions such as diabetes, hypertension, and some cancers. However, some proteins that are activated in times of oxidative stress may provide cytoprotective properties. In this study, we aim to gain further understanding of the interconnection between Nrf2 and Sesn2 during obesity-related stress and how this relationship can play a role in cardio-protection. Cardiomyocyte-specific Sesn2 knockout (cSesn2−/−) and Sesn2 overexpressed (tTa-tet-Sesn2) mice and their wildtype littermates (Sesn2flox/flox and tet-Sesn2, respectively) were assigned to either a normal chow (NC) or a high-fat (HF) diet to induce obesity. After 16 weeks of dietary intervention, heart function was evaluated via echocardiography and cardiac tissue was collected for analysis. Immunoblotting, histology, and ROS staining were completed. Human heart samples were obtained via the LifeLink Foundation and were also subjected to analysis. Overall, these results indicated that the overexpression of Sesn2 appears to have cardio-protective effects on the obese heart through the reduction of ROS and fibrosis present in the tissues and in cardiac function. These results were consistent for both mouse and human heart samples. In human samples, there was an increase in Sesn2 and Nrf2 expression in the obese patients’ LV tissue. However, there was no observable pattern of Sesn2/Nrf2 expression in mouse LV tissue samples. Further investigation into the link between the Sesn2/Nrf2 pathway and obesity-related oxidative stress is needed.

Neurogenesis occurs in the brain during embryonic development and throughout adulthood. Neurogenesis occurs in the hippocampus and under normal conditions and persists in two regions of the brain—the subgranular zone (SGZ) in the dentate gyrus of the hippocampus and the subventricular zone (SVZ) of the lateral ventricles. As the critical role in neurogenesis, the neural stem cells have the capacity to differentiate into various cells and to self-renew. This process is controlled through different methods. The mammalian target of rapamycin (mTOR) controls cellular growth, cell proliferation, apoptosis, and autophagy. The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is a major regulator of metabolism, protein quality control, and antioxidative defense, and is linked to neurogenesis. However, dysregulation in neurogenesis, mTOR, and Nrf2 activity have all been associated with neurodegenerative diseases such as Alzheimer’s, Huntington’s, and Parkinson’s. Understanding the role of these complexes in both neurogenesis and neurodegenerative disease could be necessary to develop future therapies. Here, we review both mTOR and Nrf2 complexes, their crosstalk and role in neurogenesis, and their implication in neurodegenerative diseases.

Objective The clinical efficacy of platelet-rich plasma (PRP) in the treatment of osteoarthritis remains controversial. In this paper, we evaluated the clinical efficacy of PRP in the treatment of osteoarthritis using meta-analysis, providing evidence for the selection of clinical treatment options. Methods We performed a computer-based search of PubMed, Embase, and the Cochrane Library databases to retrieve articles using the search terms “platelet-rich plasma”, “osteoarthrosis”, and “knee joint”. Quality evaluation and data extraction were performed. The combined effect was assessed using RevMan 5.3 software. Results Five randomized controlled trials, involving 320 patients, were included in this study. No significant differences were observed in the International Knee Documentation Committee score, visual analog scale (VAS) score, or the absolute value of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score between the experimental and control groups. The absolute value of the VAS score and change in the WOMAC score were significantly decreased and patient satisfaction was increased in the experimental group, as compared with the control group. Conclusion The findings of this meta-analysis suggest that intra-articular injection of PRP is an effective treatment for osteoarthritis that can reduce post-operative pain, improve locomotor function, and increase patient satisfaction.

Abstract Background Synthetic indolyl- pyridinyl- propenones (IPPs) induce methuosis, a form of non-apoptotic cell death, in glioblastoma and other cancer cell lines. Methuosis is characterized by accumulation of cytoplasmic vacuoles derived from macropinosomes and late endosomes, followed by metabolic failure and rupture of the plasma membrane. However, not all IPPs that cause vacuolization are cytotoxic. The main goals of the present study were to identify key signaling pathways that contribute to methuosis induced by cytotoxic IPPs and to evaluate the anti-tumor potential of a prototype IPP in vivo. Methods We utilized metabolic flux analysis, glucose uptake, immunoblotting, and selective pharmacological inhibitors to compare the effects of closely related cytotoxic and non-cytotoxic IPPs in cultured glioblastoma cells. To determine whether the use of methuosis-inducing IPPs might be feasible in a therapeutic context, we quantified the distribution of our lead IPP compound, MOMIPP, in mouse plasma and brain, and tested its ability to inhibit tumor growth in an intracerebral glioblastoma xenograft model. Results The cytotoxic IPP compound, MOMIPP, causes early disruptions of glucose uptake and glycolytic metabolism. Coincident with these metabolic changes, MOMIPP selectively activates the JNK1/2 stress kinase pathway, resulting in phosphorylation of c-Jun, Bcl-2 and Bcl-xL. At the same concentration, the non-cytotoxic analog, MOPIPP, does not activate these pathways. Pharmacologic inhibition of JNK activity promotes survival, even when cells are extensively vacuolated, but suppression of c-Jun transcriptional activity offers no protection. MOMIPP readily penetrates the blood-brain barrier and is moderately effective in suppressing progression of intracerebral glioblastoma xenografts. Conclusions The results suggest that interference with glucose uptake and induction of JNK-mediated phosphorylation of pro-survival members of the Bcl-2 family represent key events in the methuosis death process. In addition to providing new insights into the underlying molecular mechanism of methuosis, the results indicate that compounds of the cytotoxic IPP class may have potential for further development as therapeutic agents for brain tumors.

Cognitive impairment and decline in old age are primarily driven by the accumulation of age-related neuropathologies, and old age is thus the primary risk factor for neurodegenerative diseases such as AD. Here, we investigated the effects of Yizhi Qingxin formula (YQF) extract on cognitive impairment in aged rats and determine the role of the brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) pathway underlying the neuroprotective effects of the YQF extract. Fifty male Wistar rats were randomly divided into five groups: Control group, Model group, Donepezil group, and YQF extract groups (treatment with YQF extract at two different doses). After treatment with YQF extract for 8 weeks, learning and cognitive abilities were assessed using the Morris water maze. Morphological changes in the hippocampus were observed using hematoxylin-eosin. Activated microglia and astrocytes were assessed using immunohistochemistry. Expressions of proteins and genes were examined using western blotting and real-time PCR. The results revealed that oral treatment with YQF extract dramatically improved spatial learning and memory ability and ameliorated histopathological and morphological characteristics in aged rats. YQF extract significantly increased acetylcholine and interleukin (IL)-10 levels but markedly decreased amyloid-β peptide, tumor necrosis factor alpha (TNFα), IL-2, and IL-6 levels. In addition, it inhibited the excessive activation of microglia and astrocytes, downregulated the expressions of TNFα and IL-2, and upregulated nerve growth factor, BDNF, and TrkB expressions. Furthermore, hippocampal extracellular signal-related kinase (Erk) and protein kinase B (Akt), the upstream signaling of BDNF/TrkB, were also activated by treatment with YQF extract. Our findings indicate that YQF extract activates the BDNF/TrkB pathway through the upregulation of Erk and Akt signaling, and the activated signaling pathway might contribute to the protective effects of YQF extract on cognitive impairment in aged rats.

Abstract Nitrate is not only an important nutrient but also a signaling molecule for plants. A few of key molecular components involved in primary nitrate responses have been identified mainly by forward and reverse genetics as well as systems biology, however, many underlining mechanisms of nitrate regulation remain unclear. In this study, we show that the expression of NRT1.1, which encodes a nitrate sensor and transporter (also known as CHL1 and NPF6.3), is modulated by NIN-like protein 7 (NLP7). Genetic and molecular analyses indicate that NLP7 works upstream of NRT1.1 in nitrate regulation when NH4+ is present, while in absence of NH4+, it functions in nitrate signaling independently of NRT1.1. Ectopic expression of NRT1.1 in nlp7 resulted in partial or complete restoration of nitrate signaling (expression from nitrate-regulated promoter NRP), nitrate content and nitrate reductase activity in the transgenic lines. Transcriptome analysis revealed that four nitrogen-related clusters including amino acid synthesis-related genes and members of NRT1/PTR family were modulated by both NLP7 and NRT1.1. In addition, ChIP and EMSA assays results indicated that NLP7 may bind to specific regions of the NRT1.1 promoter. Thus, NLP7 acts as an important factor in nitrate signaling via regulating NRT1.1 under NH4+ conditions.

Protein–protein interactions (PPIs) play a key role in signal transduction and pharmacogenomics, and hence, accurate PPI prediction is crucial. Graph structures have received increasing attention owing to their outstanding performance in machine learning. In practice, PPIs can be expressed as a signed network (i.e., graph structure), wherein the nodes in the network represent proteins, and edges represent the interactions (positive or negative effects) of protein nodes. PPI predictions can be realized by predicting the links of the signed network; therefore, the use of gated graph attention for signed networks (SN-GGAT) is proposed herein. First, the concept of graph attention network (GAT) is applied to signed networks, in which “attention” represents the weight of neighbor nodes, and GAT updates the node features through the weighted aggregation of neighbor nodes. Then, the gating mechanism is defined and combined with the balance theory to obtain the high-order relations of protein nodes to improve the attention effect, making the attention mechanism follow the principle of “low-order high attention, high-order low attention, different signs opposite”. PPIs are subsequently predicted on the Saccharomyces cerevisiae core dataset and the Human dataset. The test results demonstrate that the proposed method exhibits strong competitiveness.