Salvage of Iatrogenic Sciatic Nerve Injury Caused by Operatively Treated Acetabular Fractures: Two Cases and Literature Review.

BACKGROUND: While sciatic nerve injury has been described as a complication of acetabular fractures, iatrogenic nerve injury remains sparsely reported. This study aims to assess iatrogenic sciatic nerve injuries occurring during acetabular fracture surgery, tracking their neurological recovery and clinical outcomes, and investigating any correlation between recovery and the severity of neurologic injury to facilitate physicians in providing prediction of prognosis. CASE PRESENTATION: We present two cases of male patients, aged 56 and 22, who developed sciatic palsy due to iatrogenic nerve injury during acetabular fracture surgery. Iatrogenic sciatic nerve injury resulted from operatively treated acetabular fractures. Surgical exploration, involving internal fixation removal and nerve decompression, successfully alleviated symptoms in both cases postoperatively. At the latest follow-up, one patient achieved full recovery with excellent function, while the other exhibited residual deficits at the L5/S1 root level along with minimal pain. CONCLUSION: Sciatic nerve injury likely stemmed from reduction techniques and internal fixation procedures for the posterior column, particularly when performed with the hip flexed, thereby placing tension on the sciatic nerve. Our case reports underscore the significance of liberal utilization of electrophysiologic examinations and intraoperative monitoring for the prediction of prognosis. Surgical exploration, encompassing internal fixation removal and nerve decompression, represents an effective intervention for resolving sciatic palsy, encompassing both sensory neuropathy and motor symptoms.

Pro-CRISPR PcrIIC1-associated Cas9 system for enhanced bacterial immunity.

The CRISPR system is an adaptive immune system found in prokaryotes that defends host cells against the invasion of foreign DNA1. As part of the ongoing struggle between phages and the bacterial immune system, the CRISPR system has evolved into various types, each with distinct functionalities2. Type II Cas9 is the most extensively studied of these systems and has diverse subtypes. It remains uncertain whether members of this family can evolve additional mechanisms to counter viral invasions3,4. Here we identify 2,062 complete Cas9 loci, predict the structures of their associated proteins and reveal three structural growth trajectories for type II-C Cas9. We found that novel associated genes (NAGs) tended to be present within the loci of larger II-C Cas9s. Further investigation revealed that CbCas9 from Chryseobacterium species contains a novel ß-REC2 domain, and forms a heterotetrameric complex with an NAG-encoded CRISPR-Cas-system-promoting (pro-CRISPR) protein of II-C Cas9 (PcrIIC1). The CbCas9-PcrIIC1 complex exhibits enhanced DNA binding and cleavage activity, broader compatibility for protospacer adjacent motif sequences, increased tolerance for mismatches and improved anti-phage immunity, compared with stand-alone CbCas9. Overall, our work sheds light on the diversity and 'growth evolutionary' trajectories of II-C Cas9 proteins at the structural level, and identifies many NAGs-such as PcrIIC1, which serves as a pro-CRISPR factor to enhance CRISPR-mediated immunity.

Hardware implementation of memristor-based artificial neural networks.

Artificial Intelligence (AI) is currently experiencing a bloom driven by deep learning (DL) techniques, which rely on networks of connected simple computing units operating in parallel. The low communication bandwidth between memory and processing units in conventional von Neumann machines does not support the requirements of emerging applications that rely extensively on large sets of data. More recent computing paradigms, such as high parallelization and near-memory computing, help alleviate the data communication bottleneck to some extent, but paradigm- shifting concepts are required. Memristors, a novel beyond-complementary metal-oxide-semiconductor (CMOS) technology, are a promising choice for memory devices due to their unique intrinsic device-level properties, enabling both storing and computing with a small, massively-parallel footprint at low power. Theoretically, this directly translates to a major boost in energy efficiency and computational throughput, but various practical challenges remain. In this work we review the latest efforts for achieving hardware-based memristive artificial neural networks (ANNs), describing with detail the working principia of each block and the different design alternatives with their own advantages and disadvantages, as well as the tools required for accurate estimation of performance metrics. Ultimately, we aim to provide a comprehensive protocol of the materials and methods involved in memristive neural networks to those aiming to start working in this field and the experts looking for a holistic approach.

Programming memristor arrays with arbitrarily high precision for analog computing.

In-memory computing represents an effective method for modeling complex physical systems that are typically challenging for conventional computing architectures but has been hindered by issues such as reading noise and writing variability that restrict scalability, accuracy, and precision in high-performance computations. We propose and demonstrate a circuit architecture and programming protocol that converts the analog computing result to digital at the last step and enables low-precision analog devices to perform high-precision computing. We use a weighted sum of multiple devices to represent one number, in which subsequently programmed devices are used to compensate for preceding programming errors. With a memristor system-on-chip, we experimentally demonstrate high-precision solutions for multiple scientific computing tasks while maintaining a substantial power efficiency advantage over conventional digital approaches.

P2/O3 Biphasic Cathode Material through Magnesium Substitution for Sodium-Ion Batteries.

P2-type Fe-Mn-based oxides offer excellent discharge specific capacity and are as affordable as typical layered oxide cathode materials for sodium-ion batteries (SIBs). After Cu modification, though they can improve the cycling performance and air stability, the discharge specific capacity will be reduced. Considering the complementary nature of biphasic phases in electrochemistry, hybridizing P2/O3 hybrid phases can enhance both the storage performance of the battery and specific capacity. Herein, a hybrid phase composite with high capacity and good cycle performance is deliberately designed and successfully prepared by controlling the amount of Mg doping in the layered oxide. It has been found that the introduction of Mg can activate anion redox in the oxide layer, resulting in a significant increase in the specific discharge capacity of the material. Meanwhile, the dual-phase structure can produce an interlocking effect, thus effectively alleviating structure strain. The degradation of cycling performance caused by structural damage during the high-voltage charging and discharging process is clearly mitigated. The results show that the specific discharge capacity of Na0.67Cu0.2Mg0.1Fe0.2Mn0.5O2 is as high as 212.0 mAh g-1 at 0.1C rate and 186.2 mAh g-1 at 0.2C rate. After 80 cycles, the capacity can still maintain 88.1%. Moreover, the capacity and cycle performance as well as the stability can still remain stable even in the high-voltage window. Therefore, this work offers an insightful exploration for the development of composite cathode materials for SIBs.

The adaptor protein 14-3-3zeta modulates intestinal immunity and aging in Drosophila.

The proteins that coordinate the complex transcriptional networks of aging have not been completely documented. Protein 14-3-3zeta is an adaptor protein that coordinates signaling and transcription factor networks, but its function in aging is not fully understood. Here, we showed that the protein expression of 14-3-3zeta gradually increased during aging. High levels of 14-3-3zeta led to shortened lifespan and imbalance of intestinal immune homeostasis in Drosophila, but the decrease in 14-3-3zeta protein levels by RNAi was able to significantly promote the longevity and intestinal immune homeostasis of fruit flies. Importantly, we demonstrate that adult-onset administration of TIC10, a compound that reduces the aging-related AKT and extracellular signal-regulated kinase (ERK) signaling pathways, rescues the shortened lifespan of 14-3-3zeta-overexpressing flies. This finding suggests that 14-3-3zeta plays a critical role in regulating the aging process. Our study elucidates the role of 14-3-3zeta in natural aging and provides the rationale for subsequent 14-3-3zeta-based antiaging research.

Three-dimensional printing versus traditional surgery for inveterate pelvic and acetabular fractures: A retrospective study of 37 patients.

Treatment of deformed pelvic and acetabular fractures is a considerable challenge for orthopedic surgeons. The aim of this study was to assess the availability of a three-dimensional (3D) printing model used in patients with inveterate pelvic and acetabular fractures by comparing 3D printing technology with conventional surgery. We conducted a retrospective review of patients with inveterate pelvic and acetabular fractures treated in our department between January 2008 and June 2020. The patients were divided into 2 groups according to their willingness. Perioperative data and clinical outcomes were compared to evaluate clinical efficacy. The t-test, Fisher exact test, and multivariable logistic regression analysis were conducted. A P value of .05 or less was considered to be statistically significant (two-tailed). Thirty-seven patients were enrolled in our study. Seventeen patients were divided into the case group treated by 3D printing model-assisted preoperative planning, and 20 patients were divided into the control group treated by conventional surgery. Patients treated with the 3D printing model had significantly shorter operation times, less blood loss, and shorter fluoroscopy times. Patients in the case group also showed better pain relief according to visual analog scale scores. However, the elevations in pelvis and hip joint functional outcomes were similar between the 2 groups, and no significant difference was shown in the radiological result. The usage of 3D printing techniques in patients with inveterate pelvic and acetabular fractures is of great importance in preoperative preparation and optimization of surgery but cannot improve postoperative function compared with conventional treatment.

Management and Outcome of Elderly Patients With Patellar Fracture Treated With Novel Modified Cerclage Wiring.

Introduction: The purpose of this study is to assess the efficacy and security of a fixation method for fixing patellar fractures in elderly patients utilizing modified cerclage wire. Methods: From January 2015 to December 2020, 31 cases (age≥65 years old) of closed patellar fracture were treated by modified cerclage wiring. Patients in these instances ranged in age from 65 to 87 (73.7 ± 7.2 years), with 15 men and 16 women. 4 instances were type 34-C1 (transverse fracture) according to the AO/OTA classification, 27 cases (87%) were comminuted fractures, including 11 cases that were type 34-C2 (3 fragments), and 16 cases that were type 34-C3 (more than 3 fragments). Postoperative problems such as fragment re-displacement, nonunion, internal fixation loosening, infection, and internal fixation rupture were evaluated. The clinical grading systems of Böstman were used to assess the postoperative clinical outcomes. Results: Thirty one patients in all were monitored for 14 to 31 months (22.2 ± 4.5 months). After the procedure, the fracture took 2.5-3.5 months (2.92 ± .25 months) to heal. There were no postoperative issues like infection, dislocation, implant breakage, uncomfortable hardware, or post-traumatic osteoarthritis. According to the clinical grading scales of Böstman, the average score of the final follow-up was 28.6 ± 1.1 (range 26-30). 29 (94%) of the patients had excellent results, whereas just 2 (6%) had good results. The patient's knee flexion activity ranged from 110 to 140°, making for a favorable prognosis. Conclusion: Most patella fractures in the elderly are comminuted. Elderly patients with patellar fractures may be successfully treated with modified cerclage wire, with good results and no noticeable side effects.

Trans-olecranon fracture posterior dislocation: a novel type of elbow injury.

BACKGROUND: Based on our experiences, we found that a kind of elbow injury is characterized by an olecranon fracture accompanied by elbow joint posterior dislocation with the proximal radioulnar joint intact. The aim of this study was to better define this kind of severe elbow instability, which has not been previously reported. METHODS: We retrospectively analyzed all patients with olecranon fractures who were treated at our institution from January 2013 to April 2021. Data on these patient demographics, injury characteristics, preoperative and postoperative imaging, surgical management, and outcomes were recorded and analyzed. We also made the inclusion criteria and exclusion criteria. RESULTS: A total of 309 patients were diagnosed olecranon fractures in our institution, and ten patients met the inclusion criteria, 9 males and 1 female, with an average age of 40.6 ± 12.7 years (26-68 years). Eight patients (80%) were comminuted, and two were oblique olecranon fracture. Nine patients (90%) suffered coronoid process fractures, eight fractures were type III, and one was type II. Eight patients (80%) suffered radial head fractures, seven fractures were type II, and one was type III. All patients suffered lateral collateral ligament complex injury. All patients underwent surgical management and were followed up on average for 15.8 ± 3.2 months (12-20 months). The motion of the elbow and functional outcome were evaluated with several methods. The mean arc of the elbow movement was 131.6° ± 6.0° (124°-140°), and the mean arc of the forearm rotation was 158.5° ± 17.8° (128°-180°). Nine patients' functional results according to the Mayo Elbow Performance Score (MEPS) were excellent with a mean score of 96.5 ± 5.3 points (85-100 points), and another was good. The mean score according to the Broberg and Morrey functional rating index was 98.8 ± 2.5 points (92-100 points), nine patients were excellent, and another was good. The mean Disabilities of the Arm, Shoulder, and Hand (DASH) score was 0.75 ± 1.2 points (0-3.3 points). CONCLUSIONS: Trans-olecranon fracture posterior dislocation is a rare injury and has unique characteristics, and it is a kind of complex elbow instability involving the coronoid process and radial head fractures. After bony structure is restored, the repairment of lateral collateral ligament complex is also important to the stability of the elbow joint. Correct understanding of this kind of injury and reasonable treatment plan can achieve good function.

Thousands of conductance levels in memristors integrated on CMOS.

Neural networks based on memristive devices1-3 have the ability to improve throughput and energy efficiency for machine learning4,5 and artificial intelligence6, especially in edge applications7-21. Because training a neural network model from scratch is costly in terms of hardware resources, time and energy, it is impractical to do it individually on billions of memristive neural networks distributed at the edge. A practical approach would be to download the synaptic weights obtained from the cloud training and program them directly into memristors for the commercialization of edge applications. Some post-tuning in memristor conductance could be done afterwards or during applications to adapt to specific situations. Therefore, in neural network applications, memristors require high-precision programmability to guarantee uniform and accurate performance across a large number of memristive networks22-28. This requires many distinguishable conductance levels on each memristive device, not only laboratory-made devices but also devices fabricated in factories. Analog memristors with many conductance states also benefit other applications, such as neural network training, scientific computing and even 'mortal computing'25,29,30. Here we report 2,048 conductance levels achieved with memristors in fully integrated chips with 256 × 256 memristor arrays monolithically integrated on complementary metal-oxide-semiconductor (CMOS) circuits in a commercial foundry. We have identified the underlying physics that previously limited the number of conductance levels that could be achieved in memristors and developed electrical operation protocols to avoid such limitations. These results provide insights into the fundamental understanding of the microscopic picture of memristive switching as well as approaches to enable high-precision memristors for various applications. Fig. 1 HIGH-PRECISION MEMRISTOR FOR NEUROMORPHIC COMPUTING.: a, Proposed scheme of the large-scale application of memristive neural networks for edge computing. Neural network training is performed in the cloud. The obtained weights are downloaded and accurately programmed into a massive number of memristor arrays distributed at the edge, which imposes high-precision requirements on memristive devices. b, An eight-inch wafer with memristors fabricated by a commercial semiconductor manufacturer. c, High-resolution transmission electron microscopy image of the cross-section view of a memristor. Pt and Ta serve as the bottom electrode (BE) and top electrode (TE), respectively. Scale bars, 1 µm and 100 nm (inset). d, Magnification of the memristor material stack. Scale bar, 5 nm. e, As-programmed (blue) and after-denoising (red) currents of a memristor are read by a constant voltage (0.2 V). The denoising process eliminated the large-amplitude RTN observed in the as-programmed state (see Methods). f, Magnification of three nearest-neighbour states after denoising. The current of each state was read by a constant voltage (0.2 V). No large-amplitude RTN was observed, and all of the states can be clearly distinguished. g, An individual memristor on the chip was tuned into 2,048 resistance levels by high-resolution off-chip driving circuitry, and each resistance level was read by a d.c. voltage sweeping from 0 to 0.2 V. The target resistance was set from 50 µS to 4,144 µS with a 2-µS interval between neighbouring levels. All readings at 0.2 V are less than 1 µS from the target conductance. Bottom inset, magnification of the resistance levels. Top inset, experimental results of an entire 256 × 256 array programmed by its 6-bit on-chip circuitry into 64 32 × 32 blocks, and each block is programmed into one of the 64 conductance levels. Each of the 256 × 256 memristors has been previously switched over one million cycles, demonstrating the high endurance and robustness of the devices.

Memristive Field-Programmable Analog Arrays for Analog Computing.

The increasing interests in analog computing nowadays call for multipurpose analog computing platforms with reconfigurability. The advancement of analog computing, enabled by novel electronic elements like memristors, has shown its potential to sustain the exponential growth of computing demand in the new era of analog data deluge. Here, a platform of a memristive field-programmable analog array (memFPAA) is experimentally demonstrated with memristive devices serving as a variety of core analog elements and CMOS components as peripheral circuits. The memFPAA is reconfigured to implement a first-order band pass filter, an audio equalizer, and an acoustic mixed frequency classifier, as application examples. The memFPAA, featured with programmable analog memristors, memristive routing networks, and memristive vector-matrix multipliers, opens opportunities for fast prototyping analog designs as well as efficient analog applications in signal processing and neuromorphic computing.

The Behavior-Driven Mechanism of Consumer Participation in "Carbon Neutrality": Based on the Promotion of Replacing Coal with Biomass Briquette Fuel.

"replacing coal with biomass briquette fuel" can effectively reduce carbon emissions. This study takes this as an example to discuss consumers' "willingness to consume (WTC)", "willingness to spend (WTS)" and related influencing factors to find the behavior-driven mechanism of consumer participation in "carbon neutrality". Through the survey and analysis, the results show that 81.64% of the respondents support to consume Biomass Briquette Fuel (BBF) to replace coal. The annual WTS is 157.78 CNY per capita. The factors, such as the education, the relevant government policy support cognition, the level of cognition of health concepts, ecological environmental protection and resource regeneration, have a significant positive impact on the promotion in rural areas. Finally, we put forward corresponding policy recommendations. It provides a reference for motivating consumers to participate in "carbon neutrality" and promoting rural energy transformation to achieve the goal of "carbon neutrality".

Low-Light Image Enhancement Based on Constraint Low-Rank Approximation Retinex Model.

Images captured in a low-light environment are strongly influenced by noise and low contrast, which is detrimental to tasks such as image recognition and object detection. Retinex-based approaches have been continuously explored for low-light enhancement. Nevertheless, Retinex decomposition is a highly ill-posed problem. The estimation of the decomposed components should be combined with proper constraints. Meanwhile, the noise mixed in the low-light image causes unpleasant visual effects. To address these problems, we propose a Constraint Low-Rank Approximation Retinex model (CLAR). In this model, two exponential relative total variation constraints were imposed to ensure that the illumination is piece-wise smooth and that the reflectance component is piece-wise continuous. In addition, the low-rank prior was introduced to suppress the noise in the reflectance component. With a tailored separated alternating direction method of multipliers (ADMM) algorithm, the illumination and reflectance components were updated accurately. Experimental results on several public datasets verify the effectiveness of the proposed model subjectively and objectively.

Family Networks, Social Networks, and Life Satisfaction of Older Adults in China.

Older adults' family networks and social networks are important factors that influence life satisfaction, but their transmission mechanisms have not been adequately discussed. The objective of this study was to examine the mechanisms through which family networks and social networks influence the life satisfaction of older adults. We empirically examined the effects and mechanisms of older adults' family networks and social networks on their life satisfaction using the 2018 China Longitudinal Aging Social Survey with a sample size of 11,418 older adults aged 60 years and older. In the research sample, 6.47% of older adults were subjected to at least one form of mistreatment. The research results indicate that family networks (ß = 0.0060, p < 0.05) and social networks (ß = 0.0122, p < 0.01) have a significant positive effect on older adults' life satisfaction. The mechanism-of-action test found that family networks and social networks enhance older adults' life satisfaction, mainly by reducing the level of physical mistreatment they experience, but these networks cannot improve the life satisfaction of the elderly by reducing their emotional mistreatment. Further research found that community-provided medical escorts, home chores, and meal delivery services can all alleviate the decline in life satisfaction among older adults due to emotional mistreatment. This study deepens our understanding of how older adults' family and social networks affect their life satisfaction as we examine the mediating role of the physical and emotional mistreatment of older adults and discuss the effects of potential policy interventions.

Let the Farmers Embrace "Carbon Neutrality": Taking the Centralized Biogas as an Example.

The promotion of rural centrally produced biogas (CPB) is an effective carbon neutrality development solution in rural areas. How to better encourage farmers to adopt such products is an important part of the sustainable development of a project. For this reason, focus is needed on the "willingness to embrace (WTE)" and "Willingness to motivate (WTM)" of rural residents for CPB projects and their influencing factors. We chose to conduct questionnaire surveys in rural areas of the Hebei and Shandong provinces of China, using the contingent valuation method (CVM). The results show that 85% of the respondents support CPB. Compared with urban gas, the subsidy demand of rural residents for CPB is 56.78%. The influencing factors of the residents' WTE are affected by the number of children in the family, whether the village cadres are installed in the family, solar water heaters installed in the family, knowledge and attitudes towards environmental protection, and the embracing of daily energy habits. The influencing factors on the residents' WTM are age, education level, ownership of arable land, knowledge of environmental protection, etc. Therefore, we propose policy recommendations. First, we must fully understand the willingness and demands of farmers, adopt a reasonable compensation response mechanism, and scientifically calculate financial inputs. The second step is to guide farmers through multi-channel publicity. Third, we aim to improve project operation efficiency, reduce operating costs, and minimize the government's financial burden on the basis of ensuring that farmers' demands are considered in a coordinated manner.

The etiology of poststroke-depression: a hypothesis involving HPA axis.

Approximately, one in three ischemic stroke survivors suffered from depression, namely, post-stroke depression (PSD). PSD affects functional rehabilitation and may lead to poor quality of life of patients. There are numerous explanations about the etiologies of PSD. Here, we speculated that PSD are likely to be the result of specific changes in brain pathology. We hypothesized that the stroke-induced hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis plays an important role in PSD. Stroke initiates a complex sequence of events in neuroendocrine system including HPA axis. The HPA axis is involved in the pathophysiology of depression, especially, the overactivity of the HPA axis occurs in major depressive disorder. This review summarizes the possible etiologies of PSD, focusing on the stroke-induced activation of HPA axis, mainly including the stress followed by severe brain damage and the proinflammatory cytokines release. The role of hyperactive of HPA axis in PSD was discussed in detail, which includes the role of high level corticotropin-releasing hormone in PSD, the effects of glucocorticoids on the alterations in specific brain structures, the expression of enzymes, excitotoxicity, the change in intestinal permeability, and the activation of microglia. The relationship between neuroendocrine regulation and inflammation was also described. Finally, the therapy of PSD by regulating HPA axis, neuroendocrine, and immunity was discussed briefly. Nevertheless, the change of HPA axis and the occurring of PSD maybe interact and promote on each other, and future investigations should explore this hypothesis in more depth.

Meldonium Ameliorates Hypoxia-Induced Lung Injury and Oxidative Stress by Regulating Platelet-Type Phosphofructokinase-Mediated Glycolysis.

Hypoxic environments at high altitudes influence the long-term non-altitude health of residents, by inducing changes in metabolism and the mitochondria, severe lung injury, and endangering life. This study was aimed to determine whether meldonium can ameliorate hypoxia-induced lung injury and investigate its possible molecular mechanisms. We used Swiss mice and exposed type Ⅱ alveolar epithelial cell to hypobaric hypoxic conditions to induce lung injury and found that meldonium has significant preventive effect, which was associated with the regulation of glycolysis. We found using human proteome microarrays assay, molecular docking, immunofluorescence and pull-down assay that the target protein of meldonium is a platelet-type phosphofructokinase (PFKP), which is a rate-limiting enzyme of glycolysis. Also, meldonium promotes the transfer of nuclear factor erythroid 2-related factor 2 (Nrf2) from the cytoplasm to the nucleus, which mitigates oxidative stress and mitochondrial damage under hypoxic condition. Mechanistically, meldonium ameliorates lung injury by targeting PFKP to regulate glycolysis, which promotes Nrf2 translocation from the cytoplasm to the nucleus to alleviate oxidative stress and mitochondrial damage under hypoxic condition. Our study provides a novel potential prevention and treatment strategy against hypoxia-induced lung injury.

Do China's Urban-Environmental Quality and Economic Growth Conform to the Environmental Kuznets Curve?

The environmental Kuznets curve (EKC) expresses the relationship between environmental quality and economic growth. Based on the defects of previous studies on EKC using only environmental pollution indicators, this study holds that environmental quality is the result of pollutants after treatment, absorption, and self-purification, including two dimensions of pollution and absorption. Therefore, the environmental pollution and absorption data of 74 key environmental monitoring cities in China from 2005 to 2017 were selected, and a comprehensive index of environmental quality was constructed using the vertical and horizontal grading method. Then, based on the relevant economic growth indicators of these cities, they were divided into first-tier and new first-tier, second-tier, third-tier, and below. It was found that the EKC of the total sample, the first-tier and new first-tier cities, and the second-tier cities presented an inverted N-shape and had passed the second inflection point, where environmental quality continues to improve with the deepening of economic growth. There was no EKC in the third-tier and below cities. The findings have important implications. China can cross the second inflection point of the EKC and improve environmental quality at a low income level. Therefore, by vigorously developing cleaner production technologies and raising residents' awareness of environmental protection, it is possible to improve environmental quality at a lower income level than expected, which provides a useful reference for other developing countries.

14-3-3 epsilon is an intracellular component of TNFR2 receptor complex and its activation protects against osteoarthritis.

OBJECTIVES: Osteoarthritis (OA) is the most common joint disease; however, the indeterminate nature of mechanisms by which OA develops has restrained advancement of therapeutic targets. TNF signalling has been implicated in the pathogenesis of OA. TNFR1 primarily mediates inflammation, whereas emerging evidences demonstrate that TNFR2 plays an anti-inflammatory and protective role in several diseases and conditions. This study aims to decipher TNFR2 signalling in chondrocytes and OA. METHODS: Biochemical copurification and proteomics screen were performed to isolate the intracellular cofactors of TNFR2 complex. Bulk and single cell RNA-seq were employed to determine 14-3-3 epsilon (14-3-3ε) expression in human normal and OA cartilage. Transcription factor activity screen was used to isolate the transcription factors downstream of TNFR2/14-3-3ε. Various cell-based assays and genetically modified mice with naturally occurring and surgically induced OA were performed to examine the importance of this pathway in chondrocytes and OA. RESULTS: Signalling molecule 14-3-3ε was identified as an intracellular component of TNFR2 complexes in chondrocytes in response to progranulin (PGRN), a growth factor known to protect against OA primarily through activating TNFR2. 14-3-3ε was downregulated in OA and its deficiency deteriorated OA. 14-3-3ε was required for PGRN regulation of chondrocyte metabolism. In addition, both global and chondrocyte-specific deletion of 14-3-3ε largely abolished PGRN's therapeutic effects against OA. Furthermore, PGRN/TNFR2/14-3-3ε signalled through activating extracellular signal-regulated kinase (ERK)-dependent Elk-1 while suppressing nuclear factor kappa B (NF-κB) in chondrocytes. CONCLUSIONS: This study identifies 14-3-3ε as an inducible component of TNFR2 receptor complex in response to PGRN in chondrocytes and presents a previously unrecognised TNFR2 pathway in the pathogenesis of OA.

The genetic mechanism of heterosis utilization in maize improvement.

BACKGROUND: In maize hybrid breeding, complementary pools of parental lines with reshuffled genetic variants are established for superior hybrid performance. To comprehensively decipher the genetics of heterosis, we present a new design of multiple linked F1 populations with 42,840 F1 maize hybrids, generated by crossing a synthetic population of 1428 maternal lines with 30 elite testers from diverse genetic backgrounds and phenotyped for agronomic traits. RESULTS: We show that, although yield heterosis is correlated with the widespread, minor-effect epistatic QTLs, it may be resulted from a few major-effect additive and dominant QTLs in early developmental stages. Floral transition is probably one critical stage for heterosis formation, in which epistatic QTLs are activated by paternal contributions of alleles that counteract the recessive, deleterious maternal alleles. These deleterious alleles, while rare, epistatically repress other favorable QTLs. We demonstrate this with one example, showing that Brachytic2 represses the Ubiquitin3 locus in the maternal lines; in hybrids, the paternal allele alleviates this repression, which in turn recovers the height of the plant and enhances the weight of the ear. Finally, we propose a molecular design breeding by manipulating key genes underlying the transition from vegetative-to-reproductive growth. CONCLUSION: The new population design is used to dissect the genetic basis of heterosis which accelerates maize molecular design breeding by diminishing deleterious epistatic interactions.