Improving resilience to high temperature in drought: water replenishment enhances sucrose and amino acid metabolisms in maize grain.

Heat stress poses a significant threat to maize, especially when combined with drought. Recent research highlights the potential of water replenishment to ameliorate grain weight loss. However, the mitigating mechanisms of heat in drought stress, especially during the crucial early grain-filling stage, remain poorly understood. We investigated the mechanism for mitigating heat in drought stress by water replenishment from the 12th to the 32nd days after silking in a controlled greenhouse experiment (Exp. I) and field trial (Exp. II). A significant reduction in grain weight was observed in heat stress compared to normal conditions. When water replenishment was applied to increase soil water content (SWC) under heat stress, the grain yield exhibited a notable increase ranging from 28.4 to 76.9%. XY335 variety was used for transcriptome sequencing to analyze starch biosynthesis and amino acid metabolisms in Exp. I. With water replenishment, the transcripts of genes responsible for trehalose 6-phosphate phosphates (TPP), alpha-trehalase (TRE), ADP-glcpyrophosphorylase, and starch synthase activity were stimulated. Additionally, the expression of genes encoding TPP and TRE contributed to an enhanced conversion of trehalose to glucose. This led to the conversion of sucrose from glucose-1-phosphate to ADP-glucose and ADP-glucose to amylopectin, ultimately increasing starch production by 45.1%. Water replenishment to boost SWC during heat stress also elevated the levels of essential amino acids in maize, including arginine, serine, tyrosine, leucine, glutamic acid, and methionine, providing valuable support to maize plants in adversity. Field trials further validated the positive impact of water replenishment on SWC, resulting in a notable increase in grain yield ranging from 7.1 to 9.2%. This study highlights the vital importance of adapting to abiotic stress and underscores the necessity of developing strategies to counteract its adverse effects on crop yield.

Research progress and perspective of metallic implant biomaterials for craniomaxillofacial surgeries.

Craniomaxillofacial bone serves a variety of functions. However, the increasing number of cases of craniomaxillofacial bone injury and the use of selective rare implants make the treatment difficult, and the cure rate is low. If such a bone injury is not properly treated, it can lead to a slew of complications that can seriously disrupt a patient's daily life. For example, premature closure of cranial sutures or skull fractures can lead to increased intracranial pressure, which can lead to headaches, vomiting, and even brain hernia. At present, implant placement is one of the most common approaches to repair craniomaxillofacial bone injury or abnormal closure, especially with biomedical metallic implants. This review analyzes the research progress in the design and development of degradable and non-degradable metallic implants in craniomaxillofacial surgery. The mechanical properties, corrosion behaviours, as well as in vitro and in vivo performances of these materials are summarized. The challenges and future research directions of metallic biomaterials used in craniomaxillofacial surgery are also identified.

A novel marker integrating multiple genetic alterations better predicts platinum sensitivity in ovarian cancer than HRD score.

Introduction: Platinum-based chemotherapy is the first-line treatment strategy for ovarian cancer patients. The dismal prognosis of ovarian cancer was shown to be stringently associated with the heterogeneity of tumor cells in response to this therapy, therefore understanding platinum sensitivity in ovarian cancer would be helpful for improving patients' quality of life and clinical outcomes. HRDetect, utilized to characterize patients' homologous recombination repair deficiency, was used to predict patients' response to platinum-based chemotherapy. However, whether each of the single features contributing to HRD score is associated with platinum sensitivity remains elusive. Methods: We analyzed the whole-exome sequencing data of 196 patients who received platinum-based chemotherapy from the TCGA database. Genetic features were determined individually to see if they could indicate patients' response to platinum-based chemotherapy and prognosis, then integrated into a Pt-score employing LASSO regression model to assess its predictive performance. Results and discussion: Multiple genetic features, including bi-allelic inactivation of BRCA1/2 genes and genes involved in HR pathway, multiple somatic mutations in genes involved in DNA damage repair (DDR), and previously reported HRD-related features, were found to be stringently associated with platinum sensitivity and improved prognosis. Higher contributions of mutational signature SBS39 or ID6 predicted improved overall survival. Besides, arm-level loss of heterozygosity (LOH) of either chr4p or chr5q predicted significantly better disease-free survival. Notably, some of these features were found independent of HRD. And SBS3, an HRD-related feature, was found irrelevant to platinum sensitivity. Integrated all candidate markers using the LASSO model to yield a Pt-score, which showed better predictive ability compared to HRDetect in determining platinum sensitivity and predicting patients' prognosis, and this performance was validated in an independent cohort. The outcomes of our study will be instrumental in devising effective strategies for treating ovarian cancer with platinum-based chemotherapy.

Loss and recovery of myocardial mitochondria in mice under different tail suspension time: Apoptosis and mitochondrial fission, fusion and autophagy.

Long-term weightlessness in animals can cause changes in myocardial structure and function, in which mitochondria play an important role. Here, a tail suspension (TS) Kunming mouse (Mus musculus) model was used to simulate the effects of weightlessness on the heart. We investigated the effects of 2 and 4 weeks of TS (TS2 and TS4) on myocardial mitochondrial ultrastructure and oxidative respiratory function and on the molecular mechanisms of apoptosis and mitochondrial fission, autophagy and fusion-related signalling. Our study revealed significant changes in the ultrastructural features of cardiomyocytes in response to TS. The results showed: (1) mitochondrial swelling and disruption of cristae in TS2, but mitochondrial recovery and denser cristae in TS4; (2) an increase in the total number of mitochondria and number of sub-mitochondria in TS4; (3) no significant changes in the nuclear ultrastructure or DNA fragmentation among the two TS groups and the control group; (4) an increase in the bax/bcl-2 protein levels in the two TS groups, indicating increased activation of the bax-mediated apoptosis pathway; (5) no change in the phosphorylation ratio of dynamin-related protein 1 in the two TS groups; (6) an increase in the protein levels of optic atrophy 1 and mitofusin 2 in the two TS groups; and (7) in comparison to the TS2 group, an increase in the phosphorylation ratio of parkin and the ratio of LC3II to LC3I in TS4, suggesting an increase in autophagy. Taken together, these findings suggest that mitochondrial autophagy and fusion levels increased after 4 weeks of TS, leading to a restoration of the bax-mediated myocardial apoptosis pathway observed after 2 weeks of TS. NEW FINDINGS: What is the central question of this study? What are the effects of 2 and 4 weeks of tail suspension on myocardial mitochondrial ultrastructure and oxidative respiratory function and on the molecular mechanisms of apoptosis and mitochondrial fission, autophagy and fusion-related signalling? What is the main finding and its importance? Increased mitochondrial autophagy and fusion levels after 4 weeks of tail suspension help to reshape the morphology and increase the number of myocardial mitochondria.

Forward looking statement, investor sentiment and stock liquidity.

Information is a critical element of capital markets, and liquidity is the lifeblood of capital markets. Relative to historical information, forward-looking information is of significant value to investors. Based on textual analysis calculations, we selected Chinese A-share listed companies as a research sample to explore the impact of forward-looking information disclosure level on stock liquidity. It is found that the higher the level of forward-looking information disclosure, the better the stock liquidity. Investor sentiment is the transmission mechanism through which the forward looking statement disclosure level affects stock liquidity. The heterogeneity analysis shows that the level of forward-Looking statement disclosure has a more significant effect on stock liquidity improvement for state-owned enterprises and enterprises in low-market regions than those in regions with high marketization levels. The article expands and enriches the research on forward-looking information disclosure, and also has some reference value for regulators to formulate laws and regulations and regulate forward-looking information disclosure.

Synchronization and Control for Multiweighted and Directed Complex Networks.

The study of complex networks with multiweights (CNMWs) has been a hot topic recently. For a network with a single weight, previous studies have shown that they can promote synchronization, but for CNMWs, there are no rigorous analyses about the role of coupling matrices. In this brief, the complex network is allowed to be directed, which is the main difference with previous studies and may make the synchronization analysis difficult for multiple couplings. At first, we prove that if the inner coupling matrices are all diagonal, then synchronization can be realized only if the weighted sum (or union) of multiple coupling matrices is strongly connected, which bridges the gap between single-weighted and multiweighted networks. Moreover, we also consider the case that inner coupling matrices are positive definite but not diagonal. We design two techniques for this hard problem. One technique is to decompose inner coupling matrices into diagonal matrices and residual matrices. The other one is to measure the similarity between outer coupling matrices. In virtue of the normalized left eigenvectors (NLEVecs) corresponding to the zero eigenvalue of coupling matrices, we prove that if the Chebyshev distance between NLEVec is less than some value, defined as the allowable deviation bound, then the synchronization and control will be realized with sufficiently large coupling strengths. Furthermore, adaptive rules are also designed for coupling strength.

Robust Passivity and Control for Directed and Multiweighted Coupled Dynamical Networks.

In this article, the passivity and control issues for directed uncertain coupled dynamical networks are solved. The presented model is directly coupled with multiple coupling matrices and parametric uncertainty, while previous literatures of multiweighted networks usually suppose that outer coupling matrices (OMs) are connected, undirected, and certain. The viewpoint of inner coupling matrices (IMs) in this article is added and OMs can be directed and not connected, which is a great improvement on the existing results. First, for all diagonal IMs, considering each dimension separately, we can derive if the weighted combination of multiple OMs for each dimension is strongly connected, then passivity and pinning control rules can be established. In addition, we also discuss the situation that IMs are positive definite but not diagonal. By means of the weighted combination of normalized left eigenvectors (NLEVec) corresponding to zero eigenvalue for multiple coupling matrices, we prove if the Chebyshev distance (Cheb-Dist) among these NLEVec is less than a tolerant deviation interval, then passivity, synchronization, and pinning control criteria are acquired. Moreover, a matter of adaptive coupling strengths is also settled. Examples are provided to verify the validity of established results.

Simulated weightlessness led to the transformation of glycolipid metabolism in the livers of mice / La antigravedad simulada provocó la transformación del metabolismo de los glicolípidos en el hígado de ratones / Antigravidade simulada levou à transformação do metabolismo de glicolipídios no fígado de camundongos

ABSTRACT Objectives: The effects of weightlessness on the liver were studied using a tail suspension (TS) male mouse model. Methods: The effects of 0-, 2- and 4-week TS (CON, TS2 and TS4 groups) on glycogen and lipid content, as well as on the molecular processes of the synthesis and degradation pathways, were examined. Results: (1) The number of glycogenosomes under ultrastructure and the glycogen content were considerably larger in the TS4 group than in the other two groups. (2) In the TS4 group, glycogen synthase activity remained constant while glycogen phosphorylase activity dropped, indicating that glycogen breakdown was reduced. (3) The livers of the TS2 group had the highest lipid and triglyceride content, indicating lipid buildup in the liver at this time. (4) In the TS2 group, the activities of the fatty acid synthesis-related factors acetyl-CoA carboxylase and fatty acid synthase increased, while hepatic lipase decreased, indicating that lipid synthesis increased, while decomposition decreased. (5) In the TS2 group, the protein expression of glucose transporters 1 and 2 increased. Conclusions: From TS2 weeks to TS4 weeks, the main energy consumption mode in the livers of mice transitioned from glucose metabolism to lipid metabolism as glucose use decreased. Level of evidence II; Comparative prospective study.

RESUMEN Objetivos: Se estudiaron los efectos de la antigravedad en el hígado utilizando un modelo de ratón macho en prueba de suspensión de la cola (TS, tail suspension). Métodos: Se examinaron los efectos de la TS a las 0, 2 y 4 semanas (grupos CON, TS2 y TS4) sobre el contenido de glucógeno y lípidos, así como sobre los procesos moleculares de las vías de síntesis y degradación. Resultados: (1) El número de glucogenosomas ultraestructurales y el contenido de glucógeno fueron expresivamente más altos en el grupo TS4 que en los otros dos grupos. (2) En el grupo TS4, la actividad de la glucógeno sintasa se mantuvo constante, mientras que la actividad de la glucógeno fosforilasa disminuyó, lo que indica que la degradación del glucógeno se redujo. (3) Los hígados del grupo TS2 presentaron el mayor contenido de lípidos y triglicéridos, lo que indica la acumulación de lípidos en el hígado en ese momento. (4) En el grupo TS2, la actividad de los factores relacionados con la síntesis de ácidos grasos acetil-CoA carboxilasa y ácido graso sintasa aumentó, mientras que la lipasa hepática disminuyó, indicando que la síntesis de lípidos aumentó mientras que la descomposición disminuyó. (5) En el grupo TS2, la expresión proteica de los transportadores de glucosa 1 y 2 aumentó. Conclusiones: Desde la semana TS2 hasta la semana TS4, el principal modo de consumo de energía en el hígado de los ratones pasó del metabolismo de la glucosa al metabolismo de los lípidos a medida que disminuía el uso de la glucosa. Nivel de Evidencia II, Estudio retrospectivo comparativo.

RESUMO Objetivos: Os efeitos da antigravidade no fígado foram estudados usando um modelo de camundongo macho com a suspensão pela cauda (TS, tail suspension). Métodos: Foram examinados os efeitos da TS em 0, 2 e 4 semanas (grupos CON, TS2 e TS4) sobre o conteúdo de glicogênio e lipídios, bem como nos processos moleculares das vias de síntese e degradação. Resultados: (1) O número de glicogenossomos ultraestruturais e o teor de glicogênio foram expressivamente maiores no grupo TS4 do que nos outros dois grupos. (2) No grupo TS4, a atividade de glicogênio sintase permaneceu constante, enquanto a atividade de glicogênio fosforilase caiu, indicando que a degradação do glicogênio foi reduzida. (3) Os fígados do grupo TS2 tiveram o maior teor lipídico e de triglicérides, indicando acúmulo de lipídios no fígado no momento. (4) No grupo TS2, a atividade dos fatores relacionados com a síntese de ácidos graxos acetil-CoA carboxilase e ácido graxo sintase aumentaram, enquanto a lipase hepática diminuiu, indicando que a síntese de lipídios aumentou, enquanto a decomposição diminuiu. (5) No grupo TS2, a expressão proteica dos transportadores de glicose 1 e 2 aumentou. Conclusões: De TS2 semanas para TS4 semanas, o principal modo de consumo de energia no fígado de camundongos passou do metabolismo da glicose para o metabolismo lipídico, à medida que o uso de glicose diminuiu. Nível de evidência II, Estudo retrospectivo comparativo.

Sports Deep Learning Method Based on Cognitive Human Behavior Recognition.

An in-depth learning-based approach is designed to develop the ability to recognize human behavior on the move. We introduce 3D residual structures and create 3D residual models. In order to get the most out of the data relationship of several consecutive frames, this study introduces 3D techniques for assigning different values to the existing frames. Experiments show that both structures improve recognition performance. For the 3D residual model, 3D attention model, and 3D attention residual model, this study proposes two model fusion strategies: average and weighted. Among them, the weighted fusion is to give a higher fusion proportion to the high accuracy model by using the model weight calculation method designed in this study. The experimental results show that the additive fusion strategy based on feature contribution has an obvious improvement effect on the test results of the two benchmark datasets, with an increase of more than 2% points, including an increase of 2.69% on HMDB51. The effect of splicing and fusion strategy has also increased by more than 1% point, including 1.34% on UCF101 dataset and about 1.9% on HMDB51. It is proven that deep learning can effectively recognize human behavior in sports.

The influence of the career calling on the employees' creative deviance.

As creative deviance can improve organizational innovation ability and competitiveness effectively, scholars have recently paid much attention to this innovative manner. This paper examines the mechanism between career calling and creative deviance based on 304 surveyed samples via a cross-temporal questionnaire. The results show that employees' career calling exerts a significant positive impact on their creative deviance, and employee creativity plays a mediating role in this relationship. Furthermore, ethical leadership positively moderates the relationship between career calling and employee creativity as well as the relationship between career calling and creative deviance.

Mitigating global warming potential while coordinating economic benefits by optimizing irrigation managements in maize production.

China is the second largest irrigated country in the world. Increasing irrigation intensity costs more water and energy, and produces more greenhouse gas (GHG). In the present study, the responses of maize economic and environmental benefits to different irrigation managements were analyzed in a 2-year field study. A purposely designed tube-study was conducted to explore mechanism underlying effects of irrigation managements in detail. Three treatments, rainfed (RF), flood irrigation (FI), and drip irrigation (DI) were included in the field. Five treatments, no irrigation, flood irrigation, irrigation in 0-30, 30-60, and 0-90 cm depth were conducted in the tube study. Compared to RF, grain yields of FI and DI significantly increased by 22.1 % and 35.7 %, respectively, the net ecosystem economic budget significantly increased by 34.2 % and 35.6 %, and carbon footprint decreased by 7.0 % and 12.7 % in the field study. The irrigation treatments in the tube study increased the global warming potential by 12.0-32.8 % and grain yield by 44.5-203.9 %, and reduced GHG intensity by 24.3-57.4 %, compared with no irrigation treatment. Water content at the top soil layer had the greatest impact on GHG emissions. In conclusion, the differences in grain yield and GHG emissions among irrigation managements are mainly due to the soil water content in space and time. Drip irrigation decreases GHG intensity by producing more grain yield due to the optimized soil water distribution in the root zone. Irrigation management with appropriate amount and frequency can increase economic benefit and reduce environmental cost in maize production.

PD-L1 degradation is regulated by electrostatic membrane association of its cytoplasmic domain.

The cytoplasmic domain of PD-L1 (PD-L1-CD) regulates PD-L1 degradation and stability through various mechanism, making it an attractive target for blocking PD-L1-related cancer signaling. Here, by using NMR and biochemical techniques we find that the membrane association of PD-L1-CD is mediated by electrostatic interactions between acidic phospholipids and basic residues in the N-terminal region. The absence of the acidic phospholipids and replacement of the basic residues with acidic residues abolish the membrane association. Moreover, the basic-to-acidic mutations also decrease the cellular abundance of PD-L1, implicating that the electrostatic interaction with the plasma membrane mediates the cellular levels of PD-L1. Interestingly, distinct from its reported function as an activator of AMPK in tumor cells, the type 2 diabetes drug metformin enhances the membrane dissociation of PD-L1-CD by disrupting the electrostatic interaction, thereby decreasing the cellular abundance of PD-L1. Collectively, our study reveals an unusual regulatory mechanism that controls the PD-L1 level in tumor cells, suggesting an alternative strategy to improve the efficacy of PD-L1-related immunotherapies.

Finite time convergence of pinning synchronization with a single nonlinear controller.

In this paper, we discuss distributive synchronization of complex networks in finite time, with a single nonlinear pinning controller. The results apply to heterogeneous dynamic networks, too. Different from many models, which assume the coupling matrix being symmetric (or the connecting graph is undirected), here, the coupling matrix is asymmetric (or the connecting graph is directed).

Vertical distribution and seasonal variation of soil moisture after drip-irrigation affects greenhouse gas emissions and maize production during the growth season.

Providing enough food for the increasing global population is difficult due to water shortages, which can be partially resolved by regulating soil moisture. Soil moisture influences soluble nutrient uptake and microbial activity, which determine crop growth, but also affects greenhouse gas (GHG) emissions. Farming is increasingly contributing to GHG emission, but little is known about the effects of the vertical soil moisture distribution on GHG or maize (Zea mays L.) yield over the growth season. In this study, there were five irrigation treatments: no irrigation (NI), and irrigation of the top (0-30 cm) (TI), middle (30-60 cm) (MI), bottom (60-90 cm) (BI), and all (0-90 cm) (AI) soil layers. The results showed that TI, MI, BI, and AI increased CO2 (25-60%), CH4 (80-270%), and N2O (17-96%) emissions, and the global warming potential (25-63%), while also increasing grain yield (13-119%) and reducing GHG intensity by 12-27%. While higher soil moisture in the shallow soil layer increased grain yield and GHG emissions, GHG intensity was lowest. Subsurface irrigation or control of the "drip irrigation interval" improve grain yield and resource use efficiency with lower environmental costs contributing agricultural sustainable development.

Silent Counterattack: The Impact of Workplace Bullying on Employee Silence.

The purpose of this paper is to explore the relationship between workplace bullying (WB) and employee silence (ES) as well as its mechanism. This paper collects data from 322 employees of three Chinese enterprises in two waves, with a 2 months interval between the two waves. Moreover, this paper uses confirmatory factor analysis, a bootstrapping mediation test, a simple slope test, and other methods to verify the hypothesis. We find that: (1) WB is positively correlated with ES; (2) psychological safety (PS) and affective commitment mediated the relationship between WB and ES, respectively, and these two variables have a chain mediating effect in the above relationship; and (3) a forgiveness climate moderates this chain mediating effect by weakening the negative impact of WB on PS. Our findings can effectively guide organizations to ultimately adjust their management style, pay attention to employees' cognitive and emotional resources, and formulate some measures to curb WB in organizations.

Microstructure, mechanical properties, and in vitro behavior of biodegradable Zn-1Mg-0.1Ca and Zn-1Mg-0.5Ca.

In the present study, the microstructure, mechanical properties, corrosion behavior, wettability, haemocompatibility, and cytocompatibility of the as-cast and as-rolled biodegradable Zn-1Mg-0.1Ca and Zn-1Mg-0.5Ca have been systematically investigated to evaluate their feasibility as potential biodegradable materials. The results demonstrated that the Zn-1Mg-0.1Ca have significantly improved mechanical properties, with the yield strength (YS), ultimate tensile strength (UTS), and elongation of as-rolled Zn-1Mg-0.1Ca are (209.04 ± 28.31) MPa, (331.51 ± 40.06) MPa, and (35.43 ± 3.53)%, respectively. Wettability test results demonstrated that the Zn-1Mg-0.1Ca and Zn-1Mg-0.5Ca have hydrophilic surfaces that can enhance cell responses and tissue-implant interactions. The haemocompatibility evaluation showed that the hemolysis ratio of Zn-1Mg-0.1Ca have a low hemolysis ratio of 0.6%; the platelets remain sphere morphology and are not activated. High cell viability indicates the cytocompatibility of the as-rolled Zn-1Mg-0.1Ca alloy. The Zn-1Mg-0.1Ca alloy can be considered as new suitable biodegradable Zn-based alloys for further biomedical applications.

Effects of hypogonadism on brain development during adolescence in girls with Turner syndrome.

Gonadal steroids play an important role in brain development, particularly during puberty. Girls with Turner syndrome (TS), a genetic disorder characterized by the absence of all or part of the second X chromosome, mostly present a loss of ovarian function and estrogen deficiency, as well as neuroanatomical abnormalities. However, few studies have attempted to isolate the indirect effects of hormones from the direct genetic effects of X chromosome insufficiency. Brain structural (i.e., gray matter [GM] morphology and white matter [WM] connectivity) and functional phenotypes (i.e., resting-state functional measures) were investigated in 23 adolescent girls with TS using multimodal MRI to assess the role of hypogonadism in brain development in TS. Specifically, all girls with TS were divided into a hormonally subnormal group and an abnormal subgroup according to their serum follicle-stimulating hormone (FSH) levels, with the karyotypes approximately matched between the two groups. Statistical analyses revealed significant effects of the "group-by-age" interaction on GM volume around the left medial orbitofrontal cortex and WM diffusion parameters around the bilateral corticospinal tract, anterior thalamic radiation, left superior longitudinal fasciculus, and cingulum bundle, but no significant "group-by-age" or group differences were observed in resting-state functional measures. Based on these findings, estrogen deficiency has a nontrivial impact on the development of the brain structure during adolescence in girls with TS. Our present study provides novel insights into the mechanism by which hypogonadism influences brain development during adolescence in girls with TS, and highlights the important role of estrogen replacement therapy in treating TS.

Upregulation of miR­95-3p inhibits growth of osteosarcoma by targeting HDGF.

Osteosarcoma is the most common bone malignancy and miR-95-3p plays an important role in multiple cancers. The purpose of this study was to explore the effect and potential mechanism of miR-95-3p on the growth of osteosarcoma. In vitro, the osteosarcoma cell lines, SAOS-2 and U2OS cells, were transfected with miR-95-agomir to assess the role of miR-95-3p in proliferation and apoptosis of osteosarcoma cells. We determined that overexpression of miR-95-3p significantly attenuated cell proliferation but enhanced apoptosis in SAOS-2 and U2OS cells. We also found that overexpression of miR-95-3p in osteosarcoma cells downregulated the expression of hepatoma-derived growth factor (HDGF). Next, knockdown of HDGF by siRNA targeting HDGF clearly inhibited cell proliferation and induced apoptosis in U2OS cells. In vivo, a tumor formation assay in BALB/c nude mice was conducted by injecting the pre-miR-95 or control vector lentivirus-infected U2OS cells to determine the effect of miR-95-3p on the growth of osteosarcoma. Results showed miR-95-3p overexpression inhibited the osteosarcoma growth and downregulated the HDGF expression in xenografted tumor. For mechanism study, we co-transfected HDGF/pcDNA3.1 plasmid and miR-95-agomir to U2OS cells, and we demonstrated that overexpression of HDGF could attenuate the effects of miR-95-3p on U2OS cell proliferation, apoptosis and migration. These findings indicated that miR-95-3p might act as a potential tumor suppressor in osteosarcoma by targeting HDGF. Thus, miR-95-3p may become a potential therapeutic in treatment of osteosarcoma.

FBXO38 mediates PD-1 ubiquitination and regulates anti-tumour immunity of T cells.

Dysfunctional T cells in the tumour microenvironment have abnormally high expression of PD-1 and antibody inhibitors against PD-1 or its ligand (PD-L1) have become commonly used drugs to treat various types of cancer1-4. The clinical success of these inhibitors highlights the need to study the mechanisms by which PD-1 is regulated. Here we report a mechanism of PD-1 degradation and the importance of this mechanism in anti-tumour immunity in preclinical models. We show that surface PD-1 undergoes internalization, subsequent ubiquitination and proteasome degradation in activated T cells. FBXO38 is an E3 ligase of PD-1 that mediates Lys48-linked poly-ubiquitination and subsequent proteasome degradation. Conditional knockout of Fbxo38 in T cells did not affect T cell receptor and CD28 signalling, but led to faster tumour progression in mice owing to higher levels of PD-1 in tumour-infiltrating T cells. Anti-PD-1 therapy normalized the effect of FBXO38 deficiency on tumour growth in mice, which suggests that PD-1 is the primary target of FBXO38 in T cells. In human tumour tissues and a mouse cancer model, transcriptional levels of FBXO38 and Fbxo38, respectively, were downregulated in tumour-infiltrating T cells. However, IL-2 therapy rescued Fbxo38 transcription and therefore downregulated PD-1 levels in PD-1+ T cells in mice. These data indicate that FBXO38 regulates PD-1 expression and highlight an alternative method to block the PD-1 pathway.