Gut microbiome and metabolome profiling in Framingham heart study reveals cholesterol-metabolizing bacteria.

Accumulating evidence suggests that cardiovascular disease (CVD) is associated with an altered gut microbiome. Our understanding of the underlying mechanisms has been hindered by lack of matched multi-omic data with diagnostic biomarkers. To comprehensively profile gut microbiome contributions to CVD, we generated stool metagenomics and metabolomics from 1,429 Framingham Heart Study participants. We identified blood lipids and cardiovascular health measurements associated with microbiome and metabolome composition. Integrated analysis revealed microbial pathways implicated in CVD, including flavonoid, γ-butyrobetaine, and cholesterol metabolism. Species from the Oscillibacter genus were associated with decreased fecal and plasma cholesterol levels. Using functional prediction and in vitro characterization of multiple representative human gut Oscillibacter isolates, we uncovered conserved cholesterol-metabolizing capabilities, including glycosylation and dehydrogenation. These findings suggest that cholesterol metabolism is a broad property of phylogenetically diverse Oscillibacter spp., with potential benefits for lipid homeostasis and cardiovascular health.

m6A-modified RIPK4 facilitates proliferation and cisplatin resistance in epithelial ovarian cancer.

BACKGROUND: Cisplatin (DDP)-based chemotherapy is a common chemotherapeutic regimen for the treatment of advanced epithelial ovarian cancer (EOC). However, most patients rapidly develop chemoresistance. N6-methyladenosine (m6A) is a pervasive RNA modification, and its specific role and potential mechanism in the regulation of chemosensitivity in EOC remain unclear. METHODS: The expression of RIPK4 and its clinicopathological impact were evaluated in EOC cohorts. The biological effects of RIPK4 were investigated using in vitro and in vivo models. RNA m6A quantification was used to measure total m6A levels in epithelial ovarian cancer cells. Luciferase reporter, MeRIP-qPCR, RIP-qPCR and actinomycin-D assays were used to investigate RNA/RNA interactions and m6A modification of RIPK4 mRNA. RESULTS: We demonstrated that RIPK4, an upregulated mRNA in EOC, acts as an oncogene in EOC cells by promoting tumor cell proliferation and DDP resistance at the clinical, database, cellular, and animal model levels. Mechanistically, METTL3 facilitates m6A modification, and YTHDF1 recognizes the specific m6A-modified site to prevent RIPK4 RNA degradation and upregulate RIPK4 expression. This induces NF-κB activation, resulting in tumor growth and DDP resistance in vitro and in vivo. CONCLUSIONS: Collectively, the present findings reveal a novel mechanism underlying the induction of DDP resistance by m6A-modified RIPK4, that may contribute to overcoming chemoresistance in EOC.

Exosomal YB-1 facilitates ovarian restoration by MALAT1/miR-211-5p/FOXO3 axis.

Premature ovarian failure (POF) affects many adult women less than 40 years of age and leads to infertility. Mesenchymal stem cells-derived small extracellular vesicles (MSCs-sEVs) are attractive candidates for ovarian function restoration and folliculogenesis for POF due to their safety and efficacy, however, the key mediator in MSCs-sEVs that modulates this response and underlying mechanisms remains elusive. Herein, we reported that YB-1 protein was markedly downregulated in vitro and in vivo models of POF induced with H2O2 and CTX respectively, accompanied by granulosa cells (GCs) senescence phenotype. Notably, BMSCs-sEVs transplantation upregulated YB-1, attenuated oxidative damage-induced cellular senescence in GCs, and significantly improved the ovarian function of POF rats, but that was reversed by YB-1 depletion. Moreover, YB-1 showed an obvious decline in serum and GCs in POF patients. Mechanistically, YB-1 as an RNA-binding protein (RBP) physically interacted with a long non-coding RNA, MALAT1, and increased its stability, further, MALAT1 acted as a competing endogenous RNA (ceRNA) to elevate FOXO3 levels by sequestering miR-211-5p to prevent its degradation, leading to repair of ovarian function. In summary, we demonstrated that BMSCs-sEVs improve ovarian function by releasing YB-1, which mediates MALAT1/miR-211-5p/FOXO3 axis regulation, providing a possible therapeutic target for patients with POF.

Temporal fingerprints of cortical gyrification in marmosets and humans.

Recent neuroimaging studies in humans have reported distinct temporal dynamics of gyri and sulci, which may be associated with putative functions of cortical gyrification. However, the complex folding patterns of the human cortex make it difficult to explain temporal patterns of gyrification. In this study, we used the common marmoset as a simplified model to examine the temporal characteristics and compare them with the complex gyrification of humans. Using a brain-inspired deep neural network, we obtained reliable temporal-frequency fingerprints of gyri and sulci from the awake rs-fMRI data of marmosets and humans. Notably, the temporal fingerprints of one region successfully classified the gyrus/sulcus of another region in both marmosets and humans. Additionally, the temporal-frequency fingerprints were remarkably similar in both species. We then analyzed the resulting fingerprints in several domains and adopted the Wavelet Transform Coherence approach to characterize the gyro-sulcal coupling patterns. In both humans and marmosets, sulci exhibited higher frequency bands than gyri, and the two were temporally coupled within the same range of phase angles. This study supports the notion that gyri and sulci possess unique and evolutionarily conserved features that are consistent across functional areas, and advances our understanding of the functional role of cortical gyrification.

Modeling functional difference between gyri and sulci within intrinsic connectivity networks.

Recently, the functional roles of the human cortical folding patterns have attracted increasing interest in the neuroimaging community. However, most existing studies have focused on the gyro-sulcal functional relationship on a whole-brain scale but possibly overlooked the localized and subtle functional differences of brain networks. Actually, accumulating evidences suggest that functional brain networks are the basic unit to realize the brain function; thus, the functional relationships between gyri and sulci still need to be further explored within different functional brain networks. Inspired by these evidences, we proposed a novel intrinsic connectivity network (ICN)-guided pooling-trimmed convolutional neural network (I-ptFCN) to revisit the functional difference between gyri and sulci. By testing the proposed model on the task functional magnetic resonance imaging (fMRI) datasets of the Human Connectome Project, we found that the classification accuracy of gyral and sulcal fMRI signals varied significantly for different ICNs, indicating functional heterogeneity of cortical folding patterns in different brain networks. The heterogeneity may be contributed by sulci, as only sulcal signals show heterogeneous frequency features across different ICNs, whereas the frequency features of gyri are homogeneous. These results offer novel insights into the functional difference between gyri and sulci and enlighten the functional roles of cortical folding patterns.

M6A demethylase FTO-stabilized exosomal circBRCA1 alleviates oxidative stress-induced granulosa cell damage via the miR-642a-5p/FOXO1 axis.

BACKGROUND: Premature ovarian insufficiency (POI) is an important cause of female infertility and seriously impacts the physical and psychological health of patients. Human umbilical cord mesenchymal stem cell-derived exosomes (HucMSCs-Exs, H-Exs) have exhibited protective effects on ovarian function with unclear mechanisms. METHODS: A comprehensive analysis of the Gene Expression Omnibus (GEO) database were used to identify POI-associated circRNAs and miRNAs. The relationship between HucMSC-derived exosomal circBRCA1/miR-642a-5p/FOXO1 axis and POI was examined by RT-qPCR, Western blotting, reactive oxygen species (ROS) staining, senescence-associated ß-gal (SA-ß-gal) staining, JC-1 staining, TEM, oxygen consumption rate (OCR) measurements and ATP assay in vivo and in vitro. RT-qPCR detected the expression of circBRCA1 in GCs and serum of patients with normal ovarian reserve function (n = 50) and patients with POI (n = 50); then, the correlation of circBRCA1 with ovarian reserve function indexes was analyzed. RESULTS: Herein, we found that circBRCA1 was decreased in the serum and ovarian granulosa cells (GCs) of patients with POI and was associated with decreased ovarian reserve. H-Exs improved the disorder of the estrous cycles and reproductive hormone levels, reduced the number of atretic follicles, and alleviated the apoptosis and senescence of GCs in rats with POI. Moreover, H-Exs mitigated mitochondrial damage and reversed the reduced circBRCA1 expression induced by oxidative stress in GCs. Mechanistically, FTO served as an eraser to increase the stability and expression of circBRCA1 by mediating the m6A demethylation of circBRCA1, and exosomal circBRCA1 sponged miR-642a-5p to block its interaction with FOXO1. CircBRCA1 insufficiency aggravated mitochondrial dysfunction, mimicking FTO or FOXO1 depletion effects, which was counteracted by miR-642a-5p inhibition. CONCLUSION: H-Exs secreted circBRCA1 regulated by m6A modification, directly sponged miR-642a-5p to upregulate FOXO1, resisted oxidative stress injuries in GCs and protected ovarian function in rats with POI. Exosomal circBRCA1 supplementation may be a general prospect for the prevention and treatment of POI.

Method for Estimating Road Impulse Ahead of Vehicles in Urban Environment with Microelectromechanical System Three-Dimensional Sensor.

Most automated vehicles (AVs) are equipped with abundant sensors, which enable AVs to improve ride comfort by sensing road elevation, such as speed bumps. This paper proposes a method for estimating the road impulse features ahead of vehicles in urban environments with microelectromechanical system (MEMS) light detection and ranging (LiDAR). The proposed method deploys a real-time estimation of the vehicle pose to solve the problem of sparse sampling of the LiDAR. Considering the LiDAR error model, the proposed method builds the grid height measurement model by maximum likelihood estimation. Moreover, it incorporates height measurements with the LiDAR error model by the Kalman filter and introduces motion uncertainty to form an elevation weight method by confidence eclipse. In addition, a gate strategy based on the Mahalanobis distance is integrated to handle the sharp changes in elevation. The proposed method is tested in the urban environment. The results demonstrate the effectiveness of our method.

Mass Spectrometry-Based Proteomic Analysis of Potential Host Proteins Interacting with GP5 in PRRSV-Infected PAMs.

Porcine reproductive and respiratory syndrome virus (PRRSV) is a typical immunosuppressive virus causing a large economic impact on the swine industry. The structural protein GP5 of PRRSV plays a pivotal role in its pathogenicity and immune evasion. Virus-host interactions play a crucial part in viral replication and immune escape. Therefore, understanding the interactions between GP5 and host proteins are significant for porcine reproductive and respiratory syndrome (PRRS) control. However, the interaction network between GP5 and host proteins in primary porcine alveolar macrophages (PAMs) has not been reported. In this study, 709 GP5-interacting host proteins were identified in primary PAMs by immunoprecipitation coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Bioinformatics analysis revealed that these proteins were involved in multiple cellular processes, such as translation, protein transport, and protein stabilization. Subsequently, immunoprecipitation and immunofluorescence assay confirmed that GP5 could interact with antigen processing and presentation pathways related proteins. Finally, we found that GP5 may be a key protein that inhibits the antigen processing and presentation pathway during PRRSV infection. The novel host proteins identified in this study will be the candidates for studying the biological functions of GP5, which will provide new insights into PRRS prevention and vaccine development.

A Color- and Geometric-Feature-Based Approach for Denoising Three-Dimensional Cultural Relic Point Clouds.

In the acquisition process of 3D cultural relics, it is common to encounter noise. To facilitate the generation of high-quality 3D models, we propose an approach based on graph signal processing that combines color and geometric features to denoise the point cloud. We divide the 3D point cloud into patches based on self-similarity theory and create an appropriate underlying graph with a Markov property. The features of the vertices in the graph are represented using 3D coordinates, normal vectors, and color. We formulate the point cloud denoising problem as a maximum a posteriori (MAP) estimation problem and use a graph Laplacian regularization (GLR) prior to identifying the most probable noise-free point cloud. In the denoising process, we moderately simplify the 3D point to reduce the running time of the denoising algorithm. The experimental results demonstrate that our proposed approach outperforms five competing methods in both subjective and objective assessments. It requires fewer iterations and exhibits strong robustness, effectively removing noise from the surface of cultural relic point clouds while preserving fine-scale 3D features such as texture and ornamentation. This results in more realistic 3D representations of cultural relics.

Arousal modulates the amygdala-insula reciprocal connectivity during naturalistic emotional movie watching.

Emotional arousal is a complex state recruiting distributed cortical and subcortical structures, in which the amygdala and insula play an important role. Although previous neuroimaging studies have showed that the amygdala and insula manifest reciprocal connectivity, the effective connectivities and modulatory patterns on the amygdala-insula interactions underpinning arousal are still largely unknown. One of the reasons may be attributed to static and discrete laboratory brain imaging paradigms used in most existing studies. In this study, by integrating naturalistic-paradigm (i.e., movie watching) functional magnetic resonance imaging (fMRI) with a computational affective model that predicts dynamic arousal for the movie stimuli, we investigated the effective amygdala-insula interactions and the modulatory effect of the input arousal on the effective connections. Specifically, the predicted dynamic arousal of the movie served as regressors in general linear model (GLM) analysis and brain activations were identified accordingly. The regions of interest (i.e., the bilateral amygdala and insula) were localized according to the GLM activation map. The effective connectivity and modulatory effect were then inferred by using dynamic causal modeling (DCM). Our experimental results demonstrated that amygdala was the site of driving arousal input and arousal had a modulatory effect on the reciprocal connections between amygdala and insula. Our study provides novel evidence to the underlying neural mechanisms of arousal in a dynamical naturalistic setting.

MicroRNA-376b-3p Promotes Porcine Reproductive and Respiratory Syndrome Virus Replication by Targeting Viral Restriction Factor TRIM22.

Porcine reproductive and respiratory syndrome virus (PRRSV) is a major economically significant pathogen and has evolved several strategies to evade host antiviral response and provide favorable conditions for survival. In the present study, we demonstrated that a host microRNA, miR-376b-3p, was upregulated by PRRSV infection through the viral components, nsp4 and nsp11, and that miR-376b-3p can directly target tripartite motif-containing 22 (TRIM22) to impair its anti-PRRSV activity, thus facilitating the replication of PRRSV. Meanwhile, we found that TRIM22 induced degradation of the nucleocapsid protein (N) of PRRSV by interacting with N protein to inhibit PRRSV replication, and further study indicated that TRIM22 could enhance the activation of the lysosomal pathway by interacting with LC3 to induce lysosomal degradation of N protein. In conclusion, PRRSV increased miR-376b-3p expression and hijacked the host miR-376b-3p to promote PRRSV replication by impairing the antiviral effect of TRIM22. Therefore, our finding outlines a novel strategy of immune evasion exerted by PRRSV, which is helpful for better understanding the pathogenesis of PRRSV. IMPORTANCE Porcine reproductive and respiratory syndrome virus (PRRSV) causes enormous economic losses each year in the swine industry worldwide. MicroRNAs (miRNAs) play important roles during viral infections via modulating the expression of viral or host genes at the posttranscriptional level. TRIM22 has recently been identified as a key restriction factor that inhibited the replication of a number of human viruses, such as HIV, encephalomyocarditis virus (ECMV), hepatitis C virus (HCV), HBV, influenza A virus (IAV), and respiratory syncytial virus (RSV). In this study, we showed that host miR-376b-3p could be upregulated by PRRSV and functioned to impair the anti-PRRSV role of TRIM22 to facilitate PRRSV replication. Meanwhile, we found that TRIM22 inhibited the replication of PRRSV by interacting with viral N protein and accelerating its degradation through the lysosomal pathway. Collectively, the findings reveal a novel mechanism that PRRSV used to exploit the host miR-376b-3p to evade antiviral responses and provide new insight into the study of virus-host interactions.

The potential regulatory role of RNA methylation in ovarian cancer.

Updates in whole genome sequencing technologies have revealed various RNA modifications in cancer, among which RNA methylation is a frequent posttranscriptional modification. RNA methylation is essential for regulating biological processes such as RNA transcription, splicing, structure, stability, and translation. Its dysfunction is strongly associated with the development of human malignancies. Research advances with respect to the regulatory role of RNA modifications in ovarian cancer include N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), and N7-methylguanosine (m7G). Numerous studies have demonstrated that epigenetic modifications of RNA can influence the progression and metastasis of ovarian cancer and may provide excellent targets for cancer therapy. This review highlights advances in research on RNA methylation modifications and ovarian cancer prognosis, carcinogenesis, and resistance, which could provide a theoretical foundation for designing therapeutic strategies for ovarian cancer based on RNA methylation modifications.

Monitoring of the glazing state of the pitch polishing lap by an image texture analysis method in full-aperture continuous polishing.

Full-aperture continuous polishing using a pitch lap is one of the key processes in finishing large flat optical elements. The pitch lap has relief lines cutting into the surface to increase its surface roughness and to improve the polishing results. During polishing, the pitch lap surface is glazed due to the transverse rheologic flow and creep of the pitch lap by the element and conditioner, which has significant influence on the polishing results. In this study, an image texture analysis method is proposed to monitor the glazing state of the pitch lap. The images of the pitch lap surface are captured online, and the image textures are analyzed with the gray level co-occurrence matrix (GLCM) method. The experiments revealed that the GLCM eigenvalues of the surface image are strongly correlative with the glazing state of the pitch lap, which has a linear impact on the material removal rate and material removal uniformity. To the best of our knowledge, this study provides a novel and useful method to monitor the surface glazing state of the pitch lap.

Research on Deep Reinforcement Learning Control Algorithm for Active Suspension Considering Uncertain Time Delay.

The uncertain delay characteristic of actuators is a critical factor that affects the control effectiveness of the active suspension system. Therefore, it is crucial to develop a control algorithm that takes into account this uncertain delay in order to ensure stable control performance. This study presents a novel active suspension control algorithm based on deep reinforcement learning (DRL) that specifically addresses the issue of uncertain delay. In this approach, a twin-delayed deep deterministic policy gradient (TD3) algorithm with system delay is employed to obtain the optimal control policy by iteratively solving the dynamic model of the active suspension system, considering the delay. Furthermore, three different operating conditions were designed for simulation to evaluate the control performance: deterministic delay, semi-regular delay, and uncertain delay. The experimental results demonstrate that the proposed algorithm achieves excellent control performance under various operating conditions. Compared to passive suspension, the optimization of body vertical acceleration is improved by more than 30%, and the proposed algorithm effectively mitigates body vibration in the low frequency range. It consistently maintains a more than 30% improvement in ride comfort optimization even under the most severe operating conditions and at different speeds, demonstrating the algorithm's potential for practical application.

The Host E3-Ubiquitin Ligase TRIM28 Impedes Viral Protein GP4 Ubiquitination and Promotes PRRSV Replication.

Porcine reproductive and respiratory syndrome (PRRS), caused by the PRRS virus (PRRSV), is a highly pathogenic porcine virus that brings tremendous economic losses to the global swine industry. PRRSVs have evolved multiple elegant strategies to manipulate the host proteins and circumvent against the antiviral responses to establish infection. Therefore, the identification of virus-host interactions is critical for understanding the pathogenesis of PRRSVs. Tripartite motif protein 28 (TRIM28) is a transcriptional co-repressor involved in the regulation of viral and cellular transcriptional programs; however, its precise role in regulating PRRSV infection remains unknown. In this study, we found that the mRNA and protein levels of TRIM28 were up-regulated in PRRSV-infected porcine alveolar macrophages (PAMs) and MARC-145 cells. Ectopic TRIM28 expression dramatically increased viral yields, whereas the siRNA-mediated knockdown of TRIM28 significantly inhibited PRRSV replication. Furthermore, we used a co-immunoprecipitation (co-IP) assay to demonstrate that TRIM28 interacted with envelope glycoprotein 4 (GP4) among PRRSV viral proteins. Intriguingly, TRIM28 inhibited the degradation of PRRSV GP4 by impeding its ubiquitination. Taken together, our work provides evidence that the host E3-ubiquitin ligase TRIM28 suppresses GP4 ubiquitination and is important for efficient virus replication. Therefore, our study identifies a new host factor, TRIM28, as a potential target in the development of anti-viral drugs against PRRSV.

Amblyopinae Mitogenomes Provide Novel Insights into the Paraphyletic Origin of Their Adaptation to Mudflat Habitats.

The water-to-land transition is one of the most important events in evolutionary history of vertebrates. However, the genetic basis underlying many of the adaptations during this transition remains unclear. Mud-dwelling gobies in the subfamily Amblyopinae are one of the teleosts lineages that show terrestriality and provide a useful system for clarifying the genetic changes underlying adaptations to terrestrial life. Here, we sequenced the mitogenome of six species in the subfamily Amblyopinae. Our results revealed a paraphyletic origin of Amblyopinae with respect to Oxudercinae, which are the most terrestrial fishes and lead an amphibious life in mudflats. This partly explains the terrestriality of Amblyopinae. We also detected unique tandemly repeated sequences in the mitochondrial control region in Amblyopinae, as well as in Oxudercinae, which mitigate oxidative DNA damage stemming from terrestrial environmental stress. Several genes, such as ND2, ND4, ND6 and COIII, have experienced positive selection, suggesting their important roles in enhancing the efficiency of ATP production to cope with the increased energy requirements for life in terrestrial environments. These results strongly suggest that the adaptive evolution of mitochondrial genes has played a key role in terrestrial adaptions in Amblyopinae, as well as in Oxudercinae, and provide new insights into the molecular mechanisms underlying the water-to-land transition in vertebrates.

Characterization of Insulin-like Peptide (ILP) and Its Potential Role in Ovarian Development of the Cuttlefish Sepiella japonica.

The insulin-like peptide (ILP) family is well known for regulating reproduction in invertebrates, while its role in mollusks remains largely unknown. In this study, we first isolated and characterized the ILP gene in the cuttlefish Sepiella japonica. The full-length SjILP cDNA obtained was 926 bp and encoded a precursor protein of 161 amino acids. The precursor protein consisted of a signal peptide, a B chain, a C-peptide, and an A chain. It possessed the typical features of ILP proteins, including two cleavage sites (KR) and eight conserved cysteines. To define the function of SjILP, the expression of SjILP in different tissues and ovarian development stages were analyzed using qRT-PCR. SjILP was mainly expressed in the ovary, and its gene expression correlated with ovarian development. Furthermore, silencing SjILP using RNA interference (RNAi) dramatically decreased the expression levels of four ovarian-development-related genes (vitellogenin1, vitellogenin2, cathepsin L1-like, and follistatin). These data suggest the critical role of SjILP in the regulation of ovarian development in S. japonica.

Test-retest reliability of dynamic functional connectivity in naturalistic paradigm functional magnetic resonance imaging.

Dynamic functional connectivity (dFC) has been increasingly used to characterize the brain transient temporal functional patterns and their alterations in diseased brains. Meanwhile, naturalistic neuroimaging paradigms have been an emerging approach for cognitive neuroscience with high ecological validity. However, the test-retest reliability of dFC in naturalistic paradigm neuroimaging is largely unknown. To address this issue, we examined the test-retest reliability of dFC in functional magnetic resonance imaging (fMRI) under natural viewing condition. The intraclass correlation coefficients (ICC) of four dFC statistics including standard deviation (Std), coefficient of variation (COV), amplitude of low frequency fluctuation (ALFF), and excursion (Excursion) were used to measure the test-retest reliability. The test-retest reliability of dFC in naturalistic viewing condition was then compared with that under resting state. Our experimental results showed that: (a) Global test-retest reliability of dFC was much lower than that of static functional connectivity (sFC) in both resting-state and naturalistic viewing conditions; (b) Both global and local (including visual, limbic and default mode networks) test-retest reliability of dFC could be significantly improved in naturalistic viewing condition compared to that in resting state; (c) There existed strong negative correlation between sFC and dFC, weak negative correlation between dFC and dFC-ICC (i.e., ICC of dFC), as well as weak positive correlation between dFC-ICC and sFC-ICC (i.e., ICC of sFC). The present study provides novel evidence for the promotion of naturalistic paradigm fMRI in functional brain network studies.

Has breeding altered the light environment, photosynthetic apparatus, and photosynthetic capacity of wheat leaves?

Whether photosynthesis has improved with increasing yield in major crops remains controversial. Research in this area has often neglected to account for differences in light intensity experienced by cultivars released in different years. Light intensity is expected to be positively associated with photosynthetic capacity and the resistance of the photosynthetic apparatus to high light but negatively associated with light-utilization efficiency under low light. Here, we analyzed the light environment, photosynthetic activity, and protein components of leaves of 26 winter wheat cultivars released during the past 60 years in China. Over time, light levels on flag leaves significantly decreased due to architectural changes, but photosynthetic rates under high or low light and the resistance of the photosynthetic apparatus to high light remained steady, contrary to expectations. We propose that the difference between the actual and expected trends is due to breeding. Specifically, breeding has optimized photosynthetic performance under high light rather than low light. Moreover, breeding selectivity altered the stoichiometry of several proteins related to dynamic photosynthesis, canopy light distribution, and photoprotection. These results indicate that breeding has significantly altered the photosynthetic mechanism in wheat and its response to the light environment. These changes likely have helped increase wheat yields.

PD-1/PD-L1 inhibitor monotherapy in recurrent or metastatic squamous cell carcinoma of the head and neck: a meta-analysis.

PURPOSE: To evaluate the efficacy and safety of programmed cell death-1/programmed cell death-ligand 1 inhibitor monotherapy compared to the standard of care in the first-line setting for recurrent or metastatic head and neck squamous cell carcinoma. MATERIALS AND METHODS: The PubMed, Embase, and Cochrane Library databases were searched for relevant randomized controlled trials. The clinical outcomes of overall survival, progression-free survival, objective response rates, and grade 3 or higher adverse events were analyzed using Stata SE 15 software with a significance level set to 0.05. RESULTS: We identified four randomized controlled trials (1 nivolumab, 2 pembrolizumab, and 1 durvalumab), including a total of 2474 patients. The results of the meta-analysis showed pooled hazard ratios of overall and progression-free survival for programmed cell death-1/programmed cell death-ligand 1 inhibitor monotherapy of 0.82 (95% CI: 0.73-0.91, p < 0.001) and 0.96 (95%CI: 0.84-1.07, p < 0.001) and pooled odds ratios of objective response rates and grade 3 or higher adverse events of 1.04 (95%CI: 0.46-2.37; p = 0.926) and 0.28 (95%CI: 0.22-0.35, p < 0.001), respectively. Subgroup analysis showed that inhibitors for both programmed cell death-1 (nivolumab and pembrolizumab) and programmed cell death-ligand 1 (durvalumab) were associated with significantly longer overall survival (HR = 0.80, 95% CI: 0.70-0.90, p < 0.001 and HR = 0.88, 95%CI: 0.70-1.06, p < 0.001, respectively). CONCLUSIONS: Programmed cell death-1/programmed cell death-ligand 1 inhibitor monotherapy showed more clinical benefit versus the standard of care in patients with recurrent or metastatic head and neck squamous cell carcinoma, with an acceptable safety profile.