ARBUSCULAR MYCORRHIZA-INDUCED KINASES AMK8 and AMK24 associate with the receptor-like kinase KINASE3 to regulate arbuscular mycorrhizal symbiosis in Lotus japonicus.

Arbuscular mycorrhizal (AM) symbiosis is a widespread, ancient mutualistic association between plants and fungi, and facilitates nutrient uptake into plants. Cell surface receptor-like kinases (RLKs) and receptor-like cytoplasmic kinases (RLCKs) play pivotal roles in transmembrane signaling, while few RLCKs are known to function in AM symbiosis. Here, we show that 27 out of 40 AM-induced kinases (AMKs) are transcriptionally upregulated by key AM transcription factors in Lotus japonicus. Nine AMKs are only conserved in AM-host lineages, among which the SPARK-RLK-encoding gene KINASE3 (KIN3) and the RLCK paralogues AMK8 and AMK24 are required for AM symbiosis. KIN3 expression is directly regulated by the AP2 transcription factor CTTC MOTIF-BINDING TRANSCRIPTION FACTOR1 (CBX1), which regulates the reciprocal exchange of nutrients in AM symbiosis, via the AW-box motif in the KIN3 promoter. Loss of function mutations in KIN3, AMK8, or AMK24 result in reduced mycorrhizal colonization in L. japonicus. AMK8 and AMK24 physically interact with KIN3. KIN3 and AMK24 are active kinases and AMK24 directly phosphorylates KIN3 in vitro. Moreover, CRISPR-Cas9-mediated mutagenesis of OsRLCK171, the sole homolog of AMK8 and AMK24 in rice (Oryza sativa), leads to diminished mycorrhization with stunted arbuscules. Overall, our results reveal a crucial role of the CBX1-driven RLK/RLCK complex in the evolutionarily conserved signaling pathway enabling arbuscule formation.

Deregulation of the G1/S-phase transition is the proximal cause of mortality in old yeast mother cells.

Budding yeast cells produce a finite number of daughter cells before they die. Why old yeast cells stop dividing and die is unclear. We found that age-induced accumulation of the G1/S-phase inhibitor Whi5 and defects in G1/S cyclin transcription cause cell cycle delays and genomic instability that result in cell death. We further identified extrachromosomal rDNA (ribosomal DNA) circles (ERCs) to cause the G1/S cyclin expression defect in old cells. Spontaneous segregation of Whi5 and ERCs into daughter cells rejuvenates old mothers, but daughters that inherit these aging factors die rapidly. Our results identify deregulation of the G1/S-phase transition as the proximal cause of age-induced proliferation decline and cell death in budding yeast.

The Epworth sleepiness scale may have more advantages than the multiple sleep latency test in assessing sleepiness in patients with obstructive sleep apnea.

This study aimed to analyze the brain function of severe obstructive sleep apnea patients with various sleepiness assessment methods and explore the brain imaging basis for the differences between these methods. This study included 30 severe obstructive sleep apnea patients and 19 healthy controls. Obstructive sleep apnea patients were divided into a subjective excessive daytime sleepiness group and a subjective non-excessive daytime sleepiness group according to the Epworth sleepiness scale. Moreover, they were divided into an objective excessive daytime sleepiness group and an objective non-excessive daytime sleepiness group according to the multiple sleep latency test. The fractional amplitude of low-frequency fluctuation was used to assess the features of brain function. Compared with healthy controls, participants in the subjective excessive daytime sleepiness group exhibited higher fractional amplitude of low-frequency fluctuation signals in the right thalamus, left cerebellar lobe 6, left putamen, and pallidum. Participants in the objective excessive daytime sleepiness group showed higher fractional amplitude of low-frequency fluctuation signals in the right thalamus and lower fractional amplitude of low-frequency fluctuation signals in the right superior frontal gyrus, the dorsolateral and superior frontal gyrus, and the medial orbital. We concluded that the thalamus may be involved in subjective and objective sleepiness regulation. Functional abnormalities in the putamen and pallidum may be involved in subjective sleepiness, whereas the frontal lobe may be involved in objective sleepiness.

Arabidopsis PHYTOALEXIN DEFICIENT 4 promotes the maturation and nuclear accumulation of immune-related cysteine protease RD19.

Arabidopsis PHYTOALEXIN DEFICIENT 4 (PAD4) has an essential role in pathogen resistance as a heterodimer with ENHANCED DISEASE SUSCEPTIBILITY 1 (EDS1). Here we investigated an additional PAD4 role in which it associates with and promotes the maturation of the immune-related cysteine protease RESPONSIVE TO DEHYDRATION 19 (RD19). We found that RD19 and its paralog RD19c promoted EDS1- and PAD4-mediated effector-triggered immunity to an avirulent Pseudomonas syringae strain, DC3000, expressing the effector AvrRps4 and basal immunity against the fungal pathogen Golovinomyces cichoracearum. Overexpression of RD19, but not RD19 protease-inactive catalytic mutants, in Arabidopsis transgenic lines caused EDS1- and PAD4-dependent autoimmunity and enhanced pathogen resistance. In these lines, RD19 maturation to a pro-form required its catalytic residues, suggesting that RD19 undergoes auto-processing. In transient assays, PAD4 interacted preferentially with the RD19 pro-protease and promoted its nuclear accumulation in leaf cells. Our results lead us to propose a model for PAD4-stimulated defense potentiation. PAD4 promotes maturation and nuclear accumulation of processed RD19, and RD19 then stimulates EDS1-PAD4 dimer activity to confer pathogen resistance. This study highlights potentially important additional PAD4 functions that eventually converge on canonical EDS1-PAD4 dimer signaling in plant immunity.

Biomimetic MDSCs membrane coated black phosphorus nanosheets system for photothermal therapy/photodynamic therapy synergized chemotherapy of cancer.

Photothermal therapy is favored by cancer researchers due to its advantages such as controllable initiation, direct killing and immune promotion. However, the low enrichment efficiency of photosensitizer in tumor site and the limited effect of single use limits the further development of photothermal therapy. Herein, a photo-responsive multifunctional nanosystem was designed for cancer therapy, in which myeloid-derived suppressor cell (MDSC) membrane vesicle encapsulated decitabine-loaded black phosphorous (BP) nanosheets (BP@ Decitabine @MDSCs, named BDM). The BDM demonstrated excellent biosafety and biochemical characteristics, providing a suitable microenvironment for cancer cell killing. First, the BDM achieves the ability to be highly enriched at tumor sites by inheriting the ability of MDSCs to actively target tumor microenvironment. And then, BP nanosheets achieves hyperthermia and induces mitochondrial damage by its photothermal and photodynamic properties, which enhancing anti-tumor immunity mediated by immunogenic cell death (ICD). Meanwhile, intra-tumoral release of decitabine induced G2/M cell cycle arrest, further promoting tumor cell apoptosis. In vivo, the BMD showed significant inhibition of tumor growth with down-regulation of PCNA expression and increased expression of high mobility group B1 (HMGB1), calreticulin (CRT) and caspase 3. Flow cytometry revealed significantly decreased infiltration of MDSCs and M2-macrophages along with an increased proportion of CD4+, CD8+ T cells as well as CD103+ DCs, suggesting a potentiated anti-tumor immune response. In summary, BDM realizes photothermal therapy/photodynamic therapy synergized chemotherapy for cancer.

Comprehensive analysis of transcriptome-wide N6-methyladenosine methylomes in the Barrett's esophagus in rats.

PURPOSE: As the most abundant RNA modification, N6-methyladenosine (m6A) methylation plays crucial roles in various diseases. The aim of this study is to comprehensively map the landscape of the mRNA m6A modification pattern in Barrett's esophagus (BE) in order to find key genes and potential therapy for BE and even esophageal adenocarcinoma (EAC). METHODS: Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-sequencing (RNA-seq) were performed to compare the difference in mRNA m6A methylation and differentially expressed mRNAs between BE and normal control (NC) tissues. Bioinformatics analysis was used to describe the m6A modification pattern and specific genes in BE and NC tissues. RESULTS: Through MeRIP-seq, we obtained m6A methylation profiling in BE and NC tissues. In total, 11,026 unique peaks were detected in the BE groups, whereas 8564 unique peaks were detected in the NC groups. Peaks were primarily enriched within CDS with GGACU motifs and most of the peaks were within 1000 bp in width. Moreover, functional enrichment analysis demonstrated that hypermethylated and hypomethylated genes were significantly enriched in coronavirus disease pathway, calcium signaling pathway and MAPK signaling pathways. Furthermore, PPI network was conducted and 18 hub genes were identified via STRING database and Cystoscope. Among them, ACTA1, CDC20, CKM, KIF20a, MYH11, TPM2, MYL9, DES, TNNT3 were overexpressed in EAC in the GEPIA gene bank and TPM1, KIF20a impaired patients' survival in the Kaplan-Meier plotter database. Finally, functional enrichment analysis demonstrated that co-expressed genes of TPM1 were significantly enriched in calcium signaling pathway, cGMP-PKG signaling pathway and PI3K-Akt signaling pathway. CONCLUSION: Our study is the first to perform comprehensive and transcriptome-wide maps to identify the potential roles played by m6A methylation in BE, which widely involved in oxidative stress. This foresees a guiding role in revealing the molecular mechanism of m6A-mediated genes that govern the pathogenesis and progression of BE and EAC.

STAT3 promotes differentiation of monocytes to MDSCs via CD39/CD73-adenosine signal pathway in oral squamous cell carcinoma.

Myeloid-derived suppressor cells (MDSCs) are one of the tumor-infiltrating immune cell population, which play a powerful role in inhibiting anti-tumor immune response. Our previous studies have shown that STAT3 blockade can decrease the number of MDSCs in tumor microenvironment. However, it is unclear for the molecular mechanism of down-regulation MDSCs with STAT3 inhibitor. In this study, we first detected and analyzed the expression of p-STAT3, CD33, CD14, CD39 and CD73 via oral squamous cell carcinoma (OSCC) tissue array. We found that p-STAT3 was positively correlated with CD14, CD33, CD39, and CD73 in OSCC patient specimens. Then we found STAT3 blockade with S3I-201 reduced the expression of CD39/CD73 and the synthesis of adenosine, as well as inhibiting monocytes to MDSCs differentiation in vitro. Furthermore, we found that S3I-201 displayed prominent anti-tumor efficacy in C3H/He OSCC mouse model via inhibiting CD39/CD73-adenosine signal pathway and decreasing MDSCs. These results suggest that STAT3 signal can induce the differentiation of monocytes into MDSCs in tumor microenvironment depending on CD39/CD73-adenosine signal pathway and STAT3 blockade is a promising therapeutic strategy for OSCC.

Ferroptosis promotes anti-tumor immune response by inducing immunogenic exposure in HNSCC.

Accumulated evidence indicates that immune cell populations play pivotal roles in the process of tumor initiation, progression, recurrence, metastasis, and immune escape. Ferroptosis is a form of regulating cell death in the nexus between metabolism, redox biology, and human health. Ferroptosis is considered as a vital important event in HNSCC, but the underling mechanism of regulating immune cell populations remains poorly understood. Our tissue microarray study showed that patients with high expression of GPX4 were related to poor survival. Moreover, the expression of GPX4 has been negatively associated with immunogenic cell death-related protein calreticulin in HNSCC tissue cohort. Further, RSL3 was used to induce ferroptosis in HNSCC xenograft of C3H/He mouse. We found that the occurrence of ferroptosis had significantly reduced the number of myeloid-derived suppressor cells (MDSCs) and tumor-associated M2-like macrophages (M2 TAMs) in tumor microenvironment. Meanwhile, the tumor-infiltrating CD4+ and CD8+ T cells were increased. And the calreticulin and HMGB1 may be potential candidate proteins improving the immunosuppressive tumor microenvironment. Taken together, our project suggests that ferroptosis can promote anti-tumor immune response by reversing immunosuppressive microenvironment, indicating that ferroptosis inducer is a promising therapeutic strategy in HNSCC.

Artificial intelligence-assisted determination of available sites for palatal orthodontic mini implants based on palatal thickness through CBCT.

OBJECTIVES: To develop an artificial intelligence (AI) system for automatic palate segmentation through CBCT, and to determine the personalized available sites for palatal mini implants by measuring palatal bone and soft tissue thickness according to the AI-predicted results. MATERIALS AND METHODS: Eight thousand four hundred target slices (from 70 CBCT scans) from orthodontic patients were collected, labelled by well-trained orthodontists and randomly divided into two groups: a training set and a test set. After the deep learning process, we evaluated the performance of our deep learning model with the mean Dice similarity coefficient (DSC), average symmetric surface distance (ASSD), sensitivity (SEN), positive predictive value (PPV) and mean thickness percentage error (MTPE). The pixel traversal method was proposed to measure the thickness of palatal bone and soft tissue, and to predict available sites for palatal orthodontic mini implants. Then, an example of available sites for palatal mini implants from the test set was mapped. RESULTS: The average DSC, ASSD, SEN, PPV and MTPE for the segmented palatal bone tissue were 0.831%, 1.122%, 0.876%, 0.815% and 6.70%, while that for the palatal soft tissue were 0.741%, 1.091%, 0.861%, 0.695% and 12.2%, respectively. Besides, an example of available sites for palatal mini implants was mapped according to predefined criteria. CONCLUSIONS: Our AI system showed high accuracy for palatal segmentation and thickness measurement, which is helpful for the determination of available sites and the design of a surgical guide for palatal orthodontic mini implants.

Advanced materials and technologies for oral diseases.

Oral disease, as a class of diseases with very high morbidity, brings great physical and mental damage to people worldwide. The increasing burden and strain on individuals and society make oral diseases an urgent global health problem. Since the treatment of almost all oral diseases relies on materials, the rapid development of advanced materials and technologies has also promoted innovations in the treatment methods and strategies of oral diseases. In this review, we systematically summarized the application strategies in advanced materials and technologies for oral diseases according to the etiology of the diseases and the comparison of new and old materials. Finally, the challenges and directions of future development for advanced materials and technologies in the treatment of oral diseases were refined. This review will guide the fundamental research and clinical translation of oral diseases for practitioners of oral medicine.

Gray matter reduction in bilateral insula mediating adverse psychiatric effects of body mass index in schizophrenia.

BACKGROUND: Both schizophrenia (SZ) and overweight/obesity (OWB) have shown some structural alterations in similar brain regions. As higher body mass index (BMI) often contributes to worse psychiatric outcomes in SZ, this study was designed to examine the effects of OWB on gray matter volume (GMV) in patients with SZ. METHODS: Two hundred fifty subjects were included and stratified into four groups (n = 69, SZ patients with OWB, SZ-OWB; n = 74, SZ patients with normal weight, SZ-NW; n = 54, healthy controls with OWB, HC-OWB; and n = 53, HC with NW, HC-NW). All participants were scanned using high-resolution T1-weighted sequence. The whole-brain voxel-based morphometry was applied to examine the GMV alterations, and a 2 × 2 full factorial analysis of variance was performed to identify the main effects of diagnosis (SZ vs HC), BMI (NW vs OWB) factors, and their interactions. Further, the post hoc analysis was conducted to compare the pairwise differences in GMV alterations. RESULTS: The main effects of diagnosis were located in right hippocampus, bilateral insula, rectus, median cingulate/paracingulate gyri and thalamus (SZ < HC); while the main effects of BMI were displayed in right amygdala, left hippocampus, bilateral insula, left lingual gyrus, and right superior temporal gyrus (OWB < NW). There were no significant diagnosis-by-BMI interaction effects in the present study, but the results showed that both SZ and OWB were additively associated with lower GMV in bilateral insula. Moreover, mediation analyses revealed the indirect effect of BMI on negative symptom via GMV reduction in bilateral insula. CONCLUSION: This study further supports that higher BMI is associated with lower GMV, which may increase the risk of unfavourable disease courses in SZ.

CD24 blockade promotes anti-tumor immunity in oral squamous cell carcinoma.

OBJECTIVES: Our study elucidates the prognostic role of cluster of differentiation (CD) 24 expression in oral squamous cell carcinoma (OSCC) and determines whether targeting CD24 enhances the anti-tumor immune response by inhibiting tumor-associated macrophages (TAMs). MATERIALS AND METHODS: The expression of CD24 and CD68 was analyzed immunohistochemically via tissue microarrays constructed using 56 cohorts of patients with OSCC and 20 control specimens. Further, CD24 was inhibited in an allograft squamous cell carcinoma (SCC) related mouse model with CD24mAb to determine the tumor volume and weight. Changes in immune cells such as TAMs and T cells in the tumor microenvironment (TME) were analyzed by Flow cytometry. The expression of CD4, CD8, and Ki67 was analyzed via immunohistochemistry. The inhibition of CD24 was confirmed by Western blot and immunohistochemistry. RESULTS: CD24 was overexpressed in OSCC. High expression of CD24 indicated poor survival in patients with OSCC (p = 0.0334). CD24 expression was significantly correlated with CD68 (p = 0.0424). The inhibition of CD24 delayed tumor growth in vivo. A decrease in TAMs number and an increase in T cell number were confirmed, while the ability of tumor proliferation was impaired. CONCLUSION: Targeting CD24 could enhance anti-tumor immune response by inhibiting TAMs.

Flavonoid fisetin reverses impaired hippocampal synaptic plasticity and cognitive function by regulating the function of AMPARs in a male rat model of schizophrenia.

Cognitive deficits are the core feature of schizophrenia and effective treatment strategies are still missing. Previous studies have reported that fisetin promotes long-term potentiation (LTP) and cognitive function in normal rodents and other model animals of neurological diseases. The aim of this study was to assess the effect of fisetin on synaptic plasticity and cognitive deficits caused by a brief disruption of N-methyl-D-aspartate receptors (NMDARs) with dizocilpine (MK-801) during early development in rats. The cognitive performance was examined by the Morris water maze task and a fear conditioning test. Hippocampal synaptic plasticity was investigated by field potential recording. The expression of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) and cognition-related proteins was measured by western blotting. We found that intraperitoneal administration of fisetin rescued hippocampus-dependent spatial and contextual fear memory in MK-801 rats. In parallel with these behavioral results, fisetin treatment in MK-801 rats reversed the impairment of hippocampal LTP. At the molecular level, fisetin treatment selectively increased the phosphorylation and surface expression of AMPA receptor subunit 1 (GluA1) in MK-801-treated rats. Moreover, fisetin restored the phosphorylation levels of calcium-calmodulin-dependent kinaseII (CaMKII), cAMP response element-binding protein (CREB), and the extracellular signal-regulated kinase (ERK1/2) in MK-801-treated rats. Collectively, our findings demonstrate that fisetin treatment can reverse the deficits of hippocampal synaptic plasticity and memory in a male rat model of schizophrenia by restoring the phosphorylation and surface expression of AMPAR GluA1 subunit, suggesting fisetin as a promising therapeutic candidate for schizophrenia-associated cognitive deficits.

D-Serine produces antidepressant-like effects in mice through suppression of BDNF signaling pathway and regulation of synaptic adaptations in the nucleus accumbens.

OBJECTIVE: D-Serine is a crucial endogenous co-agonist of N-methyl-D-aspartate receptors (NMDARs) in the central nervous system and can affect the function of the brain derived neurotrophic factor (BDNF) system, which plays an essential role in modulating synaptic plasticity. The current study aimed to systematically evaluate the role and mechanisms of D-serine in depressive behavior in nucleus accumbens (NAc). METHODS: D-Serine concentration in the chronic social defeat stress (CSDS) model in NAc was measured using high-performance liquid chromatography (HPLC). The antidepressant-like effects of D-serine were identified using forced swim test (FST) and tail suspension test (TST) in control mice and then assessed in CSDS model. We applied social interaction and sucrose preference tests to identify the susceptibility of CSDS model. Western blotting was further performed to assess the changes of BDNF signaling cascade in NAc after CSDS and D-serine treatment. The BDNF signaling inhibitor (K252a) was also used to clarify the antidepressant-like mechanism of D-serine. Moreover, D-serine effects on synaptic plasticity in NAc were investigated using electrophysiological methods. RESULTS: D-Serine concentration was decreased in depression susceptible mice in NAc. D-Serine injections into NAc exhibited antidepressant-like effects in FST and TST without affecting the locomotor activity of mice. D-Serine was also effective in CSDS model of depression. Moreover, D-serine down-regulated the BDNF signaling pathway in NAc during CSDS procedure. Furthermore, BDNF signaling inhibitor (K252a) enhanced the antidepressant effects of D-serine. We also found that D-serine was essential for NMDARs-dependent long-term depression (LTD). CONCLUSION: D-Serine exerts antidepressant-like effects in mice mediated through restraining the BDNF signaling pathway and regulating synaptic plasticity in NAc.

Anxiety and depression-like behaviours are more frequent in aged male mice conceived by ART compared with natural conception.

The number of children born after assisted reproductive technology (ART) is accumulating rapidly, and the health problems of the children are extensively concerned. This study aims to evaluate whether ART procedures alter behaviours in male offspring. Mouse models were utilized to establish three groups of offspring conceived by natural conception (NC), in vitro fertilization and embryo transfer (IVF-ET), and frozen-thawed embryo transfer (IVF-FET), respectively. A battery of behaviour experiments for evaluating anxiety and depression levels, including the open field test (OFT), elevated plus maze (EPM) test, light/dark transition test (L/DTT), tail suspension test (TST), forced swimming test (FST), and sucrose preference test (SPT) was carried out. Aged (18 months old), but not young (3 months old), male offspring in the IVF-ET and IVF-FET groups, compared with those in the NC group, exhibited increased anxiety and depression-like behaviours. The protein expression levels of three neurotrophins in PFC or hippocampus in aged male offspring from the IVF-ET and IVF-FET groups reduced at different extent, in comparison to NC group. RNA sequencing (RNA-Seq) was performed in the hippocampus of 18 months old offspring to further explore the gene expression profile changes in the three groups. KEGG analyses revealed the coexisted pathways, such as PI3K-Akt signalling pathway, which potentially reflected the similarity and divergence in anxiety and depression between the offspring conceived by IVF-ET and IVF-FET. Our research suggested the adverse effects of advanced age on the psychological health of children born after ART should be highlighted in the future.

Track-to-Track Association for Intelligent Vehicles by Preserving Local Track Geometry.

Track-to-track association (T2TA) is a challenging task in situational awareness in intelligent vehicles and surveillance systems. In this paper, the problem of track-to-track association with sensor bias (T2TASB) is considered. Traditional T2TASB algorithms only consider a statistical distance cost between local tracks from different sensors, without exploiting the geometric relationship between one track and its neighboring ones from each sensor. However, the relative geometry among neighboring local tracks is usually stable, at least for a while, and thus helpful in improving the T2TASB. In this paper, we propose a probabilistic method, called the local track geometry preservation (LTGP) algorithm, which takes advantage of the geometry of tracks. Assuming that the local tracks of one sensor are represented by Gaussian mixture model (GMM) centroids, the corresponding local tracks of the other sensor are fitted to those of the first sensor. In this regard, a geometrical descriptor connectivity matrix is constructed to exploit the relative geometry of these tracks. The track association problem is formulated as a maximum likelihood estimation problem with a local track geometry constraint, and an expectation-maximization (EM) algorithm is developed to find the solution. Simulation results demonstrate that the proposed methods offer better performance than the state-of-the-art methods.

Robust Non-Rigid Feature Matching for Image Registration Using Geometry Preserving.

In this paper, a robust non-rigid feature matching approach for image registration with geometry constraints is proposed. The non-rigid feature matching approach is formulated as a maximum likelihood (ML) estimation problem. The feature points of one image are represented by Gaussian mixture model (GMM) centroids, and are fitted to the feature points of the other image by moving coherently to encode the global structure. To preserve the local geometry of these feature points, two local structure descriptors of the connectivity matrix and Laplacian coordinate are constructed. The expectation maximization (EM) algorithm is applied to solve this ML problem. Experimental results demonstrate that the proposed approach has better performance than current state-of-the-art methods.

A Review of Point Set Registration: From Pairwise Registration to Groupwise Registration.

This paper presents a comprehensive literature review on point set registration. The state-of-the-art modeling methods and algorithms for point set registration are discussed and summarized. Special attention is paid to methods for pairwise registration and groupwise registration. Some of the most prominent representative methods are selected to conduct qualitative and quantitative experiments. From the experiments we have conducted on 2D and 3D data, CPD-GL pairwise registration algorithm and JRMPC groupwise registration algorithm seem to outperform their rivals both in accuracy and computational complexity. Furthermore, future research directions and avenues in the area are identified.

A global characterization of the translational and transcriptional programs induced by methionine restriction through ribosome profiling and RNA-seq.

BACKGROUND: Among twenty amino acids, methionine has a special role as it is coded by the translation initiation codon and methionyl-tRNAi (Met-tRNAi) is required for the assembly of the translation initiation complex. Thus methionine may play a special role in global gene regulation. Methionine has also been known to play important roles in cell growth, development, cancer, and aging. In this work, we characterize the translational and transcriptional programs induced by methionine restriction (MetR) and investigate the potential mechanisms through which methionine regulates gene expression, using the budding yeast S. cerevisiae as the model organism. RESULTS: Using ribosomal profiling and RNA-seq, we observed a broad spectrum of gene expression changes in response to MetR and identified hundreds of genes whose transcript level and/or translational efficiency changed significantly. These genes show clear functional themes, suggesting that cell slows down its growth and cell cycle progression and increases its stress resistance and maintenance in response to MetR. Interestingly, under MetR cell also decreases glycolysis and increases respiration, and increased respiration was linked to lifespan extension caused by caloric restriction. Analysis of genes whose translational efficiency changed significantly under MetR revealed different modes of translational regulation: 1) Ribosome loading patterns in the 5'UTR and coding regions of genes with increased translational efficiency suggested mechanisms both similar and different from that for the translational regulation of Gcn4 under general amino acid starvation condition; 2) Genes with decreased translational efficiency showed strong enrichment of lysine, glutamine, and glutamate codons, supporting the model that methionine can regulate translation by controlling tRNA thiolation. CONCLUSIONS: MetR induced a broad spectrum of gene expression changes at both the transcriptional and translational levels, with clear functional themes indicative of the physiological state of the cell under MetR. Different modes of translational regulation were induced by MetR, including the regulation of the ribosome loading at 5'UTR and regulation by tRNA thiolation. Since MetR extends the lifespan of many species, the list of genes we identified in this study can be good candidates for studying the mechanisms of lifespan extension.