Population-level exploration of alternative splicing and its unique role in controlling agronomic traits of rice.

Alternative splicing (AS) plays crucial roles in regulating various biological processes in plants. However, the genetic mechanisms underlying AS and its role in controlling important agronomic traits in rice (Oryza sativa) remain poorly understood. In this study, we explored AS in rice leaves and panicles using the rice minicore collection. Our analysis revealed a high level of transcript isoform diversity, with approximately one fifth of potential isoforms acting as major transcripts in both tissues. Regarding the genetic mechanism of AS, we found that the splicing of 833 genes in the leaf and 1,230 genes in the panicle was affected by cis-genetic variation. Twenty-one percent of these AS events could only be explained by large structural variations. Approximately 77.5% of genes with significant splicing quantitative trait loci (sGenes) exhibited tissue-specific regulation, and AS can cause 26.9% (leaf) and 23.6% (panicle) of sGenes to have altered, lost or gained functional domains. Additionally, through splicing-phenotype association analysis, we identified phosphate-starvation induced RING-type E3 ligase (OsPIE1; LOC_Os01g72480), whose splicing ratio was significantly associated with plant height. In summary, this study provides an understanding of AS in rice and its contribution to the regulation of important agronomic traits.

mRNA cleavage by 21-nucleotide phasiRNAs determines temperature-sensitive male sterility in rice.

Temperature-sensitive male sterility is one of the core components for hybrid rice (Oryza sativa) breeding based on the 2-line system. We previously found that knockout of ARGONAUTE 1d (AGO1d) causes temperature-sensitive male sterility in rice by influencing phased small interfering RNA (phasiRNA) biogenesis and function. However, the specific phasiRNAs and their targets underlying the temperature-sensitive male sterility in the ago1d mutant remain unknown. Here, we demonstrate that the ago1d mutant displays normal female fertility but complete male sterility at low temperature. Through a multiomics analysis of small RNA (sRNA), degradome, and transcriptome, we found that 21-nt phasiRNAs account for the greatest proportion of the 21-nt sRNA species in rice anthers and are sensitive to low temperature and markedly downregulated in the ago1d mutant. Moreover, we found that 21-nt phasiRNAs are essential for the mRNA cleavage of a set of fertility- and cold tolerance-associated genes, such as Earlier Degraded Tapetum 1 (EDT1), Tapetum Degeneration Retardation (TDR), OsPCF5, and OsTCP21, directly or indirectly determined by AGO1d-mediated gene silencing. The loss of function of 21-nt phasiRNAs can result in upregulation of their targets and causes varying degrees of defects in male fertility and grain setting. Our results highlight the essential functions of 21-nt phasiRNAs in temperature-sensitive male sterility in rice and suggest their promising application in 2-line hybrid rice breeding in the future.

The novel potential therapeutic target PSMP/MSMP promotes acute kidney injury via CCR2.

Acute kidney injury (AKI) is a major worldwide health concern that currently lacks effective medical treatments. PSMP is a damage-induced chemotactic cytokine that acts as a ligand of CCR2 and has an unknown role in AKI. We have observed a significant increase in PSMP levels in the renal tissue, urine, and plasma of patients with AKI. PSMP deficiency improved kidney function and decreased tubular damage and inflammation in AKI mouse models induced by kidney ischemia-reperfusion injury, glycerol, and cisplatin. Single-cell RNA sequencing analysis revealed that Ly6Chi or F4/80lo infiltrated macrophages (IMs) were a major group of proinflammatory macrophages with strong CCR2 expression in AKI. We observed that PSMP deficiency decreased CCR2+Ly6Chi or F4/80lo IMs and inhibited M1 polarization in the AKI mouse model. Moreover, overexpressed human PSMP in the mouse kidney could reverse the attenuation of kidney injury in a CCR2-dependent manner, and this effect could be achieved without CCL2 involvement. Extracellular PSMP played a crucial role, and treatment with a PSMP-neutralizing antibody significantly reduced kidney injury in vivo. Therefore, PSMP might be a therapeutic target for AKI, and its antibody is a promising therapeutic drug for the treatment of AKI.

A rice variation map derived from 10 548 rice accessions reveals the importance of rare variants.

Detailed knowledge of the genetic variations in diverse crop populations forms the basis for genetic crop improvement and gene functional studies. In the present study, we analyzed a large rice population with a total of 10 548 accessions to construct a rice super-population variation map (RSPVM), consisting of 54 378 986 single nucleotide polymorphisms, 11 119 947 insertion/deletion mutations and 184 736 presence/absence variations. Assessment of variation detection efficiency for different population sizes revealed a sharp increase of all types of variation as the population size increased and a gradual saturation of that after the population size reached 10 000. Variant frequency analysis indicated that ∼90% of the obtained variants were rare, and would therefore likely be difficult to detect in a relatively small population. Among the rare variants, only 2.7% were predicted to be deleterious. Population structure, genetic diversity and gene functional polymorphism of this large population were evaluated based on different subsets of RSPVM, demonstrating the great potential of RSPVM for use in downstream applications. Our study provides both a rich genetic basis for understanding natural rice variations and a powerful tool for exploiting great potential of rare variants in future rice research, including population genetics and functional genomics.

A centromere map based on super pan-genome highlights the structure and function of rice centromeres.

Rice (Oryza sativa) is a significant crop worldwide with a genome shaped by various evolutionary factors. Rice centromeres are crucial for chromosome segregation, and contain some unreported genes. Due to the diverse and complex centromere region, a comprehensive understanding of rice centromere structure and function at the population level is needed. We constructed a high-quality centromere map based on the rice super pan-genome consisting of a 251-accession panel comprising both cultivated and wild species of Asian and African rice. We showed that rice centromeres have diverse satellite repeat CentO, which vary across chromosomes and subpopulations, reflecting their distinct evolutionary patterns. We also revealed that long terminal repeats (LTRs), especially young Gypsy-type LTRs, are abundant in the peripheral CentO-enriched regions and drive rice centromere expansion and evolution. Furthermore, high-quality genome assembly and complete telomere-to-telomere (T2T) reference genome enable us to obtain more centromeric genome information despite mapping and cloning of centromere genes being challenging. We investigated the association between structural variations and gene expression in the rice centromere. A centromere gene, OsMAB, which positively regulates rice tiller number, was further confirmed by expression quantitative trait loci, haplotype analysis and clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated protein 9 methods. By revealing the new insights into the evolutionary patterns and biological roles of rice centromeres, our finding will facilitate future research on centromere biology and crop improvement.

The growth factor multimodality on treating human dental mesenchymal stem cells: a systematic review.

BACKGROUND: Ensuring the quantity, quality, and efficacy of human dental mesenchymal stem cells (MSCs) has become an urgent problem as their applications increase. Growth factors (GFs) have low toxicity, good biocompatibility, and regulate stem cell survival and differentiation. They bind to specific receptors on target cells, initiating signal transduction and triggering biological functions. So far, relatively few studies have been conducted to summarize the effect of different GFs on the application of dental MSCs. We have reviewed the literature from the past decade to examine the effectiveness and mechanism of applying one or multiple GFs to human dental MSCs. Our review is based on the premise that a single dental MSC cannot fulfill all applications and that different dental MSCs react differently to GFs. METHODS: A search for published articles was carried out using the Web of Science core collection and PubMed. The study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guidelines. This review considered studies from 2014 to 2023 that examined the effects of GFs on human dental MSCs. The final selection of articles was made on the 15th of July 2023. RESULTS: Three thousand eight hundred sixty-seven pieces of literature were gathered for this systematic review initially, only 56 of them were selected based on their focus on the effects of GFs during the application of human dental MSCs. Out of the 56, 32 literature pieces were focused on a single growth factor while 24 were focused on multiple growth factors. This study shows that GFs can regulate human dental MSCs through a multi-way processing manner. CONCLUSION: Multimodal treatment of GFs can effectively regulate human dental MSCs, ensuring stem cell quality, quantity, and curative effects.

JcSEUSS1 negatively regulates reproductive organ development in perennial woody Jatropha curcas.

MAIN CONCLUSION: Overexpression of JcSEUSS1 resulted in late flowering, reduced flower number, wrinkled kernels, and decreased seed yield in Jatopha curcas, while downregulation of JcSEUSS1 increased flower number and seed production. The seed oil of Jatropha curcas is suitable as an ideal alternative for diesel fuel, yet the seed yield of Jatropha is restricted by its small number of female flowers and low seed setting rate. Therefore, it is crucial to identify genes that regulate flowering and seed set, and hence improve seed yield. In this study, overexpression of JcSEUSS1 resulted in late flowering, fewer flowers and fruits, and smaller fruits and seeds, causing reduced seed production and oil content. In contrast, the downregulation of JcSEUSS1 by RNA interference (RNAi) technology caused an increase in the flower number and seed yield. However, the flowering time, seed number per fruit, seed weight, and size exhibited no obvious changes in JcSEUSS1-RNAi plants. Moreover, the fatty acid composition also changed in JcSEUSS1 overexpression and RNAi plants, the percentage of unsaturated fatty acids (FAs) was increased in overexpression plants, and the saturated FAs were increased in RNAi plants. These results indicate that JcSEUSS1 played a negative role in regulating reproductive growth and worked redundantly with other genes in the regulation of flowering time, seed number per fruit, seed weight, and size.

Recurrent RET fusions in fibrosarcoma-like neoplasms in adult viscera: expanding the clinicopathological and genetic spectrum.

AIMS: RET-fused mesenchymal neoplasms mostly affect the soft tissue of paediatric patients. Given their responsiveness to selective RET inhibitors, it remains critical to identify those extraordinary cases occurring in the visceral organs of adults. In this study, we report three RET-rearranged spindle-cell tumours occurring in the visceral organs of adults. METHODS AND RESULTS: Clinicopathological features were assessed and partner agnostic targeted next-generation sequencing on clinically validated platforms were performed. The patients were 18, 53, and 55 years old and included one male and two females. The tumours were located in the kidney (case 1), small intestine (case 2), and ureter (case 3), with maximum diameters of 14, 5, and 1 cm, respectively. Histologically, all tumours displayed a morphological spectrum typical of fibrosarcoma, including moderately to highly cellular, nonpleomorphic, ovoid to spindle-shaped cells arranged in long fascicles or haphazardly within collagenised to myxohyaline stroma. Foci of irregular alveolar oedema-like structures and areas with microcystic and reticular arrangements were identified in the renal tumour. Staghorn-type vessels and foci of band-like stromal hyalinisation were observed in the small intestine tumour. Cases 1 and 2 were high-grade and pursed a highly aggressive clinical course, while case 3 was of intermediate grade with no tumour recurrence or metastasis 14 years after surgery. All three tumours expressed CD34, which was coexpressed with S100 protein in cases 2 and 3. Molecular genetic testing revealed PRKAR1A::RET, KIF5B::RET, and SPECC1L::RET in-frame gene fusions. CONCLUSION: Our study expands the clinicopathological and genetic spectrum of mesenchymal neoplasms associated with RET fusions.

Uterine Tumor Resembling Ovarian Sex Cord Tumor With Aggressive Histologic Features Harboring a GREB1-NCOA2 Fusion: Case Report With a Brief Review.

Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare mesenchymal neoplasm, of uncertain lineage, that shows predominantly sex cord-like differentiation with a broad range of histologic appearances and polyphenotypic immunohistochemical features. Although generally having a favorable prognosis, a subset can recur/metastasize. Most recently, several studies of UTROSCT have described novel fusion genes involving ESR1 and GREB1 as the 5 partner, and NCOA1-3 as the 3 partner. Genotype and phenotype correlation has suggested that GREB1 -rearranged tumors may have a higher tendency to behave aggressively. Herein, we report a UTROSCT with aggressive histologic features harboring a GREB1-NCOA2 fusion. A 51-yr-old woman presented with menometrorrhagia and progressive dysmenorrhea and was found to have a submucous uterine lesion by ultrasonography. Gross examination of the hysterectomy specimen showed an 8.5-cm, polypoid, soft, intracavitary mass. Histologic examination revealed a deeply invasive neoplasm composed of uniform round to plump spindle cells, arranged predominantly in diffuse sheets and fascicles and focally in anastomosing cords patterns. Groups of rhabdoid tumor cells were occasionally noted. Worrisome features, including increased mitotic figures (up to 3/10 high power fields), geographic necrosis, and lymphovascular invasion, were evident. Immunohistochemical analysis showed variable positivity for epithelial, smooth muscle, neuroendocrine, and sex cord markers, as well as hormone receptors. RNA sequencing revealed an in-frame fusion between exon 3 of GREB1 and exon 14 of NCOA2 . Fluorescence in situ hybridization analyses confirmed rearrangements of both the GREB1 and NCOA2 loci. Our case lends further supports that GREB1 -rearranged UTROSCTs frequently exhibit aggressive histological features with inconspicuous sex cord-like differentiation.

Identification of natural allelic variation in TTL1 controlling thermotolerance and grain size by a rice super pan-genome.

Continuously increasing global temperatures present great challenges to food security. Grain size, one of the critical components determining grain yield in rice (Oryza sativa L.), is a prime target for genetic breeding. Thus, there is an immediate need for genetic improvement in rice to maintain grain yield under heat stress. However, quantitative trait loci (QTLs) endowing heat stress tolerance and grain size in rice are extremely rare. Here, we identified a novel negative regulator with pleiotropic effects, Thermo-Tolerance and grain Length 1 (TTL1), from the super pan-genomic and transcriptomic data. Loss-of-function mutations in TTL1 enhanced heat tolerance, and caused an increase in grain size by coordinating cell expansion and proliferation. TTL1 was shown to function as a transcriptional regulator and localized to the nucleus and cell membrane. Furthermore, haplotype analysis showed that hapL and hapS of TTL1 were obviously correlated with variations of thermotolerance and grain size in a core collection of cultivars. Genome evolution analysis of available rice germplasms suggested that TTL1 was selected during domestication of the indica and japonica rice subspecies, but still had much breeding potential for increasing grain length and thermotolerance. These findings provide insights into TTL1 as a novel potential target for the development of high-yield and thermotolerant rice varieties.

Impact of occlusal reconstruction positions on airway dimensions in patients with edentulism and long centric occlusion.

OBJECTIVE: To study the airway changes of edentulous patients with a magnitude of long centric (MLC) ≥ 1.5 mm during occlusal reconstruction at the centric relation position (CRP) and muscular position (MP). METHODS: The CRP and MP were determined by Gothic arch. The cephalometric analysis was taken at the two occlusal positions. The sagittal distance of each part of the upper airway was measured. The differences between two occlusal positions were compared. The difference values were calculated by subtracting the two. The correlation between the MLC and the difference value was analyzed. RESULTS: The sagittal diameters of palatopharynx and glossopharynx airway at MP were statistically larger than those at CRP (P < 0.05). The MLC had a strong correlation with the ANB angle (r = 0.745, P < 0.001). CONCLUSION: Compared with the occlusal position of CRP, occlusion reconstruction at MP can provide better airway condition for edentulous patients with large MLC.

Idiopathic retroperitoneal fibrosis with endometrial cancer: a case report and literature review.

BACKGROUND: Retroperitoneal fibrosis is a rare disease characterized by chronic nonspecific inflammation, which leads to clinical compression manifestations of retroperitoneal organs especially ureter. Approximately 70 percent of retroperitoneal fibrosis cases are idiopathic which has no clear etiology. This study reported a rare case of a 48-year-old woman presented with idiopathic retroperitoneal fibrosis and endometrial cancer. CASE PRESENTATION: A 48-year-old woman presented with irregular vaginal bleeding without abdominal pain, bloating or discomfort. The patient was diagnosed iRPF after splenectomy 13 years ago. Then she took prednisone for 2 years and took tamoxifen for about 11 years. She stopped taking the medication from October 2019 to May 2020 and then started taking tamoxifen again until November 2020. Two weeks after she stopped taking tamoxifen, she presented with irregular vaginal bleeding. Gynecological ultrasound revealed a thick endometrium with uneven echo enhancement and blood flow signals. Then diagnostic curettage was performed with pathological examination showed endometroid carcinoma. Later, the patient was admitted to Peking University Third Hospital for surgery. Preoperative imaging examinations, including CT, MRI, and PET/CT, all showed pelvic enlarged lymph nodes and they were highly suspected to have lymph node metastasis. The patient underwent laparoscopic surgical staging and enlarged lymph nodes in the pelvic and aortic regions were removed. Finally, the pathology confirmed that endometrioid adenocarcinoma and fibrosis, but there was no tumor infiltration in these enlarged lymph nodes. The patient is now in good condition. CONCLUSION: This case report stressed the difficulty to distinguish between lymph node metastasis and inflammatory hyperplasia by common imaging methods. Due to increased surgical difficulty among retroperitoneal patients, lymphadenectomy should be carefully evaluated to avoid additional surgical complications and over-treatment.

Loci and natural alleles for cadmium-mediated growth responses revealed by a genome wide association study and transcriptome analysis in rice.

BACKGROUND: Cadmium (Cd) is a toxic heavy metal that is harmful to the environment and human health. Cd pollution threatens the cultivation of rice (Oryza sativa L.) in many countries. Improving rice performance under Cd stress could potentially improve rice productivity. RESULTS: In this study, 9 growth traits of 188 different cultivated rice accessions under normal and Cd stress conditions were found to be highly variable during the seedling stage. Based on ~3.3 million single nucleotide polymorphisms (SNPs), 119 Cd-mediated growth response (CGR) quantitative trait loci (QTL) were identified by a genome-wide association study (GWAS), 55 of which have been validated by previously reported QTL and 64 were new CGR loci. Combined with the data from the GWAS, transcriptome analysis, gene annotations from the gene ontology (GO) Slim database, and annotations and functions of homologous genes, 148 CGR candidate genes were obtained. Additionally, several reported genes have been found to play certain roles in CGRs. Seven Cd-related cloned genes were found among the CGR genes. Natural elite haplotypes/alleles in these genes that increased Cd tolerance were identified by a haplotype analysis of a diverse mini core collection. More importantly, this study was the first to uncover the natural variations of 5 GST genes that play important roles in CGRs. CONCLUSION: The exploration of Cd-resistant rice germplasm resources and the identification of elite natural variations related to Cd-resistance will help improve the tolerance of current major rice varieties to Cd, as well as provide raw materials and new genes for breeding Cd-resistant varieties.

Linkage analysis, GWAS, transcriptome analysis to identify candidate genes for rice seedlings in response to high temperature stress.

BACKGROUND: Rice plants suffer from the rising temperature which is becoming more and more prominent. Mining heat-resistant genes and applying them to rice breeding is a feasible and effective way to solve the problem. RESULT: Three main biomass traits, including shoot length, dry weight, and fresh weight, changed after abnormally high-temperature treatment in the rice seedling stage of a recombinant inbred lines and the natural indica germplasm population. Based on a comparison of the results of linkage analysis and genome-wide association analysis, two loci with lengths of 57 kb and 69 kb in qDW7 and qFW6, respectively, were associated with the rice response to abnormally high temperatures at the seedling stage. Meanwhile, based on integrated transcriptome analysis, some genes are considered as important candidate genes. Combining with known genes and analysis of homologous genes, it was found that there are eight genes in candidate intervals that need to be focused on in subsequent research. CONCLUSIONS: The results indicated several relevant loci, which would help researchers to further discover beneficial heat-resistant genes that can be applied to rice heat-resistant breeding.

New developments in existing WHO entities and evolving molecular concepts: The Genitourinary Pathology Society (GUPS) update on renal neoplasia.

The Genitourinary Pathology Society (GUPS) reviewed recent advances in renal neoplasia, particularly post-2016 World Health Organization (WHO) classification, to provide an update on existing entities, including diagnostic criteria, molecular correlates, and updated nomenclature. Key prognostic features for clear cell renal cell carcinoma (RCC) remain WHO/ISUP grade, AJCC/pTNM stage, coagulative necrosis, and rhabdoid and sarcomatoid differentiation. Accrual of subclonal genetic alterations in clear cell RCC including SETD2, PBRM1, BAP1, loss of chromosome 14q and 9p are associated with variable prognosis, patterns of metastasis, and vulnerability to therapies. Recent National Comprehensive Cancer Network (NCCN) guidelines increasingly adopt immunotherapeutic agents in advanced RCC, including RCC with rhabdoid and sarcomatoid changes. Papillary RCC subtyping is no longer recommended, as WHO/ISUP grade and tumor architecture better predict outcome. New papillary RCC variants/patterns include biphasic, solid, Warthin-like, and papillary renal neoplasm with reverse polarity. For tumors with 'borderline' features between oncocytoma and chromophobe RCC, a term "oncocytic renal neoplasm of low malignant potential, not further classified" is proposed. Clear cell papillary RCC may warrant reclassification as a tumor of low malignant potential. Tubulocystic RCC should only be diagnosed when morphologically pure. MiTF family translocation RCCs exhibit varied morphologic patterns and fusion partners. TFEB-amplified RCC occurs in older patients and is associated with more aggressive behavior. Acquired cystic disease (ACD) RCC-like cysts are likely precursors of ACD-RCC. The diagnosis of renal medullary carcinoma requires a negative SMARCB1 (INI-1) expression and sickle cell trait/disease. Mucinous tubular and spindle cell carcinoma (MTSCC) can be distinguished from papillary RCC with overlapping morphology by losses of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22. MTSCC with adverse histologic features shows frequent CDKN2A/2B (9p) deletions. BRAF mutations unify the metanephric family of tumors. The term "fumarate hydratase deficient RCC" ("FH-deficient RCC") is preferred over "hereditary leiomyomatosis and RCC syndrome-associated RCC". A low threshold for FH, 2SC, and SDHB immunohistochemistry is recommended in difficult to classify RCCs, particularly those with eosinophilic morphology, occurring in younger patients. Current evidence does not support existence of a unique tumor subtype occurring after chemotherapy/radiation in early childhood.

Novel, emerging and provisional renal entities: The Genitourinary Pathology Society (GUPS) update on renal neoplasia.

The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in renal neoplasia, particularly focusing on the newly accumulated evidence post-2016 World Health Organization (WHO) classification. In the era of evolving histo-molecular classification of renal neoplasia, morphology is still key. However, entities (or groups of entities) are increasingly characterized by specific molecular features, often associated either with recognizable, specific morphologies or constellations of morphologies and corresponding immunohistochemical profiles. The correct diagnosis has clinical implications leading to better prognosis, potential clinical management with targeted therapies, may identify hereditary or syndromic associations, which may necessitate appropriate genetic testing. We hope that this undertaking will further facilitate the identification of these entities in practice. We also hope that this update will bring more clarity regarding the evolving classification of renal neoplasia and will further reduce the category of "unclassifiable renal carcinomas/tumors". We propose three categories of novel entities: (1) "Novel entity", validated by multiple independent studies; (2) "Emerging entity", good compelling data available from at least two or more independent studies, but additional validation is needed; and (3) "Provisional entity", limited data available from one or two studies, with more work required to validate them. For some entities initially described using different names, we propose new terminologies, to facilitate their recognition and to avoid further diagnostic dilemmas. Following these criteria, we propose as novel entities: eosinophilic solid and cystic renal cell carcinoma (ESC RCC), renal cell carcinoma with fibromyomatous stroma (RCC FMS) (formerly RCC with leiomyomatous or smooth muscle stroma), and anaplastic lymphoma kinase rearrangement-associated renal cell carcinoma (ALK-RCC). Emerging entities include: eosinophilic vacuolated tumor (EVT) and thyroid-like follicular renal cell carcinoma (TLFRCC). Finally, as provisional entities, we propose low-grade oncocytic tumor (LOT), atrophic kidney-like lesion (AKLL), and biphasic hyalinizing psammomatous renal cell carcinoma (BHP RCC).

APOA5 rs651821 confers increased risk for hypertension in Tongdao Dong population.

Hypertension is a complex disease that partially influenced by genetic factors. Up till now, the association between the rs651821 in apolipoprotein A5 (APOA5) gene and hypertension remains unknown. This study was undertaken to investigate the relationship between the APOA5 rs651821 and hypertension in Tongdao Dong population. A total of 274 participants were involved in this study (135 hypertensive patients and 139 nonhypertensive adults). The single nucleotide polymorphism (SNP) was genotyped by using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). The results showed that the genotypic and allelic frequencies of rs651821 were significantly different between the normotensives and hypertensive subjects (P = 0.009, P = 0.003 respectively). TC/CC genotypes of rs651821 were associated with an elevated risk of hypertension (TC/CC vs. TT: adjusted odds ratio (AOR) = 1.791, 95%CI = 1.067-3.006, P = 0.009). Besides, the TC/CC genotypes were related to an increased plasma triglyceride (TG) level (TC/CC vs. TT: 2.47 ± 1.91 vs. 1.82 ± 1.07, P = 0.001).The results suggest that the C carriers of APOA5 rs651821 are associated with an increased serum TG concentration and may cause the increased susceptibility of the individual to hypertension in Chinese Dong population.

Flower-Specific Overproduction of Cytokinins Altered Flower Development and Sex Expression in the Perennial Woody Plant Jatropha curcas L.

Jatropha curcas L. is monoecious with a low female-to-male ratio, which is one of the factors restricting its seed yield. Because the phytohormone cytokinins play an essential role in flower development, particularly pistil development, in this study, we elevated the cytokinin levels in J. curcas flowers through transgenic expression of a cytokinin biosynthetic gene (AtIPT4) from Arabidopsis under the control of a J. curcas orthologue of TOMATO MADS BOX GENE 6 (JcTM6) promoter that is predominantly active in flowers. As expected, the levels of six cytokinin species in the inflorescences were elevated, and flower development was modified without any alterations in vegetative growth. In the transgenic J. curcas plants, the flower number per inflorescence was significantly increased, and most flowers were pistil-predominantly bisexual, i.e., the flowers had a huge pistil surrounded with small stamens. Unfortunately, both the male and the bisexual flowers of transgenic J. curcas were infertile, which might have resulted from the continuously high expression of the transgene during flower development. However, the number and position of floral organs in the transgenic flowers were well defined, which suggested that the determinacy of the floral meristem was not affected. These results suggest that fine-tuning the endogenous cytokinins can increase the flower number and the female-to-male ratio in J. curcas.

Extracellular ATP promotes breast cancer invasion and epithelial-mesenchymal transition via hypoxia-inducible factor 2α signaling.

Extracellular ATP has been shown to play an important role in invasion and the epithelial-mesenchymal transition (EMT) process in breast cancer; however, the mechanism is unclear. Here, by using a cDNA microarray, we demonstrated that extracellular ATP could stimulate hypoxia-inducible factor (HIF) signaling and upregulate hypoxia-inducible factor 1/2α (HIF-1/2α) expression. After knocking down HIF-1/2α using siRNA, we found that ATP-driven invasion and EMT were significantly attenuated via HIF2A-siRNA in breast cancer cells. By using ChIP assays, we revealed that the biological function of extracellular ATP in invasion and EMT process depended on HIF-2α direct targets, among which lysyl oxidase-like 2 (LOXL2) and matrix metalloproteinase-9 (MMP-9) mediated ATP-driven invasion, and E-cadherin and Snail mediated ATP-driven EMT, respectively. In addition, using silver staining and mass spectrometry, we found that phosphoglycerate kinase 1 (PGK1) could interact with HIF-2α and mediate ATP-driven HIF-2α upregulation. Furthermore, we demonstrated that expressions of HIF-2α and its target proteins could be regulated via ATP by AKT-PGK1 pathway. Using a Balb/c mice model, we illustrated the function of HIF-2α in promoting tumor growth and metastasis in vivo. Moreover, by exploring online databases, we found that molecules involved in ATP-HIF-2α signaling were highly expressed in human breast carcinoma tissues and were associated with poor prognosis. Altogether, these findings suggest that extracellular ATP could promote breast carcinoma invasion and EMT via HIF-2α signaling, which may be a potential target for future anti-metastasis therapy.

Transcriptome analysis of two inflorescence branching mutants reveals cytokinin is an important regulator in controlling inflorescence architecture in the woody plant Jatropha curcas.

BACKGROUND: In higher plants, inflorescence architecture is an important agronomic trait directly determining seed yield. However, little information is available on the regulatory mechanism of inflorescence development in perennial woody plants. Based on two inflorescence branching mutants, we investigated the transcriptome differences in inflorescence buds between two mutants and wild-type (WT) plants by RNA-Seq to identify the genes and regulatory networks controlling inflorescence architecture in Jatropha curcas L., a perennial woody plant belonging to Euphorbiaceae. RESULTS: Two inflorescence branching mutants were identified in germplasm collection of Jatropha. The duo xiao hua (dxh) mutant has a seven-order branch inflorescence, and the gynoecy (g) mutant has a three-order branch inflorescence, while WT Jatropha has predominantly four-order branch inflorescence, occasionally the three- or five-order branch inflorescences in fields. Using weighted gene correlation network analysis (WGCNA), we identified several hub genes involved in the cytokinin metabolic pathway from modules highly associated with inflorescence phenotypes. Among them, Jatropha ADENOSINE KINASE 2 (JcADK2), ADENINE PHOSPHORIBOSYL TRANSFERASE 1 (JcAPT1), CYTOKININ OXIDASE 3 (JcCKX3), ISOPENTENYLTRANSFERASE 5 (JcIPT5), LONELY GUY 3 (JcLOG3) and JcLOG5 may participate in cytokinin metabolic pathway in Jatropha. Consistently, exogenous application of cytokinin (6-benzyladenine, 6-BA) on inflorescence buds induced high-branch inflorescence phenotype in both low-branch inflorescence mutant (g) and WT plants. These results suggested that cytokinin is an important regulator in controlling inflorescence branching in Jatropha. In addition, comparative transcriptome analysis showed that Arabidopsis homologous genes Jatropha AGAMOUS-LIKE 6 (JcAGL6), JcAGL24, FRUITFUL (JcFUL), LEAFY (JcLFY), SEPALLATAs (JcSEPs), TERMINAL FLOWER 1 (JcTFL1), and WUSCHEL-RELATED HOMEOBOX 3 (JcWOX3), were differentially expressed in inflorescence buds between dxh and g mutants and WT plants, indicating that they may participate in inflorescence development in Jatropha. The expression of JcTFL1 was downregulated, while the expression of JcLFY and JcAP1 were upregulated in inflorescences in low-branch g mutant. CONCLUSIONS: Cytokinin is an important regulator in controlling inflorescence branching in Jatropha. The regulation of inflorescence architecture by the genes involved in floral development, including TFL1, LFY and AP1, may be conservative in Jatropha and Arabidopsis. Our results provide helpful information for elucidating the regulatory mechanism of inflorescence architecture in Jatropha.