[Efficacy and safety of ultra rapid lispro in the treatment of type 2 diabetes mellitus: a randomized controlled clinical trial].

Objective: To evaluate and compare the efficacy and safety of ultra-rapid lispro insulin (URLi) and humalog lispro (HL) in the treatment of type 2 diabetes mellitus. Methods: This was an international multicenter, double-blind, randomized controlled study. From May 2019 to January 2021, a total of 481 patients with type 2 diabetes mellitus, who had been using insulin for at least 90 days and had poor glycemic control, were included. These patients were recruited from 34 research centers in China, including Shanghai Jiao Tong University School of Medicine Affiliated Sixth People's Hospital. They were assigned to either the URLi group (319 patients) or the HL group (162 patients) using stratified blocked randomization. The primary endpoint was the change in hemoglobin A1c (HbA1c) relative to baseline after 26 weeks of treatment. Secondary endpoints included the proportion of patients who achieved HbA1c<7.0% and ≤6.5% after 26 weeks of treatment, 1-h postprandial glucose (1hPG) or 2-h postprandial glucose (2hPG) excursions during a mixed meal tolerance test at week 26, as well as safety parameters. Continuous variables were compared using mixed model repeated measures or analysis of covariance, and categorical variables were compared using logistic regression or Fisher's exact test. Results: Data based on the Chinese subgroup showed that there were no statistically significant differences between the URLi and HL groups in terms of male percentage [56.1% (179/319) vs. 56.2% (91/162); P=0.990], age [(59.5±8.4) vs. (59.6±9.3) years; P=0.839] and other baseline characteristics. Regarding the change in HbA1c relative to baseline, the URLi group was non-inferior to the HL group (-0.59%±0.05% vs. -0.66%±0.06%; P=0.312). There were no statistically significant differences between the URLi and HL groups in proportion of patients who achieved HbA1c<7.0% [47.3% (138/292) vs. 45.2% (70/155); P=0.907] and≤6.5% [27.7% (81/292) vs. 27.7% (43/155); P=0.816]. The excursions in 1hPG [(6.20±0.21) vs. (6.90±0.25) mmol/L; P=0.001] and 2hPG [(8.10±0.27) vs. (9.30±0.31) mmol/L; P<0.001] were lower in the URLi group than the HL group, with statistically significant differences. In terms of safety, there were no statistically significant differences in the percentage of subjects who reported treatment-emergent adverse events between the URLi and HL groups [49.8% (159/319) vs. 50.0% (81/162); P=1.000]. The event rate of nocturnal hypoglycemia was lower in the URLi group than the HL group, with statistically significant differences [(0.53±0.10) vs. (0.89±0.16) events per patient-year; P=0.040]. Conclusions: With good glycemic control, URLi showed non-inferiority for HbA1c improvement versus HL and was superior to HL for postprandial glucose excursion control. Meanwhile the rate and incidence of nocturnal hypoglycemia were lower in the URLi group than the HL group.

LncRNA FAS-AS1 promotes the degradation of extracellular matrix of cartilage in osteoarthritis.

OBJECTIVE: To investigate the expression of long non-coding RNA (lncRNA) FAS-AS1 in osteoarthritis cartilage and to explore its effect on articular cartilage cells. PATIENTS AND METHODS: A total of 20 tissue samples of primary knee joint osteoarthritis and 20 tissue samples of knee joint cartilage after traumatic amputation were collected. Fluorescence quantitative polymerase chain reaction (PCR) was performed to detect the expression of FAS-AS1, MMP1, MMP13, and COL2A1 in cartilage. FAS-AS1 small interfering RNA (siRNA) was transfected to chondrocytes transiently to observe its effects on proliferation, apoptosis of chondrocytes, and the expressions of MMP1, MMP13, and COL2A1. RESULTS: The expressions of FAS-AS1, MMP1, and MMP13 in osteoarthritis tissues increased significantly, while COL2A1 presented a low expression. Reducing the expression of FAS-AS1 inhibited cell apoptosis and promote cell proliferation. Additionally, in vitro experiments showed that low expression of FAS-AS1 decreased the expressions of MMP1 and MMP13, but increased the expression of COL2A1. CONCLUSIONS: The expression of FAS-AS1 was increased in osteoarthritis, and FAS-AS1 could be involved in the development of the disease by regulating the proliferation, apoptosis of chondrocytes and promoting the degradation of extracellular matrix.

MicroRNA-520d-3p inhibits osteosarcoma progression by degradation of Akt1.

OBJECTIVE: To detect the expression of microRNA-520d-3p in osteosarcoma tissue and the function on the osteosarcoma cells proliferation. PATIENTS AND METHODS: We used qRT-PCR to access microRNA-520d-3p level from 10 cases of osteosarcoma and its adjacent tissues. The osteosarcoma cell lines were screened. The microRNA-520d-3p mimics or inhibitor was transfected into human osteosarcoma cells by liposome method, and the cell proliferation of each group was detected by the CCK8 assay. We used bioinformatics methods to detect and predict the target genes of microRNA-520d-3p. Luciferase reporter assay was utilized to detect the relative luciferase activity between microRNA-520d-3p and Akt1. Meanwhile, after cells were transfected with microRNA-520d-3p mimics, microRNA-520d-3p mimics + OE-Akt1, microRNA-520d-3p inhibitor or microRNA-520d-3p inhibitor + si-Akt1, we detected cell viability using CCK-8 assay, respectively to access the interaction between Akt1 and microRNA-520d-3p. RESULTS: Lowly expressed microRNA-520d-3p in osteosarcoma tissues was observed in comparison with adjacent tissues. After transfecting with microRNA-520d-3p mimics, the viability of MG63 and U-20S cells decreased, which was higher in cells transfecting microRNA-520d-3p inhibitor. Bioinformatics prediction and dual luciferase reporter assay illustrated that microRNA-520d-3p targeted on Akt1. At the same time, Akt1 expression was higher in osteosarcoma tissues than in adjacent ones, cell proliferation was inhibited after blocking its expression. In addition, after transfected with microRNA-520d-3p mimic, viability of MG63 and U-20S cells decreased, which can be reversed by OE-Akt1. In contrast, the viability of MG63 and U-20S cells increased after transfection with microRNA-520d-3p inhibitor and which were reversed by si-Akt1. CONCLUSIONS: Lowly expressed microRNA-520d-3p was observed in osteosarcoma; overexpression of microRNA-520d-3p can target Akt1 thus inhibiting proliferation of osteosarcoma cells.

Association between H19 polymorphisms and osteosarcoma risk.

OBJECTIVE: The long non-coding RNA (lncRNA) H19, a maternally expressed imprinted gene, has involvement in cancer susceptibility and disease progression. However, the association between H19 polymorphisms and osteosarcoma susceptibility has remained elusive. We designed this case-control study to explore the association between H19 polymorphism and osteosarcoma risk. PATIENTS AND METHODS: In this study, we genotyped 4 tagger SNPs of the H19 gene in a case-control study including 193 osteosarcoma cases and 393 cancer-free controls. RESULTS: For the main effect analysis, rs217727 (G>A) was associated with osteosarcoma risk (GA/GG: adjusted OR = 1.51, 95% CI: 1.06-2.17, p = 0.024; AA/GG: adjusted OR = 1.89, 95% CI: 1.23-2.91, p = 0.004; additive model: adjusted OR = 1.35, 95% CI: 1.01-1.80, p = 0.043). CONCLUSIONS: This finding indicates that rs217727 polymorphism may play a role in genetic susceptibility to the risk of osteosarcoma, which may improve our understanding of the potential contribution of H19 SNPs to cancer pathogenesis.

Active DNA demethylation in plants and animals.

Active DNA demethylation regulates many vital biological processes, including early development and locus-specific gene expression in plants and animals. In Arabidopsis, bifunctional DNA glycosylases directly excise the 5-methylcytosine base and then cleave the DNA backbone at the abasic site. Recent evidence suggests that mammals utilize DNA glycosylases after 5-methylcytosine is oxidized and/or deaminated. In both cases, the resultant single-nucleotide gap is subsequently filled with an unmodified cytosine through the DNA base excision repair pathway. The enzymatic removal of 5-methylcytosine is tightly integrated with histone modifications and possibly noncoding RNAs. Future research will increase our understanding of the mechanisms and critical roles of active DNA demethylation in various cellular processes as well as inspire novel genetic and chemical therapies for epigenetic disorders.

CD16+ monocytes in breast cancer patients: expanded by monocyte chemoattractant protein-1 and may be useful for early diagnosis.

Human peripheral blood monocytes are a heterogeneous population, including CD14(+) CD16(-) 'classical' monocytes and CD14(+) CD16(+) 'proinflammatory' monocytes. CD16(+) monocytes are expanded in various inflammatory conditions. However, little is known about the CD14(+) CD16(+) monocytes in patients with breast cancer. We detected CD14(+) CD16(+) monocytes in 96 patients with breast cancer and 54 control subjects using flow cytometry. Receiver-operating characteristic (ROC) curve analysis was used to determine the feasibility of CD14(+) CD16(+) monocytes as an indicator for diagnosis of breast cancer. We found that the frequency of CD14(+) CD16(+) monocytes showed a significantly greater increase in breast cancer patients than in controls (16·96% versus 10·84%, P < 0·0001). The area under the ROC curve for CD14(+) CD16(+) monocytes was 0·805 [95% confidence interval (95% CI): 0·714-0·877, P = 0·0001]. Furthermore, the levels of CD16(+) monocytes were significantly negatively associated with the tumour size and pathological staging. In vitro, we showed that CD14(+) CD16(+) monocytes were expanded significantly when the purified CD14(+) monocytes were exposed to Michigan Cancer Foundation (MCF)-7 cells-conditioned medium (MCF-CM) or, separately, to monocyte chemotactic protein 1 (MCP-1). Neutralizing antibodies against MCP-1 inhibited the expansion of CD14(+) CD16(+) monocytes by MCF-CM. Collectively, our findings indicated that MCP-1 can expand CD14(+) CD16(+) monocytes in patients with breast cancer. Furthermore, the CD14(+) CD16(+) monocyte may be a useful indicator in early diagnosis of breast cancer.

An unusual alphasatellite associated with monopartite begomoviruses attenuates symptoms and reduces betasatellite accumulation.

The Oman strain of Tomato yellow leaf curl virus (TYLCV-OM) and its associated betasatellite, an isolate of Tomato leaf curl betasatellite (ToLCB), were previously reported from Oman. Here we report the isolation of a second, previously undescribed, begomovirus [Tomato leaf curl Oman virus (ToLCOMV)] and an alphasatellite from that same plant sample. This alphasatellite is closely related (90 % shared nucleotide identity) to an unusual DNA-2-type Ageratum yellow vein Singapore alphasatellite (AYVSGA), thus far identified only in Singapore. ToLCOMV was found to have a recombinant genome comprising sequences derived from two extant parents, TYLCV-OM, which is indigenous to Oman, and Papaya leaf curl virus from the Indian subcontinent. All possible combinations of ToLCOMV, TYLCV-OM, ToLCB and AYVSGA were used to agro-inoculate tomato and Nicotiana benthamiana. Infection with ToLCOMV yielded mild leaf-curl symptoms in both hosts; however, plants inoculated with TYLCV-OM developed more severe symptoms. Plants infected with ToLCB in the presence of either helper begomovirus resulted in more severe symptoms. Surprisingly, symptoms in N. benthamiana infected with the alphasatellite together with either of the helper viruses and the betasatellite were attenuated and betasatellite DNA accumulation was substantially reduced. However, in the latter plants no concomitant reduction in the accumulation of helper virus DNA was observed. This is the first example of an attenuation of begomovirus-betasatellite symptoms by this unusual class of alphasatellites. This observation suggests that some DNA-2 alphasatellites encode a pathogenicity determinant that may modulate begomovirus-betasatellite infection by reducing betasatellite DNA accumulation.

Radically rethinking agriculture for the 21st century.

Population growth, arable land and fresh water limits, and climate change have profound implications for the ability of agriculture to meet this century's demands for food, feed, fiber, and fuel while reducing the environmental impact of their production. Success depends on the acceptance and use of contemporary molecular techniques, as well as the increasing development of farming systems that use saline water and integrate nutrient flows.

Nuclear RNA export and its importance in abiotic stress responses of plants.

Transduction of developmental and environmental cues into the nucleus to induce transcription and the export of RNAs to the cytoplasm through the nuclear pore complex (NPC) play pivotal roles in regulation of gene expression. The process of bulk export of mRNAs from nucleus to cytoplasm is highly conserved across eukaryotes. Assembly of export-competent mRNA ribonucleoprotein (mRNP) is coupled with both transcription and mRNA processing. The export-competent mRNP consists of mRNAs and a dozen nucleocytoplasmic shuttling nuclear proteins, including RNA export factors (Mex67-Mtr2 heterodimer, Npl3), poly(A)-binding proteins, DEAD-box protein 5 (Dbp5), and nucleoporins (NUPs) in yeast. Mobile NUPs help docking of mRNP to the NPC nuclear basket. A partially unfolded mRNP complex appears to be pulled through the NPC by using energy from Dbp5-catalyzed ATP hydrolysis. Dbp5 probably catalyzes the release of mRNA from mRNP in the cytoplasm. In contrast to bulk export of mRNAs by a Mex67-Mtr2/Npl3-dependent pathway, a specific subset of mRNA export under stress and export of microRNAs are mediated through the karyopherin (importin beta) family of proteins in a Ran-GTPase-dependent pathway. Our knowledge of mRNA export mechanisms in flowering plants is in its infancy. Some proteins of the NUP107-160 complex, NUPs and DEAD-box proteins (DBPs), have been studied in flowering plants. Arabidopsis NUP160/SAR1 plays a critical role in mRNA export, regulation of flowering, and hormone and abiotic stress responses, whereas NUP96/ SAR3/MOS3 is required for mRNA export to modulate hormonal and biotic stress responses. DEAD-box proteins have been implicated in mRNA export and abiotic stress response of yeast and higher plants. Arabidopsis DBP CRYOPHYTE/LOS4 plays an important role in mRNA export, abiotic stress response, germination, and plant development. Further studies on various components of nuclear mRNA export in plants during nonstress and stress conditions will be necessary to understand the link between mRNA export and stress-responsive gene expression.

Tissue-engineered peripheral nerve grafting by differentiated bone marrow stromal cells.

Bone marrow stromal cells are multipotential stem cells that contribute to the differentiation of tissues such as bone, cartilage, fat and muscle. In the experiment, we found that bone marrow stromal cells can be induced to differentiate into cells expressing characteristic markers of Schwann cells, such as S-100 and glial fibrillary acidic protein, promoting peripheral nerve regeneration. Tissue-engineered bioartificial nerve grafting of rats by differentiated bone marrow stromal cells was applied for bridging a 10 mm-long sciatic nerve defect. Twenty-eight inbred strains of female F344 rats weighing 160 approximately 200 g were randomly divided into four nerve grafting groups, with seven rats in each group. Differentiated bone marrow stromal cell-laden group: poly(lactic-co-glycolic) acid tubes with an intrinsic framework were seeded with syngeneic bone marrow stromal cells which were induced for 5 days; Schwann cell-laden group: poly(lactic-co-glycolic) acid tubes with an intrinsic framework were seeded with syngeneic Schwann cells; acellular group: poly(lactic-co-glycolic) acid tubes were only filled with an intrinsic framework; autografts group. Three months later, a series of examinations was performed, including electrophysiological methods, walking track analysis, immunohistological staining of nerves, immunostaining of S-100 and neurofilament, and axon counts. The outcome indicated that bone marrow stromal cells are able to differentiate into Schwann-like cells and Schwann-like cells could promote nerve regeneration. Bone marrow stromal cells may be potentially optional seed cells for peripheral nerve tissue engineering because of abilities of promoting axonal regeneration.

Before and beyond ABA: upstream sensing and internal signals that determine ABA accumulation and response under abiotic stress.

Sensing and signalling events that detect abiotic stress-induced changes in plant water status and initiate downstream stress responses such as ABA (abscisic acid) accumulation and osmoregulation remain uncharacterized in plants. Although conclusive results are lacking, recent results from plants, and analogies to signalling in other organisms, suggest possible mechanisms for sensing altered water status and initial transduction of that signal. Internal signals that act downstream of ABA and modulate stress responses to reflect the type and severity of the stress and the metabolic status of the plant are also not well understood. Two specific types of signalling, sugar sensing and reactive oxygen signalling, are likely to be modulators of ABA response under stress. For both upstream sensing and signalling of plant water status as well as downstream modulation of ABA response, present results suggest several genetic strategies with high potential to increase our understanding of the molecular basis by which plants sense and respond to altered water status.

SOS3 (salt overly sensitive 3) from Arabidopsis thaliana: expression, purification, crystallization and preliminary X-ray analysis.

The salt-tolerance gene SOS3 (salt overly sensitive 3) of Arabidopsis thaliana encodes a calcium-binding protein that is able to sense the cytosolic calcium signal elicited by salt stress. SOS3 activates the SOS2 protein kinase, which activates various ion transporters. SOS3 was cloned into a plasmid and expressed in Escherichia coli, allowing purification of the protein to homogeneity. Two crystals with different additive contents were grown. Both diffract to 3.2 A resolution and belong to space group I4(1), with unit-cell parameters a = 93.65, c = 80.08 A and a = 91.79, c = 85.78 A, respectively. A promising molecular-replacement solution has been found using neuronal calcium-sensor 1 as the search model. Interestingly, no solution was found using AtCBL2 (A. thaliana calcineurin B-like protein) structure as a search model, although this protein belongs to the same family and displays 50% sequence identity.

Molecular and genetic aspects of plant responses to osmotic stress.

Drought, high salinity and freezing impose osmotic stress on plants. Plants respond to the stress in part by modulating gene expression, which eventually leads to the restoration of cellular homeostasis, detoxification of toxins and recovery of growth. The signal transduction pathways mediating these adaptations can be dissected by combining forward and reverse genetic approaches with molecular, biochemical and physiological studies. Arabidopsis is a useful genetic model system for this purpose and its relatives including the halophyte Thellungiella halophila, can serve as valuable complementary genetic model systems.

Effects of dexamethasone on Flt3 receptor expression and proliferation induced by recombinant human Flt3 ligand in malignant hematopoietic cells.

AIM: To investigate the effect of dexamethasone (DXM) on the expression of Flt3 receptor and the proliferation mediated by recombinant human Flt3 ligand (rhFL) in leukemia cells. METHODS: Eighteen malignant hematopoietic cell lines and 10 leukemia blasts from leukemia patients were examined by flow cytometry for the expression of Flt3 receptor before and after incubation with DXM 0.1 micromol/L for 24 h. The effect of DXM on the proliferation of malignant hematopoietic cells was measured by MTT assay. RESULTS: (1) Expression of the Flt3 receptor in malignant hematopoietic cell lines and leukemia blasts was widespread and extremely heterogeneous; (2) The presence of receptor on the surface of malignant hematopoietic cell didn't necessarily imply a significant ligand-induced response, at least in terms of proliferation. Conversely, some Flt3 receptor-negative malignant hematopoietic cells responded to rhFL; (3) DXM down-regulated the expression of Flt3 receptor and inhibited the proliferation induced by rhFL in some malignant hematopoietic cell lines and fresh leukemia cells. CONCLUSION: DXM may down-regulate the expression of Flt3 receptor on the surface of malignant hematopoietic cells and inhibit the proliferation induced by rhFL. A combination of rhFL and DXM may serve to control hematopoietic defects in malignant hematopoietic diseases.

Modulation of abscisic acid signal transduction and biosynthesis by an Sm-like protein in Arabidopsis.

The phytohormone abscisic acid (ABA) regulates plant growth and development as well as stress tolerance. The Arabidopsis sad1 (supersensitive to ABA and drought) mutation increases plant sensitivity to drought stress and ABA in seed germination, root growth, and the expression of some stress-responsive genes. sad1 plants are also defective in the positive feedback regulation of ABA biosynthesis genes by ABA and are impaired in drought stress induction of ABA biosynthesis. SAD1 encodes a polypeptide similar to multifunctional Sm-like snRNP proteins that are required for mRNA splicing, export, and degradation. These results suggest a critical role for mRNA metabolism in the control of ABA signaling as well as in the regulation of ABA homeostasis.

AtHKT1 is a salt tolerance determinant that controls Na(+) entry into plant roots.

Two Arabidopsis thaliana extragenic mutations that suppress NaCl hypersensitivity of the sos3-1 mutant were identified in a screen of a T-DNA insertion population in the genetic background of Col-0 gl1 sos3-1. Analysis of the genome sequence in the region flanking the T-DNA left border indicated that sos3-1 hkt1-1 and sos3-1 hkt1-2 plants have allelic mutations in AtHKT1. AtHKT1 mRNA is more abundant in roots than shoots of wild-type plants but is not detected in plants of either mutant, indicating that this gene is inactivated by the mutations. hkt1-1 and hkt1-2 mutations can suppress to an equivalent extent the Na(+) sensitivity of sos3-1 seedlings and reduce the intracellular accumulation of this cytotoxic ion. Moreover, sos3-1 hkt1-1 and sos3-1 hkt1-2 seedlings are able to maintain [K(+)](int) in medium supplemented with NaCl and exhibit a substantially higher intracellular ratio of K(+)/Na(+) than the sos3-1 mutant. Furthermore, the hkt1 mutations abrogate the growth inhibition of the sos3-1 mutant that is caused by K(+) deficiency on culture medium with low Ca(2+) (0.15 mM) and <200 microM K(+). Interestingly, the capacity of hkt1 mutations to suppress the Na(+) hypersensitivity of the sos3-1 mutant is reduced substantially when seedlings are grown in medium with low Ca(2+) (0.15 mM). These results indicate that AtHKT1 is a salt tolerance determinant that controls Na(+) entry and high affinity K(+) uptake. The hkt1 mutations have revealed the existence of another Na(+) influx system(s) whose activity is reduced by high [Ca(2+)](ext).

Cell signaling under salt, water and cold stresses.

Forward genetics and biochemical approaches to studying plant responses to salt, water and cold stresses began to bear fruit recently. Analysis of salt overly sensitive (sos) Arabidopsis mutants revealed a novel calcium-regulated protein kinase pathway for response to the ionic aspect of salt stress. In-gel kinase assays identified several SOS-independent protein kinases that are either activated specifically by osmotic stress or by multiple abiotic and biotic stresses. Molecular analysis revealed a transcriptional cascade in cold-regulated gene expression.

The Arabidopsis LOS5/ABA3 locus encodes a molybdenum cofactor sulfurase and modulates cold stress- and osmotic stress-responsive gene expression.

To understand low temperature and osmotic stress signaling in plants, we isolated and characterized two allelic Arabidopsis mutants, los5-1 and los5-2, which are impaired in gene induction by cold and osmotic stresses. Expression of RD29A-LUC (the firefly luciferase reporter gene under the control of the stress-responsive RD29A promoter) in response to cold and salt/drought is reduced in the los5 mutants, but the response to abscisic acid (ABA) remains unaltered. RNA gel blot analysis indicates that the los5 mutation reduces the induction of several stress-responsive genes by cold and severely diminishes or even completely blocks the induction of RD29A, COR15, COR47, RD22, and P5CS by osmotic stresses. los5 mutant plants are compromised in their tolerance to freezing, salt, or drought stress. los5 plants are ABA deficient, as indicated by increased transpirational water loss and reduced accumulation of ABA under drought stress in the mutant. A comparison with another ABA-deficient mutant, aba1, reveals that the impaired low-temperature gene regulation is specific to the los5 mutation. Genetic tests suggest that los5 is allelic to aba3. Map-based cloning reveals that LOS5/ABA3 encodes a molybdenum cofactor (MoCo) sulfurase. MoCo sulfurase catalyzes the generation of the sulfurylated form of MoCo, a cofactor required by aldehyde oxidase that functions in the last step of ABA biosynthesis in plants. The LOS5/ABA3 gene is expressed ubiquitously in different plant parts, and the expression level increases in response to drought, salt, or ABA treatment. Our results show that LOS5/ABA3 is a key regulator of ABA biosynthesis, stress-responsive gene expression, and stress tolerance.

FIERY1 encoding an inositol polyphosphate 1-phosphatase is a negative regulator of abscisic acid and stress signaling in Arabidopsis.

The plant hormone abscisic acid (ABA) plays a wide range of important roles in plant growth and development, including embryogenesis, seed dormancy, root and shoot growth, transpiration, and stress tolerance. ABA and various abiotic stresses also activate the expression of numerous plant genes through undefined signaling pathways. To gain insight into ABA and stress signal transduction, we conducted a genetic screen based on ABA- and stress-inducible gene transcription. Here we report the identification of an Arabidopsis mutation, fiery1 (fry1), which results in super-induction of ABA- and stress-responsive genes. Seed germination and postembryonic development of fry1 are more sensitive to ABA or stress inhibition. The mutant plants are also compromised in tolerance to freezing, drought, and salt stresses. Map-based cloning revealed that FRY1 encodes an inositol polyphosphate 1-phosphatase, which functions in the catabolism of inositol 1, 4, 5-trisphosphate (IP(3)). Upon ABA treatment, fry1 mutant plants accumulated more IP(3) than did the wild-type plants. These results provide the first genetic evidence indicating that phosphoinositols mediate ABA and stress signal transduction in plants and their turnover is critical for attenuating ABA and stress signaling.