Cytoreductive surgery plus hyperthermic intraoperative peritoneal chemotherapy for people with peritoneal metastases from colorectal, ovarian or gastric origin: A systematic review of randomized controlled trials.

BACKGROUND: There is uncertainty in the relative benefits and harms of hyperthermic intraoperative peritoneal chemotherapy (HIPEC) when added to cytoreductive surgery (CRS) +/- systemic chemotherapy or systemic chemotherapy alone in people with peritoneal metastases from colorectal, gastric, or ovarian cancers. METHODS: We searched randomized controlled trials (RCTs) in the medical literature until April 14, 2022 and applied methods used for high-quality systematic reviews. FINDINGS: We included a total of eight RCTs (seven RCTs included in quantitative analysis as one RCT did not provide data in an analyzable format). All comparisons other than ovarian cancer contained only one trial. For gastric cancer, there is high uncertainty about the effect of CRS + HIPEC + systemic chemotherapy. For stage III or greater epithelial ovarian cancer undergoing interval cytoreductive surgery, CRS + HIPEC + systemic chemotherapy probably decreases all-cause mortality compared to CRS + systemic chemotherapy. For colorectal cancer, CRS + HIPEC + systemic chemotherapy probably results in little to no difference in all-cause mortality and may increase the serious adverse events proportions compared to CRS +/- systemic chemotherapy, but probably decreases all-cause mortality compared to fluorouracil-based systemic chemotherapy alone. INTERPRETATION: The role of CRS + HIPEC in gastric peritoneal metastases is uncertain. CRS + HIPEC should be standard of care in women with stage III or greater epithelial ovarian cancer undergoing interval CRS. CRS + systemic chemotherapy should be standard of care for people with colorectal peritoneal metastases, with HIPEC given only as part of a RCT focusing on subgroups and regimes. PROSPERO REGISTRATION: CRD42019130504.

Follow-up strategies for patients with splenic trauma managed non-operatively: the 2022 World Society of Emergency Surgery consensus document.

BACKGROUND: In 2017, the World Society of Emergency Surgery published its guidelines for the management of adult and pediatric patients with splenic trauma. Several issues regarding the follow-up of patients with splenic injuries treated with NOM remained unsolved. METHODS: Using a modified Delphi method, we sought to explore ongoing areas of controversy in the NOM of splenic trauma and reach a consensus among a group of 48 international experts from five continents (Africa, Europe, Asia, Oceania, America) concerning optimal follow-up strategies in patients with splenic injuries treated with NOM. RESULTS: Consensus was reached on eleven clinical research questions and 28 recommendations with an agreement rate ≥ 80%. Mobilization after 24 h in low-grade splenic trauma patients (WSES Class I, AAST Grades I-II) was suggested, while in patients with high-grade splenic injuries (WSES Classes II-III, AAST Grades III-V), if no other contraindications to early mobilization exist, safe mobilization of the patient when three successive hemoglobins 8 h apart after the first are within 10% of each other was considered safe according to the panel. The panel suggests adult patients to be admitted to hospital for 1 day (for low-grade splenic injuries-WSES Class I, AAST Grades I-II) to 3 days (for high-grade splenic injuries-WSES Classes II-III, AAST Grades III-V), with those with high-grade injuries requiring admission to a monitored setting. In the absence of specific complications, the panel suggests DVT and VTE prophylaxis with LMWH to be started within 48-72 h from hospital admission. The panel suggests splenic artery embolization (SAE) as the first-line intervention in patients with hemodynamic stability and arterial blush on CT scan, irrespective of injury grade. Regarding patients with WSES Class II blunt splenic injuries (AAST Grade III) without contrast extravasation, a low threshold for SAE has been suggested in the presence of risk factors for NOM failure. The panel also suggested angiography and eventual SAE in all hemodynamically stable adult patients with WSES Class III injuries (AAST Grades IV-V), even in the absence of CT blush, especially when concomitant surgery that requires change of position is needed. Follow-up imaging with contrast-enhanced ultrasound/CT scan in 48-72 h post-admission of trauma in splenic injuries WSES Class II (AAST Grade III) or higher treated with NOM was considered the best strategy for timely detection of vascular complications. CONCLUSION: This consensus document could help guide future prospective studies aiming at validating the suggested strategies through the implementation of prospective trauma databases and the subsequent production of internationally endorsed guidelines on the issue.

Non-autonomous stomatal control by pavement cell turgor via the K+ channel subunit AtKC1.

Stomata optimize land plants' photosynthetic requirements and limit water vapor loss. So far, all of the molecular and electrical components identified as regulating stomatal aperture are produced, and operate, directly within the guard cells. However, a completely autonomous function of guard cells is inconsistent with anatomical and biophysical observations hinting at mechanical contributions of epidermal origins. Here, potassium (K+) assays, membrane potential measurements, microindentation, and plasmolysis experiments provide evidence that disruption of the Arabidopsis thaliana K+ channel subunit gene AtKC1 reduces pavement cell turgor, due to decreased K+ accumulation, without affecting guard cell turgor. This results in an impaired back pressure of pavement cells onto guard cells, leading to larger stomatal apertures. Poorly rectifying membrane conductances to K+ were consistently observed in pavement cells. This plasmalemma property is likely to play an essential role in K+ shuttling within the epidermis. Functional complementation reveals that restoration of the wild-type stomatal functioning requires the expression of the transgenic AtKC1 at least in the pavement cells and trichomes. Altogether, the data suggest that AtKC1 activity contributes to the building of the back pressure that pavement cells exert onto guard cells by tuning K+ distribution throughout the leaf epidermis.

Can you trust clinical practice guidelines for laparoscopic surgery? A systematic review of clinical practice guidelines for laparoscopic surgery.

BACKGROUND: Clinical practice guidelines aim to support clinicians in providing clinical care and should be supported by evidence. There is currently no information on whether clinical practice guidelines in laparoscopic surgery are supported by evidence. METHODS: We performed a systematic review and identified clinical practice guidelines of laparoscopic surgery published in PubMed and Embase between March 2016 and February 2019. We performed an independent assessment of the strength of recommendation based on the evidence provided by the guideline authors. We used the 'Appraisal of Guidelines for Research & Evaluation II' (AGREE-II) Tool's 'rigour of development', 'clarity of presentation', and 'editorial independence' domains to assess the quality of the guidelines. We performed a mixed-effects generalised linear regression modelling. RESULTS: We retrieved 63 guidelines containing 1905 guideline statements. The median proportion of 'difference in rating' of strength of recommendation between the guideline authors and independent assessment was 33.3% (quartiles: 18.3%, 55.8%). The 'rigour of development' domain score (odds ratio 0.06; 95% confidence intervals 0.01-0.48 per unit increase in rigour score; P value = 0.0071) and whether the strength of recommendation was 'strong' by independent evaluation (odds ratio 0.09 (95% confidence intervals 0.06-0.13; P value < 0.001) were the only determinants of difference in rating between the guideline authors and independent evaluation. CONCLUSION: A considerable proportion of guideline statements in clinical practice guidelines in laparoscopic surgery are not supported by evidence. Guideline authors systematically overrated the strength of the recommendation (i.e., even when the evidence points to weak recommendation, guideline authors made strong recommendations).

Smartphone GPS signatures of patients undergoing spine surgery correlate with mobility and current gold standard outcome measures.

OBJECTIVE: Patient-reported outcome measures (PROMs) are currently the gold standard to evaluate patient physical performance and ability to recover after spine surgery. However, PROMs have significant limitations due to the qualitative and subjective nature of the information reported as well as the impossibility of using this method in a continuous manner. The smartphone global positioning system (GPS) can be used to provide continuous, quantitative, and objective information on patient mobility. The aim of this study was to use daily mobility features derived from the smartphone GPS to characterize the perioperative period of patients undergoing spine surgery and to compare these objective measurements to PROMs, the current gold standard. METHODS: Eight daily mobility features were derived from smartphone GPS data in a population of 39 patients undergoing spine surgery for a period of 2 months starting 3weeks before surgery. In parallel, three different PROMs for pain (visual analog scale [VAS]), disability (Oswestry Disability Index [ODI]) and functional status (Patient-Reported Outcomes Measurement Information System [PROMIS]) were serially measured. Segmented linear regression analysis was used to assess trends before and after surgery. The Student paired t-test was used to compare pre- and postoperative PROM scores. Pearson's correlation was calculated between the daily average of each GPS-based mobility feature and the daily average of each PROM score during the recovery period. RESULTS: Smartphone GPS features provided data documenting a reduction in mobility during the immediate postoperative period, followed by a progressive and steady increase with a return to baseline mobility values 1 month after surgery. PROMs measuring pain, physical performance, and disability were significantly different 1 month after surgery compared to the 2 immediate preoperative weeks. The GPS-based features presented moderate to strong linear correlation with pain VAS and PROMIS physical score during the recovery period (Pearson r > 0.7), whereas the ODI and PROMIS mental scores presented a weak correlation (Pearson r approximately 0.4). CONCLUSIONS: Smartphone-derived GPS features were shown to accurately characterize perioperative mobility trends in patients undergoing surgery for spine-related diseases. Features related to time (rather than distance) were better at describing patient physical and performance status. Smartphone GPS has the potential to be used for the development of accurate, noninvasive and personalized tools for patient mobility monitoring after surgery.

2020 World Society of Emergency Surgery updated guidelines for the diagnosis and treatment of acute calculus cholecystitis.

BACKGROUND: Acute calculus cholecystitis (ACC) has a high incidence in the general population. The presence of several areas of uncertainty, along with the availability of new evidence, prompted the current update of the 2016 WSES (World Society of Emergency Surgery) Guidelines on ACC. MATERIALS AND METHODS: The WSES president appointed four members as a scientific secretariat, four members as an organization committee and four members as a scientific committee, choosing them from the expert affiliates of WSES. Relevant key questions were constructed, and the task force produced drafts of each section based on the best scientific evidence from PubMed and EMBASE Library; recommendations were developed in order to answer these key questions. The quality of evidence and strength of recommendations were reviewed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria (see https://www.gradeworkinggroup.org/ ). All the statements were presented, discussed and voted upon during the Consensus Conference at the 6th World Congress of the World Society of Emergency Surgery held in Nijmegen (NL) in May 2019. A revised version of the statements was voted upon via an online questionnaire until consensus was reached. RESULTS: The pivotal role of surgery is confirmed, including in high-risk patients. When compared with the WSES 2016 guidelines, the role of gallbladder drainage is reduced, despite the considerable technical improvements available. Early laparoscopic cholecystectomy (ELC) should be the standard of care whenever possible, even in subgroups of patients who are considered fragile, such as the elderly; those with cardiac disease, renal disease and cirrhosis; or those who are generally at high risk for surgery. Subtotal cholecystectomy is safe and represents a valuable option in cases of difficult gallbladder removal. CONCLUSIONS, KNOWLEDGE GAPS AND RESEARCH RECOMMENDATIONS: ELC has a central role in the management of patients with ACC. The value of surgical treatment for high-risk patients should lead to a distinction between high-risk patients and patients who are not suitable for surgery. Further evidence on the role of clinical judgement and the use of clinical scores as adjunctive tools to guide treatment of high-risk patients and patients who are not suitable for surgery is required. The development of local policies for safe laparoscopic cholecystectomy is recommended.

Who Rules the Cell? An Epi-Tale of Histone, DNA, RNA, and the Metabolic Deep State.

Epigenetics refers to the mode of inheritance independent of mutational changes in the DNA. Early evidence has revealed methylation, acetylation, and phosphorylation of histones, as well as methylation of DNA as part of the underlying mechanisms. The recent awareness that many human diseases have in fact an epigenetic basis, due to unbalanced diets, has led to a resurgence of interest in how epigenetics might be connected with, or even controlled by, metabolism. The Next-Generation genomic technologies have now unleashed torrents of results exposing a wondrous array of metabolites that are covalently attached to selective sites on histones, DNA and RNA. Metabolites are often cofactors or targets of chromatin-modifying enzymes. Many metabolites themselves can be acetylated or methylated. This indicates that the acetylome and methylome can actually be deep and pervasive networks to ensure the nuclear activities are coordinated with the metabolic status of the cell. The discovery of novel histone marks also raises the question on the types of pathways by which their corresponding metabolites are replenished, how they are corralled to the specific histone residues and how they are recognized. Further, atypical cytosines and uracil have also been found in eukaryotic genomes. Although these new and extensive connections between metabolism and epigenetics have been established mostly in animal models, parallels must exist in plants, inasmuch as many of the basic components of chromatin and its modifying enzymes are conserved. Plants are chemical factories constantly responding to stress. Plants, therefore, should lend themselves readily for identifying new endogenous metabolites that are also modulators of nuclear activities in adapting to stress.

Induction immunosuppression in adults undergoing liver transplantation: a network meta-analysis.

BACKGROUND: Liver transplantation is considered the definitive treatment for people with liver failure. As part of post-liver transplantation management, immunosuppression (suppressing the host immunity) is given to prevent graft rejections. Immunosuppressive drugs can be classified into those that are used for a short period during the beginning phase of immunosuppression (induction immunosuppression) and those that are used over the entire lifetime of the individual (maintenance immunosuppression), because it is widely believed that graft rejections are more common during the first few months after liver transplantation. Some drugs such as glucocorticosteroids may be used for both induction and maintenance immunosuppression because of their multiple modalities of action. There is considerable uncertainty as to whether induction immunosuppression is necessary and if so, the relative efficacy of different immunosuppressive agents. OBJECTIVES: To assess the comparative benefits and harms of different induction immunosuppressive regimens in adults undergoing liver transplantation through a network meta-analysis and to generate rankings of the different induction immunosuppressive regimens according to their safety and efficacy. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until July 2019 to identify randomised clinical trials in adults undergoing liver transplantation. SELECTION CRITERIA: We included only randomised clinical trials (irrespective of language, blinding, or status) in adults undergoing liver transplantation. We excluded randomised clinical trials in which participants had multivisceral transplantation and those who already had graft rejections. DATA COLLECTION AND ANALYSIS: We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the odds ratio (OR), rate ratio, and hazard ratio (HR) with 95% credible intervals (CrIs) based on an available case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. MAIN RESULTS: We included a total of 25 trials (3271 participants; 8 treatments) in the review. Twenty-three trials (3017 participants) were included in one or more outcomes in the review. The trials that provided the information included people undergoing primary liver transplantation for various indications and excluded those with HIV and those with renal impairment. The follow-up in the trials ranged from three to 76 months, with a median follow-up of 12 months among trials. All except one trial were at high risk of bias, and the overall certainty of evidence was very low. Overall, approximately 7.4% of people who received the standard regimen of glucocorticosteroid induction died and 12.2% developed graft failure. All-cause mortality and graft failure was lower with basiliximab compared with glucocorticosteroid induction: all-cause mortality (HR 0.53, 95% CrI 0.31 to 0.93; network estimate, based on 2 direct comparison trials (131 participants; low-certainty evidence)); and graft failure (HR 0.44, 95% CrI 0.28 to 0.70; direct estimate, based on 1 trial (47 participants; low-certainty evidence)). There was no evidence of differences in all-cause mortality and graft failure between other induction immunosuppressants and glucocorticosteroids in either the direct comparison or the network meta-analysis (very low-certainty evidence). There was also no evidence of differences in serious adverse events (proportion), serious adverse events (number), renal failure, any adverse events (proportion), any adverse events (number), liver retransplantation, graft rejections (any), or graft rejections (requiring treatment) between other induction immunosuppressants and glucocorticosteroids in either the direct comparison or the network meta-analysis (very low-certainty evidence). However, because of the wide CrIs, clinically important differences in these outcomes cannot be ruled out. None of the studies reported health-related quality of life. FUNDING: the source of funding for 14 trials was drug companies who would benefit from the results of the study; two trials were funded by neutral organisations who have no vested interests in the results of the study; and the source of funding for the remaining nine trials was unclear. AUTHORS' CONCLUSIONS: Based on low-certainty evidence, basiliximab induction may decrease mortality and graft failure compared to glucocorticosteroids induction in people undergoing liver transplantation. However, there is considerable uncertainty about this finding because this information is based on small trials at high risk of bias. The evidence is uncertain about the effects of different induction immunosuppressants on other clinical outcomes, including graft rejections. Future randomised clinical trials should be adequately powered, employ blinding, avoid post-randomisation dropouts (or perform intention-to-treat analysis), and use clinically important outcomes such as mortality, graft failure, and health-related quality of life.

TIR1/AFB-Aux/IAA auxin perception mediates rapid cell wall acidification and growth of Arabidopsis hypocotyls.

Despite being composed of immobile cells, plants reorient along directional stimuli. The hormone auxin is redistributed in stimulated organs leading to differential growth and bending. Auxin application triggers rapid cell wall acidification and elongation of aerial organs of plants, but the molecular players mediating these effects are still controversial. Here we use genetically-encoded pH and auxin signaling sensors, pharmacological and genetic manipulations available for Arabidopsis etiolated hypocotyls to clarify how auxin is perceived and the downstream growth executed. We show that auxin-induced acidification occurs by local activation of H+-ATPases, which in the context of gravity response is restricted to the lower organ side. This auxin-stimulated acidification and growth require TIR1/AFB-Aux/IAA nuclear auxin perception. In addition, auxin-induced gene transcription and specifically SAUR proteins are crucial downstream mediators of this growth. Our study provides strong experimental support for the acid growth theory and clarified the contribution of the upstream auxin perception mechanisms.

Casein Kinase 2 Negatively Regulates Abscisic Acid-Activated SnRK2s in the Core Abscisic Acid-Signaling Module.

SnRK2 kinases, PP2C phosphatases and the PYR/PYL/RCAR receptors constitute the core abscisic acid (ABA) signaling module that is thought to contain all of the intrinsic properties to self-regulate the hormone signal output. Here we identify Casein Kinase (CK)2 as a novel negative regulator of SnRK2. CK2 phosphorylates a cluster of conserved serines at the ABA box of SnRK2, increasing its binding to PP2C and triggering protein degradation. Consequently, CK2 action has implications on SnRK2 protein levels, as well as kinase activity and its response to abiotic stimuli.

Acetylated 1,3-diaminopropane antagonizes abscisic acid-mediated stomatal closing in Arabidopsis.

Faced with declining soil-water potential, plants synthesize abscisic acid (ABA), which then triggers stomatal closure to conserve tissue moisture. Closed stomates, however, also create several physiological dilemmas. Among these, the large CO2 influx required for net photosynthesis will be disrupted. Depleting CO2 in the plant will in turn bias stomatal opening by suppressing ABA sensitivity, which then aggravates transpiration further. We have investigated the molecular basis of how C3 plants resolve this H2 O-CO2 conflicting priority created by stomatal closure. Here, we have identified in Arabidopsis thaliana an early drought-induced spermidine spermine-N(1) -acetyltransferase homolog, which can slow ABA-mediated stomatal closure. Evidence from genetic, biochemical and physiological analyses has revealed that this protein does so by acetylating the metabolite 1,3-diaminopropane (DAP), thereby turning on the latter's intrinsic activity. Acetylated DAP triggers plasma membrane electrical and ion transport properties in an opposite way to those by ABA. Thus in adapting to low soil-water availability, acetyl-DAP could refrain stomates from complete closure to sustain CO2 diffusion to photosynthetic tissues.

The maize OST1 kinase homolog phosphorylates and regulates the maize SNAC1-type transcription factor.

The Arabidopsis kinase OPEN STOMATA 1 (OST1) plays a key role in regulating drought stress signalling, particularly stomatal closure. We have identified and investigated the functions of the OST1 ortholog in Z. mays (ZmOST1). Ectopic expression of ZmOST1 in the Arabidopsis ost1 mutant restores the stomatal closure phenotype in response to drought. Furthermore, we have identified the transcription factor, ZmSNAC1, which is directly phosphorylated by ZmOST1 with implications on its localization and protein stability. Interestingly, ZmSNAC1 binds to the ABA-box of ZmOST1, which is conserved in SnRK2s activated by ABA and is part of the contact site for the negative-regulating clade A PP2C phosphatases. Taken together, our results indicate that ZmSNAC1 is a substrate of ZmOST1 and delineate a novel osmotic stress transcriptional pathway in maize.

Constitutively active mitogen-activated protein kinase versions reveal functions of Arabidopsis MPK4 in pathogen defense signaling.

Plant mitogen-activated protein kinases (MAPKs) are involved in important processes, including stress signaling and development. In a functional yeast screen, we identified mutations that render Arabidopsis thaliana MAPKs constitutively active (CA). Importantly, CA-MAPKs maintain their specificity toward known activators and substrates. As a proof-of-concept, Arabidopsis MAPK4 (MPK4) function in plant immunity was investigated. In agreement with the phenotype of mpk4 mutants, CA-MPK4 plants were compromised in pathogen-induced salicylic acid accumulation and disease resistance. MPK4 activity was found to negatively regulate pathogen-associated molecular pattern-induced reactive oxygen species production but had no impact on callose deposition, indicating that CA-MPK4 allows discriminating between processes regulated by MPK4 activity from processes indirectly affected by mpk4 mutation. Finally, MPK4 activity was also found to compromise effector-triggered immunity conditioned by the Toll Interleukin-1 Receptor-nucleotide binding (NB)-Leu-rich repeat (LRR) receptors RPS4 and RPP4 but not by the coiled coil-NB-LRR receptors RPM1 and RPS2. Overall, these data reveal important insights on how MPK4 regulates plant defenses and establishes that CA-MAPKs offer a powerful tool to analyze the function of plant MAPK pathways.

[The ABC of abscisic acid action in plant drought stress responses]. / Mécanisme moléculaire d'action de l'acide abscissique en réponse à la sécheresse chez les végétaux.

The combined daily consumption of fresh water ranges from 200 to 700 liters per capita per day in most developed countries, with about 70% being used for agricultural needs. Unlike other resources such as the different forms of energy, water has no other alternatives. With the looming prospect of global water crisis, the recent laudable success in deciphering the early steps in the signal transduction of the "stress hormone" abscisic acid (ABA) has ignited hopes that crops can be engineered with the capacity to maintain productivity while requiring less water input. Although ABA was first discovered in plants, it has resurfaced in the human brain (and many other non-plant organisms : sea sponge, some parasites, hydra to name a few), suggesting that its existence may be widespread. In humans, more amazingly, ABA has shown anti-inflammatory and antiviral properties. Even its receptors and key signaling intermediates have homologs in the human genome suggesting that evolution has re-fashioned these same proteins into new functional contexts. Thus, learning about the molecular mechanisms of ABA in action using the more flexible plant model will be likely beneficial to other organisms, and especially in human diseases, which is topical in the medical circle. ABA can accumulate up to 10 to 30-fold in plants under drought stress relative to unstressed conditions. The built up of the hormone then triggers diverse adaptive pathways permitting plants to withstand temporary bouts of water shortage. One favorite experimental model to unravel ABA signaling mechanisms in all of its intimate detail is based on the hormone's ability to elicit stomatal closure - a rapid cellular response of land plants to limit water loss through transpiration. Each microscopic stoma, or pore, is contoured by two specialized kidney-shaped cells called the guard cells. Because land plants are protected by a waxy cuticle impermeable to gas exchange, the stomatal pores are thus the primary portals for photosynthetic CO(2) uptake. Drought, by biasing pathways that lead to rapid closure of these pores, has therefore a negative impact on photosynthesis, and consequently, biomass as well. The stomatal aperture widens and narrows by expansion and contraction, respectively, of these flanking guard cells caused by changes in the intracellular concentrations of ion fluxes. These transport mechanisms most likely share fundamental principles with any excitable cell. These events require coordination of channels, vacuolar and membrane transporters that generate a specific pattern of electrical signals that relay the ABA stimulus. Research on ABA begun in the 1960's has now been crowned by the achievement of having identified the soluble ABA receptor that turns on and off the activities of a kinase/phosphatase pair, as the heart of the signaling complex. Results distilled from the latest structural studies on these ABA receptors, characterized by the so-called START domain, are beginning to tender the most exciting promise for rational design of agonists and antagonists towards modulating stress adaptive ability in plants. This review will chart the recent extraordinary progress that has enlightened us on how ABA controls membrane transport mechanisms that evoke the fast stomatal closing pathway.

A brand new START: abscisic acid perception and transduction in the guard cell.

The soluble receptors of abscisic acid (ABA) have been identified in Arabidopsis thaliana. The 14 proteins in this family, bearing the double name of PYRABACTIN RESISTANCE/PYRABACTIN-LIKE (PYR/PYL) or REGULATORY COMPONENTS OF ABA RECEPTOR (RCAR) (collectively referred to as PYR/PYL/RCAR), contain between 150 and 200 amino acids with homology to the steroidogenic acute regulatory-related lipid transfer (START) protein. Structural studies of these receptors have provided rich insights into the early mechanisms of ABA signaling. The binding of ABA to PYR/PYL/RCAR triggers the pathway by inducing structural changes in the receptors that allows them to sequester members of the clade A negative regulating protein phosphatase 2Cs (PP2Cs). This liberates the class III ABA-activated Snf1-related kinases (SnRK2s) to phosphorylate various targets. In guard cells, a specific SnRK2, OPEN STOMATA 1 (OST), stimulates H(2)O(2) production by NADPH oxidase respiratory burst oxidase protein F and inhibits potassium ion influx by the inward-rectifying channel KAT1. OST1, the kinase CPK23, the calcium-dependent kinase CPK21, and the counteracting PP2Cs modulate the slow anion channel SLAC1, a pathway that contributes to stomatal responses to diverse stimuli, including ABA and carbon dioxide. A minimal ABA response pathway that leads to activation of the SLAC1 homolog, SLAH3, and presumably stomatal closure has been reconstituted in vitro. The identification of the soluble receptors and core components of the ABA signaling pathway provides promising targets for crop design with higher resilience to water deficit while maintaining biomass.