Association between bisphosphonate use and stroke risk: a meta-analysis.

Previous studies have suggested that bisphosphonates may reduce stroke risk. This meta-analysis, which included 21 studies with 741,274 participants, revealed that bisphosphonates might be associated with lower stroke risk. However, evidence derived from randomized controlled trials identified no statistically significant association. Future high-quality studies are still required to determine causality. PURPOSE: Whether bisphosphonates may reduce the risk of stroke remains inconclusive. We conducted a systematic review and meta-analysis to evaluate the association between bisphosphonate use and the risk of stroke based on up-to-date evidence. METHODS: We searched for studies evaluating the effects of bisphosphonate on the risk of stroke from inception until January 3, 2022, on PubMed, Embase, Scopus, and Cochrane libraries and updated our search until August 22, 2022, using PubMed to identify any new potential published studies. Two or more reviewers independently screened articles, extracted data, and assessed the study quality. We retrieved the data to synthesize the pooled relative risk (RR) of stroke associated with bisphosphonate use compared with controls; random-effects models were used for meta-analysis. RESULTS: A total of 21 studies (7 randomized controlled trials [RCTs] and 14 observational studies) involving 741,274 participants were included in our meta-analysis. Overall, bisphosphonate use was associated with a lower risk of stroke, but the result was only borderline significant (pooled RR = 0.87, 95% confidence interval [CI]: 0.76-0.99, p = 0.048), and high between-study heterogeneity was found (I2 = 83.7%). Subgroup analyses showed that the evidence derived from RCTs suggested no significant association between bisphosphonate use and stroke risk (pooled RR = 0.93, 95% CI: 0.76-1.13, p = 0.462; I2 = 13.4%). CONCLUSION: Our results suggest that bisphosphonate use is associated with a lower risk of stroke. However, the current evidence does not lead to a definite conclusion due to the borderline statistical significance and high between-study heterogeneity. Future studies, especially RCTs, are necessary to assess causality.

OAF is a DAF-like gene that controls ovule development in plants.

We previously found that the RING-type E3 ligase DEFECTIVE IN ANTHER DEHISCENCE1- (DAD1-) Activating Factor (DAF) controls anther dehiscence by activating the jasmonate biosynthetic pathway in Arabidopsis. Here, we show that in Arabidopsis, the DAF ancestor was duplicated into three genes (DAF, Ovule Activating Factor (OAF), DAFL2), which evolved divergent partial functions from their ancestor through subfunctionalization. In this case, DAF-DAD1-JA signaling regulates anther dehiscence, whereas OAF controls ovule development by negatively regulating cinnamyl alcohol dehydrogenase 9 (CAD9) activity and being negatively regulated by miR847 itself in Arabidopsis. Downregulation of OAF or upregulation of CAD9 and miR847 caused similar abortion of ovule formation due to precocious ovule lignification in transgenic Arabidopsis. Interestingly, only one DAF-like gene, PaOAF, exists in the monocot orchids, which has likely evolved through nonfunctionalization and maintains a conserved function as Arabidopsis OAF in regulating ovule development since defective ovules were observed in the virus-induced gene silencing (VIGS) PaOAF Phalaenopsis orchids. The absence of the DAF ortholog and its function in orchids is likely due to the evolution of stamens to a unique pollinium structure that lacks the feature of anther dehiscence. These findings expand the current knowledge underlying the multifunctional evolution and diverse functionalization of duplicate gene pairs within/among plants.

Design and Synthesis of a Caged Carboxylic Acid with a Donor-π-Donor Coumarin Structure: One-photon and Two-photon Uncaging Reactions Using Visible and Near-Infrared Lights.

A caged carboxylic acid with a novel two-photon (TP)-responsive donor-π-donor coumarin backbone with a quadrupolar nature was designed and synthesized in this study. The newly synthesized coumarin derivative showed a strong one-photon (OP) absorption band (ε ≈ 29000 cm-1 M-1) in the visible region (>∼400 nm). Time-dependent density functional theory calculations predicted a sizable TP absorption cross-section with a maximum at ∼650 nm significantly lager than that related to the OP absorption band. This is confirmed experimentally using TP excited fluorescence in the fs regime that leads to TP absorption cross-section of 18 and 5.6 GM at 680 and 760 nm, respectively. The OP photolysis (400 nm) and near-infrared-TP photolysis (750 nm) of the caged benzoic acid resulted in a clean formation of benzoic acid and an aldehyde.