In male reproductive development in plants, meristemoid precursor cells possessing transient, stem cell-like features undergo cell divisions and differentiation to produce the anther, the male reproductive organ. The anther contains centrally positioned microsporocytes surrounded by four distinct layers of wall: the epidermis, endothecium, middle layer, and tapetum. Here, we report that the rice (Oryza sativa) basic helix-loop-helix (bHLH) protein TDR INTERACTING PROTEIN2 (TIP2) functions as a crucial switch in the meristemoid transition and differentiation during early anther development. The tip2 mutants display undifferentiated inner three anther wall layers and abort tapetal programmed cell death, causing complete male sterility. TIP2 has two paralogs in rice, TDR and EAT1, which are key regulators of tapetal programmed cell death. We revealed that TIP2 acts upstream of TDR and EAT1 and directly regulates the expression of TDR and EAT1. In addition, TIP2 can interact with TDR, indicating a role of TIP2 in later anther development. Our findings suggest that the bHLH proteins TIP2, TDR, and EAT1 play a central role in regulating differentiation, morphogenesis, and degradation of anther somatic cell layers, highlighting the role of paralogous bHLH proteins in regulating distinct steps of plant cell-type determination.

(PASMCs). Its upregulation by chronic hypoxia is associated with enhanced myogenic tone, and genetic deletion of trpv4 suppresses the development of chronic hypoxic pulmonary hypertension (CHPH). Here we further examine the roles of TRPV4 in agonist-induced pulmonary vasoconstriction and in the enhanced vasoreactivity in CHPH. Initial evaluation of TRPV4-selective antagonists HC-067047 and RN-1734 in KCl-contracted pulmonary arteries (PAs) of trpv4 Ϫ/Ϫ mice found that submicromolar HC-067047 was devoid of off-target effect on pulmonary vasoconstriction. Inhibition of TRPV4 with 0.5 M HC-067047 significantly reduced the sensitivity of serotonin (5-HT)-induced contraction in wild-type (WT) PAs but had no effect on endothelin-1 or phenylephrine-activated response. Similar shift in the concentrationresponse curve of 5-HT was observed in trpv4 Ϫ/Ϫ PAs, confirming specific TRPV4 contribution to 5-HT-induced vasoconstriction. 5-HT-induced Ca 2ϩ response was attenuated by HC-067047 in WT PASMCs but not in trpv4 Ϫ/Ϫ PASMCs, suggesting TRPV4 is a major Ca 2ϩ pathway for 5-HT-induced Ca 2ϩ mobilization. Nifedipine also attenuated 5-HT-induced Ca 2ϩ response in WT PASMCs but did not cause further reduction in the presence of HC-067047, suggesting interdependence of TRPV4 and voltage-gated Ca 2ϩ channels in the 5-HT response. Chronic exposure (3-4 wk) of WT mice to 10% O 2 caused significant increase in 5-HT-induced maximal contraction, which was partially reversed by HC-067047. In concordance, the enhancement of 5-HT-induced contraction was significantly reduced in PAs of CH trpv4 Ϫ/Ϫ mice and HC-067047 had no further effect on the 5-HT induced response. These results suggest unequivocally that TRPV4 contributes to 5-HT-dependent pharmaco-mechanical coupling and plays a major role in the enhanced pulmonary vasoreactivity to 5-HT in CHPH.TRPV4; serotonin; pulmonary arteries; chronic hypoxia; pulmonary hypertension TRANSIENT RECEPTOR POTENTIAL vanilloid 4 (TRPV4), a member of the transient receptor potential (TRP) channel superfamily, is a Ca 2ϩ and Mg 2ϩ permeating nonselective cation channel widely distributed in various tissues including kidney, brain, lung, aorta, heart, liver, and skeletal muscle (32). TRPV4 is a highly versatile channel. It can be activated by a variety of physical and chemical stimuli, including abnormal osmolarity (37, 48), sheer stress (24, 30), pressure (59, 60), heat (5, 36, 68), endogenous substances such as arachidonic acid and its cytochrome P450-derived metabolites [epoxyeicosatrienoic acids (EETs); 64, 65, 67], as well as synthetic compounds such as PKC-activating and nonactivating phorbol ester derivatives (66). It is involved in a wide range of physiological functions, including osmotic and volume regulation, thermo-sensing and regulation, mechanosensation in endothelium and urinary bladder, vascular and epithelium permeability, synaptic transmission, nociception, as well as bone formation and remodeling (16).TRPV4 channels are highly expressed in endothelial and vascular smooth muscle cell...

Hypoxic pulmonary hypertension is characterized by increased vascular tone, altered vasoreactivity and vascular remodeling, which are associated with alterations in Ca2+ homeostasis in pulmonary arterial smooth muscle cells. We have previously shown that classical transient receptor potential 1 and 6 (TRPC1 and TRPC6) are upregulated in pulmonary arteries of chronic hypoxic rats, but it is unclear whether these channels are essential for the development of pulmonary hypertension. Here we found that pulmonary hypertension was suppressed in TRPC1 and TRPC6 knockout (Trpc1−/− and Trpc6−/−) mice compared to wildtype after exposure to 10% O2 for 1 and 3 weeks. Muscularization of pulmonary microvessels was inhibited, but rarefaction was unaltered in hypoxic Trpc1−/− and Trpc6−/− mice. Small pulmonary arteries of normoxic wildtype mice exhibited vasomotor tone, which was significantly enhanced by chronic hypoxia. Similar vasomotor tone was found in normoxic Trpc1−/− pulmonary arteries, but the hypoxia-induced enhancement was blunted. In contrast, there was minimal vascular tone in normoxic Trpc6−/− pulmonary arteries, but the hypoxia-enhanced tone was preserved. Chronic hypoxia caused significant increase in serotonin-induced vasoconstriction; the enhanced vasoreactivity was attenuated in Trpc1−/− and eliminated in Trpc6−/− pulmonary arteries. Moreover, the effects of 3-week hypoxia on pulmonary arterial pressure, right ventricular hypertrophy and muscularization of microvessels were further suppressed in Trpc1−/−Trpc6−/− double-knockout mice. Our results therefore provide clear evidence that TRPC1 and TRPC6 participate differentially in various pathophysiological processes; and the presence of TRPC1 and TRPC6 are essential for the full development of hypoxic pulmonary hypertension in the mouse model.

Copper oxide-based materials effectively electrocatalyze carbon dioxide reduction (CO 2 RR). To comprehend their role and achieve high CO 2 RR activity, Cu + in copper oxides must be stabilized. As an electrocatalyst, Cu 2 O nanoparticles were decorated with hexagonal boron nitride (h-BN) nanosheets to stabilize Cu + . The C 2 H 4 /CO ratio increased 1.62-fold in the CO 2 RR with Cu 2 OÀ BN compared to that with Cu 2 O. Experimental and theoretical studies confirmed strong electronic interactions between the two components in Cu 2 OÀ BN, which strengthens the CuÀ O bonds. Electrophilic h-BN receives partial electron density from Cu 2 O, protecting the CuÀ O bonds from electron attack during the CO 2 RR and stabilizing the Cu + species during longterm electrolysis. The well-retained Cu + species enhanced the C 2 product selectivity and improved the stability of Cu 2 OÀ BN. This work offers new insight into the metal-valence-state-dependent selectivity of catalysts, enabling the design of advanced catalysts.

An approach of decorating bacteria with triple immune nanoactivators is reported to develop tumor‐resident living immunotherapeutics. Under cytocompatible conditions, tumor‐specific antigens and checkpoint blocking antibodies are simultaneously conjugated onto bacterial surface and then polydopamine nanoparticles are formed via in situ dopamine polymerization. In addition to serving as a linker, polydopamine with its photothermal effect can repolarize tumor‐associated macrophages to a pro‐inflammatory phenotype. The linked antigens promote the maturation of dendritic cells and generate tumor‐specific immune responses, while the anchored antibodies block immune checkpoints and activate cytotoxic T lymphocytes. Decorated bacteria show spatiotemporal tumor retention and proliferation‐dependent drug release, achieving potent antitumor effects in two antigen‐overexpressing tumor models. This work provides a versatile platform to prepare multimodal and long‐acting therapeutics for cancer immunotherapy.