MAP3K2-regulated intestinal stromal cells define a distinct stem cell niche.

Intestinal stromal cells are known to modulate the propagation and differentiation of intestinal stem cells1,2. However, the precise cellular and molecular mechanisms by which this diverse stromal cell population maintains tissue homeostasis and repair are poorly understood. Here we describe a subset of intestinal stromal cells, named MAP3K2-regulated intestinal stromal cells (MRISCs), and show that they are the primary cellular source of the WNT agonist R-spondin 1 following intestinal injury in mice. MRISCs, which are epigenetically and transcriptomically distinct from subsets of intestinal stromal cells that have previously been reported3-6, are strategically localized at the bases of colon crypts, and function to maintain LGR5+ intestinal stem cells and protect against acute intestinal damage through enhanced R-spondin 1 production. Mechanistically, this MAP3K2 specific function is mediated by a previously unknown reactive oxygen species (ROS)-MAP3K2-ERK5-KLF2 axis to enhance production of R-spondin 1. Our results identify MRISCs as a key component of an intestinal stem cell niche that specifically depends on MAP3K2 to augment WNT signalling for the regeneration of damaged intestine.

Phytochromes enhance SOS2-mediated PIF1 and PIF3 phosphorylation and degradation to promote Arabidopsis salt tolerance.

Soil salinity is one of the most detrimental abiotic stresses affecting plant survival, and light is a core environmental signal regulating plant growth and responses to abiotic stress. However, how light modulates the plant's response to salt stress remains largely obscure. Here, we show that Arabidopsis (Arabidopsis thaliana) seedlings are more tolerant to salt stress in the light than in the dark, and that the photoreceptors phytochrome A (phyA) and phyB are involved in this tolerance mechanism. We further show that phyA and phyB physically interact with the salt tolerance regulator SALT OVERLY SENSITIVE2 (SOS2) in the cytosol and nucleus, and enhance salt-activated SOS2 kinase activity in the light. Moreover, SOS2 directly interacts with and phosphorylates PHYTOCHROME-INTERACTING FACTORS PIF1 and PIF3 in the nucleus. Accordingly, PIFs act as negative regulators of plant salt tolerance, and SOS2 phosphorylation of PIF1 and PIF3 decreases their stability and relieves their repressive effect on plant salt tolerance in both light and dark conditions. Together, our study demonstrates that photoactivated phyA and phyB promote plant salt tolerance by increasing SOS2-mediated phosphorylation and degradation of PIF1 and PIF3, thus broadening our understanding of how plants adapt to salt stress according to their dynamic light environment.

Paracrine orchestration of intestinal tumorigenesis by a mesenchymal niche.

The initiation of an intestinal tumour is a probabilistic process that depends on the competition between mutant and normal epithelial stem cells in crypts1. Intestinal stem cells are closely associated with a diverse but poorly characterized network of mesenchymal cell types2,3. However, whether the physiological mesenchymal microenvironment of mutant stem cells affects tumour initiation remains unknown. Here we provide in vivo evidence that the mesenchymal niche controls tumour initiation in trans. By characterizing the heterogeneity of the intestinal mesenchyme using single-cell RNA-sequencing analysis, we identified a population of rare pericryptal Ptgs2-expressing fibroblasts that constitutively process arachidonic acid into highly labile prostaglandin E2 (PGE2). Specific ablation of Ptgs2 in fibroblasts was sufficient to prevent tumour initiation in two different models of sporadic, autochthonous tumorigenesis. Mechanistically, single-cell RNA-sequencing analyses of a mesenchymal niche model showed that fibroblast-derived PGE2 drives the expansion οf a population of Sca-1+ reserve-like stem cells. These express a strong regenerative/tumorigenic program, driven by the Hippo pathway effector Yap. In vivo, Yap is indispensable for Sca-1+ cell expansion and early tumour initiation and displays a nuclear localization in both mouse and human adenomas. Using organoid experiments, we identified a molecular mechanism whereby PGE2 promotes Yap dephosphorylation, nuclear translocation and transcriptional activity by signalling through the receptor Ptger4. Epithelial-specific ablation of Ptger4 misdirected the regenerative reprogramming of stem cells and prevented Sca-1+ cell expansion and sporadic tumour initiation in mutant mice, thereby demonstrating the robust paracrine control of tumour-initiating stem cells by PGE2-Ptger4. Analyses of patient-derived organoids established that PGE2-PTGER4 also regulates stem-cell function in humans. Our study demonstrates that initiation of colorectal cancer is orchestrated by the mesenchymal niche and reveals a mechanism by which rare pericryptal Ptgs2-expressing fibroblasts exert paracrine control over tumour-initiating stem cells via the druggable PGE2-Ptger4-Yap signalling axis.

Identification of Sodium- and Chloride-Sensitive Sites in the Slack Channel.

The Slack channel (KCNT1, Slo2.2) is a sodium-activated and chloride-activated potassium channel that regulates heart rate and maintains the normal excitability of the nervous system. Despite intense interest in the sodium gating mechanism, a comprehensive investigation to identify the sodium-sensitive and chloride-sensitive sites has been missing. In the present study, we identified two potential sodium-binding sites in the C-terminal domain of the rat Slack channel by conducting electrophysical recordings and systematic mutagenesis of cytosolic acidic residues in the rat Slack channel C terminus. In particular, by taking advantage of the M335A mutant, which results in the opening of the Slack channel in the absence of cytosolic sodium, we found that among the 92 screened negatively charged amino acids, E373 mutants could completely remove sodium sensitivity of the Slack channel. In contrast, several other mutants showed dramatic decreases in sodium sensitivity but did not abolish it altogether. Furthermore, molecular dynamics (MD) simulations performed at the hundreds of nanoseconds timescale revealed one or two sodium ions at the E373 position or an acidic pocket composed of several negatively charged residues. Moreover, the MD simulations predicted possible chloride interaction sites. By screening predicted positively charged residues, we identified R379 as a chloride interaction site. Thus, we conclude that the E373 site and the D863/E865 pocket are two potential sodium-sensitive sites, while R379 is a chloride interaction site in the Slack channel.SIGNIFICANCE STATEMENT The research presented here identified two distinct sodium and one chloride interaction sites located in the intracellular C-terminal domain of the Slack (Slo2.2, KCNT1) channel. Identification of the sites responsible for the sodium and chloride activation of the Slack channel sets its gating property apart from other potassium channels in the BK channel family. This finding sets the stage for future functional and pharmacological studies of this channel.

Excitation dynamics in molecule resolved by internuclear distance driven by the strong laser field.

Rydberg-state excitation of stretched model molecules subjected to near-infrared intense laser fields has been investigated based on a fully quantum model (QM) proposed recently and the numerical solutions of time-dependent Schrödinger equation (TDSE). Given the good agreement between QM and TDSE, it is found that, as the molecules are stretched, the electron tends to be trapped into low-lying Rydberg-states after its ionization from the core, which can be attributed to the shift of the ionization moments corresponding to maximum excitation populations. Moreover, the n-distribution is broadened for molecules with increasing internuclear distance, which results from the change of momentum distribution of emitted electrons. Analysis indicates that both of the above phenomena are closely related to the interference effect of electronic wave packets emitted from different nuclei. Our study provides a more comprehensive understanding of the molecular excitation in intense laser fields, as well as a means of possible applications to related experimental observations.

To What Extent Do Iodomethane and Bromomethane Undergo Analogous Reactions?

Iodomethane and bromomethane (CH3I/CH3Br) are common chemicals, but their chemistry on nanometals is not fully understood. Here, we analyze the reactivity of Rhn+ (n = 3-30) clusters with halomethanes and unveil the spin effect and concentration dependence in the C-H and C-X bond activation. It is found that the reactions under halomethane-rich conditions differ from those under metal-rich conditions. Both CH3I and CH3Br undergo similar dehydrogenation on the Rhn+ clusters in the presence of small quantity reactants; however, different reactions are observed in the presence of sufficient CH3I/CH3Br, showing dominant Rh(CH3Br)x+ (x = 1-4) products but a series of RhnCxHyIz+ species (x = 1-4, y = 1-12, and z = 1-5) pertaining to H2, HI, or CH4 removal. Density functional theory calculations reveal that the dehydrogenation and demethanation of CH3Br are relatively less exothermic and will be deactivated by sufficient gas collisions if helium cooling takes away energy immediately; instead, the successive adsorption of CH3Br gives rise to a series of Rh(CH3Br)x+ species with accidental C-Br bond dissociation.

Systemic bevacizumab for treatment of recurrent respiratory papillomatosis.

OBJECTIVES: To characterize treatment response of recurrent respiratory papillomatosis (RRP) including adult-onset RRP (AORRP) and juvenile-onset RRP (JORRP) to systemic bevacizumab (bev), and share our treatment regimen experience. METHODS: Patients were enrolled in bev treatment based on a pathologically confirmed diagnosis of squamous papilloma. According to lesion characteristics and medical history, systemic bev was used as preoperative adjuvant therapy, postoperative adjuvant therapy, or primary therapy. The assessment of treatment response relied on the morphological changes of lesions. Vocalization and voice-related quality of life were evaluated using the voice handicap index-30 (VHI-30) for adults and the pediatric VHI (pVHI) for children. Adverse effect was monitored through patient self-reported symptoms and regular follow-ups. RESULTS: This study included 24 patients, comprising nine AORRP and 15 JORRP cases. In AORRP, all patients (100%) exhibited various degrees of response to systemic bev, with 5 (55.56%) achieving complete response (CR). Among JORRP patients, 14 (93.33%) showed a response to systemic bev, with 8 (53.33%) achieving CR and currently being followed up. No instances of aggravation were observed during systemic bev treatment. A total of 21 patients (21/24, 87.50%) reported voice improvement, accompanied by reduced VHI-30 or pVHI scores across all aspects, including total, functional, physical, and emotional dimensions. No grade 3 or higher adverse events occurred. The most common adverse events were grade 1 gum bleeding (n = 4, 16.67%) and grade 1 proteinuria (n = 4, 16.67%). CONCLUSIONS: Systemic bev can be used as a powerful therapy for both AORRP and JORRP. The findings provide a reference to the systemic bev treatment for RRP.

Functional outcome following spontaneous intracerebral hemorrhage between ultrasound guidance endoscopic surgery and conventional craniotomy: A retrospective population-based study.

OBJECTIVES: Ultrasound guidance endoscopic surgery (ES) has been widely used in the treatment of cerebral hemorrhage in recent years, but relevant research articles are still scarce. Our study aims to investigate the effect of ES compared with conventional craniotomy (CC) on the postoperative complications, and prognosis of patients with intracerebral hemorrhage. MATERIALS AND METHODS: The clinical data of 1201 patients with ICH treated in our hospital from January 2017 to January 2020 were collected. The t-test, Chi-squared test and Fisher's exact test were used to analyze the clinical baseline data. Among 1021 spontaneous ICH patients, 193 patients who underwent hematoma evacuation were included in the present analysis. RESULTS: The Glasgow Outcome Scale (GOS) score at 6 months had a favorable prognosis in ES group (p = 0.003). ES group had fewer postoperative complications compared with CC group. Operating time and intraoperative blood loss were significantly lower in ES group than CC group (p = 0.001 and p = 0.002). CONCLUSIONS: Our study revealed that receiving ES improved the prognosis of ICH patients. Additionally, endoscopic surgery diminishes operative time, and intraoperative blood loss and reduces the incidence of postoperative complications.

Targeting BCAA metabolism to potentiate metformin's therapeutic efficacy in the treatment of diabetes in mice.

AIMS/HYPOTHESIS: An increasing body of evidence has shown that the catabolism of branched-chain amino acids (BCAAs; leucine, isoleucine and valine) is impaired in obese animals and humans, contributing to the development of insulin resistance and type 2 diabetes. Promoting BCAA catabolism benefits glycaemic control. It remains unclear whether BCAA catabolism plays a role in the therapeutic efficacy of currently used glucose-lowering drugs such as metformin. METHODS: Mice were treated with vehicle or metformin (250 mg/kg per day) for more than 4 weeks to investigate the effects of metformin in vivo. In vitro, primary mouse hepatocytes and HepG2 cells were treated with 2 mmol/l metformin. The therapeutic efficacy of metformin in the treatment of type 2 diabetes was assessed in genetically obese (ob/ob) mice and high-fat-diet-induced obese (DIO) mice. Enhancing BCAA catabolism was achieved with a pharmacological agent, 3,6-dichlorobenzo[b]thiophene-2-carboxylic acid (BT2). The ob/ob mice were treated with a low-BCAA diet or intermittent protein restriction (IPR) to reduce BCAA nutritional intake. RESULTS: Metformin unexpectedly inhibited the catabolism of BCAAs in obese mice, resulting in an elevation of BCAA abundance. AMP-activated protein kinase (AMPK) mediated the impact of metformin on BCAA catabolism in hepatocytes. Importantly, enhancing BCAA catabolism via a pharmacological agent BT2 significantly potentiated the glucose-lowering effect of metformin while decreasing circulating BCAA levels in ob/ob and DIO mice. Similar outcomes were achieved by a nutritional approach of reducing BCAA intake. IPR also effectively reduced the circulating BCAA abundance and enhanced metformin's glucose-lowering effect in ob/ob mice. BT2 and IPR treatments reduced the expression of fructose-1,6-bisphosphatase 1, a rate-limiting enzyme in gluconeogenesis, in the kidney but not liver, indicating the involvement of renal gluconeogenesis. CONCLUSIONS/INTERPRETATION: Metformin self-limits its therapeutic efficacy in the treatment of type 2 diabetes by triggering the suppression of BCAA catabolism. Enhancing BCAA catabolism pharmacologically or reducing BCAA intake nutritionally potentiates the glucose-lowering effect of metformin. These data highlight the nutritional impact of protein on metformin's therapeutic efficacy and provide new strategies targeting BCAA metabolism to improve metformin's effects on the clinical outcome in diabetes.

The NG2-glia is a potential target to maintain the integrity of neurovascular unit after acute ischemic stroke.

The neurovascular unit (NVU) plays a critical role in health and disease. In the current review, we discuss the critical role of a class of neural/glial antigen 2 (NG2)-expressing glial cells (NG2-glia) in regulating NVU after acute ischemic stroke (AIS). We first introduce the role of NG2-glia in the formation of NVU during development as well as aging-induced damage to NVU and accompanying NG2-glia change. We then discuss the reciprocal interactions between NG2-glia and the other component cells of NVU, emphasizing the factors that could influence NG2-glia. Damage to the NVU integrity is the pathological basis of edema and hemorrhagic transformation, the most dreaded complication after AIS. The role of NG2-glia in AIS-induced NVU damage and the effect of NG2-glia transplantation on AIS-induced NVU damage are summarized. We next discuss the role of NG2-glia and the effect of NG2-glia transplantation in oligodendrogenesis and white matter repair as well as angiogenesis which is associated with the outcome of the patients after AIS. Finally, we review the current strategies to promote NG2-glia proliferation and differentiation and propose to use the dental pulp stem cells (DPSC)-derived exosome as a promising strategy to reduce AIS-induced injury and promote repair through maintaining the integrity of NVU by regulating endogenous NG2-glia proliferation and differentiation.

Macrophage programming is regulated by a cooperative interaction between fatty acid binding protein 5 and peroxisome proliferator-activated receptor γ.

Resolution of inflammation is an active process that is tightly regulated to achieve repair and tissue homeostasis. In the absence of resolution, persistent inflammation underlies the pathogenesis of chronic lung disease such as chronic obstructive pulmonary disease (COPD) with recurrent exacerbations. Over the course of inflammation, macrophage programming transitions from pro-inflammatory to pro-resolving, which is in part regulated by the nuclear receptor Peroxisome Proliferator-Activated Receptor γ (PPARγ). Our previous work demonstrated an association between Fatty Acid Binding Protein 5 (FABP5) expression and PPARγ activity in peripheral blood mononuclear cells of healthy and COPD patients. However, a role for FABP5 in macrophage programming has not been examined. Here, using a combination of in vitro and in vivo approaches, we demonstrate that FABP5 is necessary for PPARγ activation. In turn, PPARγ acts directly to increase FABP5 expression in primary human alveolar macrophages. We further illustrate that lack of FABP5 expression promotes a pro-inflammatory macrophage programming with increased secretion of pro-inflammatory cytokines and increased chromatin accessibility for pro-inflammatory transcription factors (e.g., NF-κB and MAPK). And finally, real-time cell metabolic analysis using the Seahorse technology shows an inhibition of oxidative phosphorylation in FABP5-deficient macrophages. Taken together, our data indicate that FABP5 and PPARγ reciprocally regulate each other's expression and function, consistent with a novel positive feedback loop between the two factors that mediates macrophage pro-resolving programming. Our studies highlight the importance of defining targets and regulatory mechanisms that control the resolution of inflammation and may serve to inform novel interventional strategies directed towards COPD.

Perfect Core-Shell Octahedral B@B38 + , Be@B38 , and Zn@B38 with an Octa-Coordinate Center as Superatoms Following the Octet Rule.

Planar, tubular, cage-like, and bilayer boron clusters Bn +/0/- (n=3∼48) have been observed in joint experimental and theoretical investigations in the past two decades. Based on extensive global searches augmented with first-principles theory calculations, we predict herein the smallest perfect core-shell octahedral borospherene Oh B@B38 + (1) and its endohedral metallo-borospherene analogs Oh Be@B38 (2), and Oh Zn@B38 (3) which, with an octa-coordinate B, Be or Zn atom located exactly at the center, turn out to be the well-defined global minima of the systems highly stable both thermodynamically and dynamically. B@B38 + (1) represents the first boron-containing molecule reported to date which contains an octa-coordinate B center covalently coordinated by eight face-capping boron atoms at the corners of a perfect cube in the first coordination sphere. Detailed natural bonding orbital (NBO) and adaptive natural density partitioning (AdNDP) bonding analyses indicate that these high-symmetry core-shell complexes X@B38 +/0/- (X=B, Be, Zn) as super-noble gas atoms follow the octet rule in coordination bonding patterns (1S2 1P6 ), with one delocalized 9c-2e S-type coordination bond and three delocalized 39c-2e P-type coordination bonds formed between the octa-coordinate X center and its octahedral Oh B38 ligand to effectively stabilize the systems. Their IR, Raman, and UV-Vis spectra are computationally simulated to facilitate their spectroscopic characterizations.

Perfect Core-Shell Octahedral B@B38 + , Be@B38 , and Zn@B38 with an Octa-Coordinate Center as Superatoms Following the Octet Rule.

The front cover artwork is provided by Prof. Si-Dian Li's group at Shanxi University, China. The image shows the smallest perfect core-shell octahedral borospherene Oh B@B38 + and its endohedral metallo-borospherene analogs Oh Be@B38 and Oh Zn@B38 obtained at first-principles theory. Read the full text of the Research Article at 10.1002/cphc.202200947.

Butyrate mitigates metabolic dysfunctions via the ERα-AMPK pathway in muscle in OVX mice with diet-induced obesity.

The higher prevalence of metabolic syndrome (MetS) in women after menopause is associated with a decrease in circulating 17ß-oestradiol. To explore novel treatments for MetS in women with oestrogen deficiency, we studied the effect of exogenous butyrate on diet-induced obesity and metabolic dysfunctions using ovariectomized (OVX) mice as a menopause model. Oral administration of sodium butyrate (NaB) reduced the body fat content and blood lipids, increased whole-body energy expenditure, and improved insulin sensitivity. Additionally, NaB induced oestrogen receptor alpha (ERα) expression, activated the phosphorylation of AMPK and PGC1α, and improved mitochondrial aerobic respiration in cultured skeletal muscle cells. In conclusion, oral NaB improves metabolic parameters in OVX mice with diet-induced obesity. Oral supplementation with NaB might provide a novel therapeutic approach to treating MetS in women with menopause. Video Abstract.

Contribution of central sleep apnea to severe sleep apnea hypopnea syndrome.

PURPOSE: Central sleep apnea (CSA) is usually distinguished from obstructive sleep apnea (OSA). In fact, CSA is often a component of severe sleep apnea hypopnea syndrome (SAHS), rather than occurring alone. We investigated the clinical characteristics and polysomnography (PSG) parameters of CSA components in patients with severe SAHS. METHODS: The clinical characteristics and PSG parameters were retrospectively analyzed. RESULTS: Pure or dominant CSA was rare (5% of all patients). Of all patients with CSA, 72% also exhibited other apnea subtypes that contributed to severe SAHS. Among patients with severe SAHS, those with CSA were more likely than others to be older; thinner; exhibit higher prevalences of comorbid coronary heart disease, arrhythmia, and heart failure; a higher apnea/hypopnea index (AHI); mixed apnea index (MAI); an elevated oxygen desaturation index (ODI); and more nighttime oxygen saturation levels < 90%. Multivariate logistic regression analysis revealed that older age, comorbid arrhythmia or heart failure, and an elevated ODI were independently associated with CSA. CONCLUSION: Patients who complain of snoring or apnea may be better evaluated by comprehensive PSG prior to treatment if they are old, show greater hypoxia, or suffer from arrhythmia and/or heart failure, because such patients are more likely than others to exhibit CSA.

Cross-sectional study of characteristics of body composition of 24,845 children and adolescents aged 3-17 years in Suzhou.

BACKGROUND: We aimed to analyze the characteristics of the body composition of children and adolescents aged 3-17 in Suzhou, China. METHODS: A cross-sectional study between January 2020 and June 2022 using bioelectrical impedance was conducted to determine the fat mass (FM), fat-free mass (FFM), skeletal muscle mass, and protein and mineral contents of 24,845 children aged 3-17 who attended the Department of Child and Adolescent Healthcare, Children's Hospital of Soochow University, China. Measurement data was presented in tables as mean ± SD, and groups were compared using the independent samples t-test. RESULTS: FM and fat-free mass increased with age in both boys and girls. The fat-free mass of girls aged 14-15 decreased after reaching a peak, and that of boys in the same age group was higher than that of the girls (p < 0.05). There were no significant differences in FM between boys and girls younger than 9- and 10-years old. The percentage body fat (PBF) and FM index of girls increased rapidly between 11 and 15 years of age (p < 0.05), and those of boys aged 11-14 were significantly lower (p < 0.05), suggesting that the increase in body mass index (BMI) was mainly contributed by muscle mass (MM) in boys. CONCLUSIONS: The body composition of children and adolescents varies according to their age and sex. A misdiagnosis of obesity made on the basis of BMI alone can be avoided if BMI is used in combination with FM index, percentage body fat, and other indexes.

Office-based 532-nm KTP laser as a therapeutic modality for recurrent laryngeal papillomatosis: efficacy and relative factors.

This study aims to investigate the efficacy of office-based potassium-titanyl-phosphate (KTP) 532-nm laser in the management of recurrent laryngeal papillomatosis (RLP) following other treatments. A retrospective assessment was performed on 55 patients in 259 cases of RLP between 2012 and 2019. Derkay scores were obtained for all patients who underwent 532-nm KTP laser procedure (6 W of power with a continuous output mode) prior to treatment and after treatment. Analysis of parameters is based on the distribution characteristics of data. An ordinal logistic regression was also performed. Patients received a median of 3 (range 1-24) office-based KTP laser treatments. Among them, 96.36% (53 patients) were previously on cold steel equipment, CO2 laser, or microdebrider treatment under general anesthesia, and all previous treatments on them had failed. One patient progressed to invasive cancer, so he was excluded from the following analyses. After final KTP treatment, 36 patients (66.67%) received complete resolution with follow-up time ranging from 12.9 to 80.53 months (median 55.54 months). Results of subjective voice-quality indicators such as VHI-30 and GRBAS all improved greatly at the last follow-up. The initial Derkay scores and treatment intervals were found to be predictive of complete lesion remission. Arytenoid involvement may also correlate with lesion resolution. Serial office-based KTP treatment is an effective option for RLP patients, with ideal disease control and voice quality preservation. KTP laser therapy should be repeated with an interval of 1 month from the beginning of treatment until the lesion has been evaluated and subsided. Non-bulk or scattered laryngeal papilloma is an appropriate indication for KTP laser treatment.

CKL2 mediates the crosstalk between abscisic acid and brassinosteroid signaling to promote swift growth recovery after stress in Arabidopsis.

Plants must adapt to the constantly changing environment. Adverse environmental conditions trigger various defensive responses, including growth inhibition mediated by phytohormone abscisic acid (ABA). When the stress recedes, plants must transit rapidly from stress defense to growth recovery, but the underlying mechanisms by which plants switch promptly and accurately between stress resistance and growth are poorly understood. Here, using quantitative phosphoproteomics strategy, we discovered that early ABA signaling activates upstream components of brassinosteroid (BR) signaling through CASEIN KINASE 1-LIKE PROTEIN 2 (CKL2). Further investigations showed that CKL2 interacts with and phosphorylates BRASSINOSTEROID INSENSITIVE1 (BRI1), the main BR receptor, to maintain the basal activity of the upstream of BR pathway in plants exposed to continuous stress conditions. When stress recedes, the elevated phosphorylation of BRI1 by CKL2 contributes to the swift reactivation of BR signaling, which results in quick growth recovery. These results suggest that CKL2 plays a critical regulatory role in the rapid switch between growth and stress resistance. Our evidence expands the understanding of how plants modulate stress defense and growth by integrating ABA and BR signaling cascades.

Erythrocyte Membrane-Coated Invisible Acoustic-Sensitive Nanoparticle for Inducing Tumor Thrombotic Infarction by Precisely Damaging Tumor Vascular Endothelium.

Selective induction of tumor thrombus infarction is a promising antitumor strategy. Non-persistent embolism due to non-compacted thrombus and activated fibrinolytic system within the tumor large blood vessels and tumor margin recurrence are the main therapeutic bottlenecks. Herein, an erythrocyte membrane-coated invisible acoustic-sensitive nanoparticle (TXA+DOX/PFH/RBCM@cRGD) is described, which can induce tumor thrombus infarction by precisely damaging tumor vascular endothelium. It is revealed that TXA+DOX/PFH/RBCM@cRGD can effectively accumulate on the endothelial surface of tumor vessels with the help of the red blood cell membrane (RBCM) stealth coating and RGD cyclic peptide (cRGD), which can be delivered in a targeted manner as nanoparticle missiles. As a kind of phase-change material, perfluorohexane (PFH) nanodroplets possess excellent acoustic responsiveness. Acoustic-sensitive missiles can undergo an acoustic phase transition and intense cavitation with response to low-intensity focused ultrasound (LIFU), damaging the tumor vascular endothelium, rapidly initiating the coagulation cascade, and forming thromboembolism in the tumor vessels. The drugs loaded in the inner water phase are released explosively. Tranexamic acid (TXA) inhibits the fibrinolytic system, and doxorubicin (DOX) eliminates the margin survival. In summary, a stealthy and acoustically responsive multifunctional nanoparticle delivery platform is successfully developed for inducing thrombus infarction by precisely damaging tumor vascular endothelium.

Modulation of α7nAchR by Melatonin Alleviates Ischemia and Reperfusion-Compromised Integrity of Blood-Brain Barrier Through Inhibiting HMGB1-Mediated Microglia Activation and CRTC1-Mediated Neuronal Loss.

The only food and drug administration (FDA)-approved drug currently available for the treatment of acute ischemic stroke is tissue plasminogen activator (tPA), yet the therapeutic benefits of this drug are partially outweighed by the increased risk of hemorrhagic transformation (HT). Analysis of the NIH trial has shown that cigarette smoking protected tPA-treated patients from HT; however, the underlying mechanism is not clear. Nicotinic acetylcholine receptors (nAChR) has shown anti-inflammatory effect and modulation nAChR could be a strategy to reduce ischemia/reperfusion-induced blood-brain barrier (BBB) damage. Since melatonin could regulate the expression of α7nAchR and melatonin's neuroprotective effect against ischemic injury is mediated via α7nAChR modulation, here, we aim to test the hypothesis that melatonin reduces ischemia and reperfusion (I/R)-induced BBB damage through modulation of α7nACh receptor (α7nAChR). Mice were subjected to 1.5 h ischemia and 24 h reperfusion and at the onset of reperfusion, mice received intraperitoneal administration (i.p.) of either drug or saline. Mice were randomly assigned into five groups: Saline; α7nAChR agonist PNU282987; Melatonin; Melatonin+Methyllycaconitine (MLA, α7nAChR antagonist), and MLA group. BBB permeability was assessed by detecting the extravasation of Evan's blue and IgG. Our results showed that I/R significantly increased BBB permeability accompanied by occludin degradation, microglia activation, and high mobility group box 1 (HMGB1) release from the neuron. In addition, I/R significantly induced neuronal loss accompanied by the decrease of CREB-regulated transcriptional coactivator 1 (CRTC1) and p-CREB expression. Melatonin treatment significantly inhibited the above changes through modulating α7nAChR. Taken together, these results demonstrate that melatonin provides a protective effect on ischemia/reperfusion-induced BBB damage, at least in part, depending on the modulation of α7nAChR.