Identification of direct connections between the dura and the brain.

The arachnoid barrier delineates the border between the central nervous system and dura mater. Although the arachnoid barrier creates a partition, communication between the central nervous system and the dura mater is crucial for waste clearance and immune surveillance1,2. How the arachnoid barrier balances separation and communication is poorly understood. Here, using transcriptomic data, we developed transgenic mice to examine specific anatomical structures that function as routes across the arachnoid barrier. Bridging veins create discontinuities where they cross the arachnoid barrier, forming structures that we termed arachnoid cuff exit (ACE) points. The openings that ACE points create allow the exchange of fluids and molecules between the subarachnoid space and the dura, enabling the drainage of cerebrospinal fluid and limited entry of molecules from the dura to the subarachnoid space. In healthy human volunteers, magnetic resonance imaging tracers transit along bridging veins in a similar manner to access the subarachnoid space. Notably, in neuroinflammatory conditions such as experimental autoimmune encephalomyelitis, ACE points also enable cellular trafficking, representing a route for immune cells to directly enter the subarachnoid space from the dura mater. Collectively, our results indicate that ACE points are a critical part of the anatomy of neuroimmune communication in both mice and humans that link the central nervous system with the dura and its immunological diversity and waste clearance systems.

Improvement of surface stability of Zn anode by a cost-effective ErCl3 additive for realizing high-performance aqueous zinc-ion batteries.

Rechargeable aqueous-zinc ion batteries (AZIB) have notable benefits in terms of high safety and low cost. Nevertheless, the challenges, such as dendrite growth, zinc anode corrosion, and hydrogen evolution reaction, impede its practical implementation. Hence, this study proposes the introduction of an economical ErCl3 electrolyte additive to stabilize the Zn anode surface and address the aforementioned issues. The introduced Er3+ will cover the raised zinc dendrite surface and weaken the "tip effect" on the surface of the zinc anode via the "electrostatic shielding" effect. Simultaneously, the introduced Cl- can reduce the polarization of the zinc anode. Due to the synergistic effect of Er3+ and Cl-, the zinc anode corrosion, dendrite growth and hydrogen evolution have been efficiently inhibited. As a result, the Zn||Zn-symmetric battery using ErCl3 additive can stably cycle for 1100 h at 1 mA cm-2, 1 mAh cm-2, and exhibit a high average coulomb efficiency (99.2 %). Meanwhile, Zn||MnO2 full battery based on ErCl3-added electrolyte also demonstrates a high reversible capacity of 157.1 mAh/g after 500 cycles. Obviously, the capacity decay rate of the full battery is also improved, only 0.113 % per cycle. This study offers a straightforward and economically efficient method for stabilizing the zinc anode and realizing high-performance AZIBs.

Synthesis of a Novel Dithiocarbamate Surfactant Derivative Adsorbent for Efficient Removal of Heavy Metal Ions.

In this work, a novel heavy metal chelating agent (DTC-SDS) containing dithiocarbamate (DTC) was synthesized using sodium dodecyl sulfate (SDS), formaldehyde, and carbon disulfide. DTC-SDS has excellent trapping performance under pH 1-7 and initial concentrations 100-500 mg/L. With the increase in adsorbent dose, the adsorption amount of DTC-SDS increases and then decreases, and the optimized dosage of DTC-SDS is 0.02 g. The DTC-SDS adsorbent exhibits superior adsorption capacity (191.01, 111.7, and 79.14 mg/g) and high removal rates (97.99%, 98.48%, and 99.91%) for Mn2+, Zn2+, and Pb2+ respectively, in wastewater. Such remarkable adsorption performance could be attributed to the strong trapping effect on heavy metal ions by the C-S bond of DTC-SDS. The liquid adsorbent was in full contact with heavy metal ions, which further enhanced the complexation of heavy metal ions. The adsorption isothermal model showed that the adsorption process was typical of Langmuir monomolecular layer adsorption. Kinetic studies showed that the pseudo-second-order kinetic model fits the experimental adsorption data better than the pseudo-first-order kinetic model. In the ternary metal species system (Mn2+, Zn2+, and Pb2+), DTC-SDS preferentially adsorbed Pb2+ due to its highest covalent index. The main controlling step is the chemical interaction between the active groups of DTC-SDS and the heavy metal ions. This work provides valuable insights into the adsorption of heavy metal ions onto dithiocarbamate, which could guide the development of other heavy metal chelating agents and be beneficial for developing novel treatments of wastewater contaminated with heavy metals.

Recent advances in catalytic synthesis of 2,5-furandimethanol from 5-hydroxymethylfurfural and carbohydrates.

5-Hydroxymethylfurfural (HMF) is a versatile platform chemical derived from the dehydration of renewable carbohydrates (typically glucose/fructose-based monosaccharides, oligosaccharides, and polysaccharides). Some useful compounds, such as 2,5-furandimethanol (FDM), 2,5-dimethylfuran (DMF) and 2,5-dimethyltetrahydrofuran (DMTHF), have been synthesized by reduction of HMF. Among these, FDM is a promising diol and can be further converted towards fine chemicals, liquid fuels and polymer materials. In this review, some typical catalytic systems for the synthesis of FDM from both HMF and carbohydrates were summarized. The discussion focused on controlling the reaction networks for the reduction of HMF. The reaction mechanisms and the stability of the catalysts were introduced briefly. Last but not least, the prospects of effective production of FDM were discussed as well.

Oxidation state-specific fluorescent copper sensors reveal oncogene-driven redox changes that regulate labile copper(II) pools.

Copper is an essential metal nutrient for life that often relies on redox cycling between Cu(I) and Cu(II) oxidation states to fulfill its physiological roles, but alterations in cellular redox status can lead to imbalances in copper homeostasis that contribute to cancer and other metalloplasias with metal-dependent disease vulnerabilities. Copper-responsive fluorescent probes offer powerful tools to study labile copper pools, but most of these reagents target Cu(I), with limited methods for monitoring Cu(II) owing to its potent fluorescence quenching properties. Here, we report an activity-based sensing strategy for turn-on, oxidation state-specific detection of Cu(II) through metal-directed acyl imidazole chemistry. Cu(II) binding to a metal and oxidation state-specific receptor that accommodates the harder Lewis acidity of Cu(II) relative to Cu(I) activates the pendant dye for reaction with proximal biological nucleophiles and concomitant metal ion release, thus avoiding fluorescence quenching. Copper-directed acyl imidazole 649 for Cu(II) (CD649.2) provides foundational information on the existence and regulation of labile Cu(II) pools, including identifying divalent metal transporter 1 (DMT1) as a Cu(II) importer, labile Cu(II) increases in response to oxidative stress induced by depleting total glutathione levels, and reciprocal increases in labile Cu(II) accompanied by decreases in labile Cu(I) induced by oncogenic mutations that promote oxidative stress.

Evaluation of anthracycline-induced subclinical LV dysfunction by using myocardial composite index and two-dimension speckle tracking echocardiography technique.

Objective: To obtain various myocardial strain parameters by using two-dimension speckle tracking echocardiography (2D-STE) technique, calculate the myocardial composite index (MCI) which combines the global longitudinal strain (GLS) of left ventricle and the left ventricular twist (LVtw), and evaluate their diagnostic efficacies for subclinical left ventricular (LV) dysfunction in patients undergoing anthracycline chemotherapy. Methods: A total of 35 female breast cancer patients, who underwent postoperative chemotherapy in the Department of Thyroid and Breast Surgery of Nantong Third People's Hospital from September 2018 to December 2019 and had successful follow-up, were included into the chemotherapy group, and the patients were evaluated respectively at baseline and in early, interim and later chemotherapy stages according to the course of chemotherapy; in addition, 30 healthy women undergoing physical examination during the same period were included into the control group. In different chemotherapy stages, the data such as left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), interventricular septal thickness (IVST), left ventricular posterior wall thickness (LVPWT) and left ventricular ejection fraction (LVEF) were collected by using conventional echocardiography, and various myocardial strain parameters such as GLS, global radial strain (GRS), global circumferential strain(GCS) and LVtw were measured using 2D-STE, and then MCI was calculated. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the application values of various parameters in the diagnosis of early cardiotoxicity. Results: There was a difference in MCI between patients at baseline and in the early chemotherapy stage; there were differences in GLS, LVtw and MCI between patients at baseline and in the interim chemotherapy stage; there were differences in four parameters such as MCI, GLS, LVtw and GCS between patients at baseline and in the later chemotherapy stage; The AUC of MCI was 0.915, when the cutoff value was -210.89 (%×°), the sensitivity and specificity were 84.37% and 90.41%, respectively. Conclusion: MCI combines the longitudinal and torsional motions of myocardium, and thus has a better diagnostic value for early detection of subclinical LV dysfunction caused by anthracycline chemotherapy drugs compared with strain parameters in a single direction.

BRAFV600E-Driven Lung Adenocarcinoma Requires Copper to Sustain Autophagic Signaling and Processing.

The transition metal copper (Cu) is an essential micronutrient required for development and proliferation, but the molecular mechanisms by which Cu contributes to these processes is not fully understood. Although traditionally studied as a static cofactor critical for the function of Cu-dependent enzymes, an expanding role for Cu is emerging to include its novel function as a dynamic mediator of signaling processes through the direct control of protein kinase activity. We now appreciate that Cu directly binds to and influences MEK1/2 and ULK1/2 kinase activity, and show here that reductions in MAPK and autophagic signaling are associated with dampened growth and survival of oncogenic BRAF-driven lung adenocarcinoma cells upon loss of Ctr1. Efficient autophagy, clonogenic survival, and tumorigenesis of BRAF-mutant cells required ULK1 Cu-binding. Although treatment with canonical MAPK inhibitors resulted in the upregulation of protective autophagy, mechanistically, the Cu chelator tetrathiomolybdate (TTM) was sufficient to target both autophagic and MAPK signaling as a means to blunt BRAF-driven tumorigenic properties. These findings support leveraging Cu chelation with TTM as an alternative therapeutic strategy to impair autophagy and MAPK signaling. As traditional MAPK monotherapies initiate autophagy signaling and promote cancer cell survival. IMPLICATIONS: We establish that copper chelation therapy inhibits both autophagy and MAPK signaling in BRAFV600E-driven lung adenocarcinoma, thus overcoming the upregulation of protective autophagy elicited by canonical MAPK pathway inhibitors.

Highly branched amylopectin binder for sulfur cathodes with enhanced performance and longevity.

The sulfur cathode of lithium-sulfur (Li-S) batteries suffers from inherent problems of insufficient mechanical strength and the dissolution of sulfur and polysulfides. Inspired by the extraordinarily resilient and strong binding force of the Great Wall binder, that is, the sticky rice mortar, we extracted highly branched amylopectin (HBA), the effective ingredient, as a low-cost, nontoxic and environmentally benign aqueous binder for the sulfur cathode. The HBA-based cells outperform the Li-S batteries based on the traditional polyvinyldene diflouride (PVDF) binder and a lowly branched polysaccharide binder. The improved electrochemical performance in the HBA-based cell could be attributed to two mechanisms. First, the branched structure of the HBA provides enhanced mechanical and adhesive properties, which allow for a robust electronic and ionic conductive framework to be maintained throughout the cathode after extended cycling. Second, the HBA shows enhanced polysulfide retention due to the polymer's abundant lone-pair rich hydroxyl groups and the formation of C─S bonds between the HBA and polysulfides prohibits the shuttle effect of polysulfides. The improved mechanical properties and polysulfide retention function of the HBA binder facilitate the HBA-based Li-S battery to deliver a long cycle life of 500 cycles at 2 C while only displaying a capacity fading of 0.104% per cycle.

Electrolyte Salts and Additives Regulation Enables High Performance Aqueous Zinc Ion Batteries: A Mini Review.

Aqueous zinc ion batteries (ZIBs) are regarded as one of the most ideally suited candidates for large-scale energy storage applications owning to their obvious advantages, that is, low cost, high safety, high ionic conductivity, abundant raw material resources, and eco-friendliness. Much effort has been devoted to the exploration of cathode materials design, cathode storage mechanisms, anode protection as well as failure mechanisms, while inadequate attentions are paid on the performance enhancement through modifying the electrolyte salts and additives. Herein, to fulfill a comprehensive aqueous ZIBs research database, a range of recently published electrolyte salts and additives research is reviewed and discussed. Furthermore, the remaining challenges and future directions of electrolytes in aqueous ZIBs are also suggested, which can provide insights to push ZIBs' commercialization.

Interface Engineering via Ti3C2Tx MXene Electrolyte Additive toward Dendrite-Free Zinc Deposition.

Zinc metal batteries have been considered as a promising candidate for next-generation batteries due to their high safety and low cost. However, their practical applications are severely hampered by the poor cyclability that caused by the undesired dendrite growth of metallic Zn. Herein, Ti3C2Tx MXene was first used as electrolyte additive to facilitate the uniform Zn deposition by controlling the nucleation and growth process of Zn. Such MXene additives can not only be absorbed on Zn foil to induce uniform initial Zn deposition via providing abundant zincophilic-O groups and subsequently participate in the formation of robust solid-electrolyte interface film, but also accelerate ion transportation by reducing the Zn2+ concentration gradient at the electrode/electrolyte interface. Consequently, MXene-containing electrolyte realizes dendrite-free Zn plating/striping with high Coulombic efficiency (99.7%) and superior reversibility (stably up to 1180 cycles). When applied in full cell, the Zn-V2O5 cell also delivers significantly improved cycling performances. This work provides a facile yet effective method for developing reversible zinc metal batteries.

Study of effects of anthracycline drugs on myocardial function in breast cancer patients by quantitative analysis of layer-specific strain via 2D-STI technology.

OBJECTIVE: This study aimed to explore the value of layer-specific strain analysis by two-dimensional speckle tracking imaging (2D-STI) in the assessment of myocardial toxicity in breast cancer patients receiving anthracycline chemotherapy. METHODS: Thirty-four breast cancer patients receiving anthracycline chemotherapy were prospectively enrolled. Conventional echocardiography and 2D-STI were evaluated at baseline after the third and sixth cycles of anthracycline chemotherapy. The strains of different layers of left ventricle (LV) including peak systolic longitudinal strain (endo-LS, mid-LS, epi-LS) and circumferential strain (endo-CS, mid-CS, epi-CS) were measured using EchoPAC analysis software. Peak systolic longitudinal strain (MV-LS, PM-LS, AP-LS), circumferential strain (MV-CS, PM-CS, AP-CS) and radial strain (MV-RS, PM-RS, AP-RS) were measured at mitral valve, papillary muscle and apex levels of LV respectively. Global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain (GRS), and left ventricular twist (LVtw) were also analyzed. RESULTS: There was no significant difference in the structural and functional parameters of conventional 2D echocardiography in different cycles of anthracycline chemotherapy (P>0.05); layer specific LS and CS in various cycles decreased layer by layer from inside to outside. LS and CS increased from basal segment to apical segment, while RS showed no obvious gradient characteristics; compared with baseline, GLS and LSs (endo-PM, endo-AP, mid-PM, mid-AP and epi-AP) of LV decreased significantly after the third cycle of chemotherapy (P<0.05); LSs (epi-MV and epi-AP) decreased significantly after the sixth cycle of chemotherapy (P<0.05). No significant changes were detected in layer specific CS, RS and LVtw (P>0.05). CONCLUSION: Layer-specific strain analysis by 2D-STI technology can quantitatively analyze global and regional functions of LV. The myocardial toxicity due to anthracycline chemotherapy can be detected by layer-specific LS of LV in early stage, which is great valuable to guiding clinical early intervention and improving prognosis.

Hyperbranched molecules having multiple functional groups as effective corrosion inhibitors for Al alloys in aqueous NaCl.

Hyperbranched molecules are a kind of promising materials due to their unique structures. In this work, two hyperbranched molecules (GON and GOH) are used as effective inhibitors for Al alloys in NaCl solution. Their inhibitive performances are evaluated by electrochemical measurements and surface characterization. The results indicate that inhibition performances of GON and GOH are closely related to the concentrations, influenced by the combination of steric hindrance and bonding effects. At relatively low concentrations (0.03-0.10 mM), GON displays a more pronounced ability to inhibit corrosion than GOH, owing to more anchoring functional groups. Oppositely, GOH has good inhibition performance at higher concentrations (0.50-1.00 mM). The interaction between the Al electrode and GOH results in the formation of a more condenser protective film than GON at high concentrations. In addition, the adsorption mechanism of two hyperbranched molecules is revealed by theoretical calculations.

Altered copper homeostasis underlies sensitivity of hepatocellular carcinoma to copper chelation.

Hepatocellular carcinoma (HCC), the most common primary liver cancer, of which ∼800 000 new cases will be diagnosed worldwide this year, portends a five-year survival rate of merely 17% in patients with unresectable disease. This dismal prognosis is due, at least in part, from the late stage of diagnosis and the limited efficacy of systemic therapies. As a result, there is an urgent need to identify risk factors that contribute to HCC initiation and provide targetable vulnerabilities to improve patient survival. While myriad risk factors are known, elevated copper (Cu) levels in HCC patients and the incidence of hepatobiliary malignancies in Wilson disease patients, which exhibit hereditary liver Cu overload, suggests the possibility that metal accumulation promotes malignant transformation. Here we found that expression of the Cu transporter genes ATP7A, ATP7B, SLC31A1, and SLC31A2 was significantly altered in liver cancer samples and were associated with elevated Cu levels in liver cancer tissue and cells. Further analysis of genomic copy number data revealed that alterations in Cu transporter gene loci correlate with poorer survival in HCC patients. Genetic loss of the Cu importer SLC31A1 (CTR1) or pharmacologic suppression of Cu decreased the viability, clonogenic survival, and anchorage-independent growth of human HCC cell lines. Mechanistically, CTR1 knockdown or Cu chelation decreased glycolytic gene expression and downstream metabolite utilization and as a result forestalled tumor cell survival after exposure to hypoxia, which mimics oxygen deprivation elicited by transarterial embolization, a standard-of-care therapy used for patients with unresectable HCC. Taken together, these findings established an association between altered Cu homeostasis and HCC and suggest that limiting Cu bioavailability may provide a new treatment strategy for HCC by restricting the metabolic reprogramming necessary for cancer cell survival.

Effects of homocysteine-induced endoplasmic reticulum protein on endoplasmic reticulum stress, autophagy, and neuronal apoptosis following intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is defined as bleeding into the brain parenchyma with a high mortality and morbidity rate. Unfortunately, it remains an unresolved medical problem. Therefore, it is necessary to find ways to reduce cellular apoptosis after ICH. Homocysteine-induced endoplasmic reticulum protein (HERP), a 54 kD transmembrane protein, is an early stress response protein encoded by ubiquitin-like domain member 1 (Herpud1) gene. In the present work, our group investigated the role of HERP after ICH and hemin stimulation, HERP expression was examined in mouse and primary cortical neurons after ICH and hemin stimulation by western blot and Immunofluorescent labeling. Using shRNA-HERP plasmid and recombinant adenovirus, we also investigated how HERP affected neuronal apoptosis after ICH and hemin stimulation. In addition, behavioral evaluation was used to ensure our models' success. In vivo and vitro studies, the expression of HERP was increased following ICH and hemin-exposed primary cortical neurons. HERP depletion activated the endoplasmic reticulum (ER) stress pathway and apoptosis in hemin-exposed primary cortical neurons, but inhibited autophagy in hemin-exposed primary cortical neurons. Overexpression of HERP inhibited the ER stress pathway and apoptosis, but activated autophagy in hemin-exposed primary cortical neurons. Consequently, we confirm that HERP plays a protective role in ICH model.

SOCS3 Attenuates GM-CSF/IFN-γ-Mediated Inflammation During Spontaneous Spinal Cord Regeneration.

SOCS3, a feedback inhibitor of the JAK/STAT signal pathway, negatively regulates axonal regrowth and inflammation in the central nervous system (CNS). Here, we demonstrated a distinct role of SOCS3 in the injured spinal cord of the gecko following tail amputation. Severing the gecko spinal cord did not evoke an inflammatory cascade except for an injury-stimulated elevation of the granulocyte/macrophage colony-stimulating factor (GM-CSF) and interferon gamma (IFN-γ) cytokines. Simultaneously, the expression of SOCS3 was upregulated in microglia, and unexpectedly not in neurons. Enforced expression of SOCS3 was sufficient to suppress the GM-CSF/IFN-γ-driven inflammatory responses through its KIR domain by attenuating the activities of JAK1 and JAK2. SOCS3 was also linked to GM-CSF/IFN-γ-induced cross-tolerance. Transfection of adenovirus overexpressing SOCS3 in the injured cord resulted in a significant decrease of inflammatory cytokines. These results reveal a distinct role of SOCS3 in the regenerating spinal cord, and provide new hints for CNS repair in mammals.

A Typha Angustifolia-Like MoS2/Carbon Nanofiber Composite for High Performance Li-S Batteries.

A Typha Angustifolia-like MoS2/carbon nanofiber composite as both a chemically trapping agent and redox conversion catalyst for lithium polysulfides has been successfully synthesized via a simple hydrothermal method. Cycling performance and coulombic efficiency have been improved significantly by applying the Typha Angustifolia-like MoS2/carbon nanofiber as the interlayer of a pure sulfur cathode, resulting in a capacity degradation of only 0.09% per cycle and a coulombic efficiency which can reach as high as 99%.

Stabilizing lithium metal anode by octaphenyl polyoxyethylene-lithium complexation.

Lithium metal is an ideal anode for lithium batteries due to its low electrochemical potential and high theoretical capacity. However, safety issues arising from lithium dendrite growth have significantly reduced the practical applicability of lithium metal batteries. Here, we report the addition of octaphenyl polyoxyethylene as an electrolyte additive to enable a stable complex layer on the surface of the lithium anode. This surface layer not only promotes uniform lithium deposition, but also facilitates the formation of a robust solid-electrolyte interface film comprising cross-linked polymer. As a result, lithium|lithium symmetric cells constructed using the octaphenyl polyoxyethylene additive exhibit excellent cycling stability over 400 cycles at 1 mA cm-2, and outstanding rate performance up to 4 mA cm-2. Full cells assembled with a LiFePO4 cathode exhibit high rate capability and impressive cyclability, with capacity decay of only 0.023% per cycle.

DFT-Guided Design and Fabrication of Carbon-Nitride-Based Materials for Energy Storage Devices: A Review.

Carbon nitrides (including CN, C2N, C3N, C3N4, C4N, and C5N) are a unique family of nitrogen-rich carbon materials with multiple beneficial properties in crystalline structures, morphologies, and electronic configurations. In this review, we provide a comprehensive review on these materials properties, theoretical advantages, the synthesis and modification strategies of different carbon nitride-based materials (CNBMs) and their application in existing and emerging rechargeable battery systems, such as lithium-ion batteries, sodium and potassium-ion batteries, lithium sulfur batteries, lithium oxygen batteries, lithium metal batteries, zinc-ion batteries, and solid-state batteries. The central theme of this review is to apply the theoretical and computational design to guide the experimental synthesis of CNBMs for energy storage, i.e., facilitate the application of first-principle studies and density functional theory for electrode material design, synthesis, and characterization of different CNBMs for the aforementioned rechargeable batteries. At last, we conclude with the challenges, and prospects of CNBMs, and propose future perspectives and strategies for further advancement of CNBMs for rechargeable batteries.

Increased expression of Triad1 is associated with neuronal apoptosis after intracerebral hemorrhage in adult rats.

Objective: It has been demonstrated that Triad1 (2 RING fingers and double RING finger linked 1) negatively regulates myeloid cell growth and induces cell apoptosis. However, its functions in intracerebral hemorrhage (ICH) disease have not been conducted. In this study, the role of Triad1 in rat model of ICH was explored.Methods: We observe an increasing expression of Triad1 in areas adjacent to hematoma after ICH. Immunofluorescence shows that Triad1 is colocalized with neurons, while not microglia or astrocyte, indicates its correlation with neuronal activities following ICH.Results: As neuronal apoptosis is the most crucial event in ICH disease, the expression of active caspase-3 and p53 is also enhanced around the hematoma, which is consistent with Triad1 in expression tendency. In turn, Triad1 depletion in primary cortical neurons decreased the apoptosis of neurons after using Triad1 shRNA.Conclusion: We conclude that inhibition of Triad1 expression might protect the brain from secondary damage following ICH.

BES1-regulated BEE1 controls photoperiodic flowering downstream of blue light signaling pathway in Arabidopsis.

BRI1-EMS-SUPPRESSOR 1 (BES1) functions as a key regulator in the brassinosteroid (BR) pathway that promotes plant growth. However, whether BES1 is involved in photoperiodic flowering is unknown. Here we report that BES1 acts as a positive regulator of photoperiodic flowering, but it cannot directly bind FLOWERING LOCUS T (FT) promoter. BR ENHANCED EXPRESSION 1 (BEE1) is the direct target of BES1 and acts downstream of BES1. BEE1 is also a positive regulator of photoperiodic flowering. BEE1 binds directly to the FT chromatin to activate the transcription of FT and promote flowering initiation. More importantly, BEE1 promotes flowering in a blue light photoreceptor CRYPTOCHROME 2 (CRY2)  partially dependent manner, as it physically interacts with CRY2 under the blue light. Furthermore, BEE1 is regulated by both BRs and blue light. The transcription of BEE1 is induced by BRs, and the BEE1 protein is stabilized under the blue light. Our findings indicate that BEE1 is the integrator of BES1 and CRY2 mediating flowering, and BES1-BEE1-FT is a new signaling pathway in regulating photoperiodic flowering.