Reconstituted Postsynaptic Density as a Molecular Platform for Understanding Synapse Formation and Plasticity.

Synapses are semi-membraneless, protein-dense, sub-micron chemical reaction compartments responsible for signal processing in each and every neuron. Proper formation and dynamic responses to stimulations of synapses, both during development and in adult, are fundamental to functions of mammalian brains, although the molecular basis governing formation and modulation of compartmentalized synaptic assemblies is unclear. Here, we used a biochemical reconstitution approach to show that, both in solution and on supported membrane bilayers, multivalent interaction networks formed by major excitatory postsynaptic density (PSD) scaffold proteins led to formation of PSD-like assemblies via phase separation. The reconstituted PSD-like assemblies can cluster receptors, selectively concentrate enzymes, promote actin bundle formation, and expel inhibitory postsynaptic proteins. Additionally, the condensed phase PSD assemblies have features that are distinct from those in homogeneous solutions and fit for synaptic functions. Thus, we have built a molecular platform for understanding how neuronal synapses are formed and dynamically regulated.

Phosphorylation-dependent membraneless organelle fusion and fission illustrated by postsynaptic density assemblies.

Membraneless organelles formed by phase separation of proteins and nucleic acids play diverse cellular functions. Whether and, if yes, how membraneless organelles in ways analogous to membrane-based organelles also undergo regulated fusion and fission is unknown. Here, using a partially reconstituted mammalian postsynaptic density (PSD) condensate as a paradigm, we show that membraneless organelles can undergo phosphorylation-dependent fusion and fission. Without phosphorylation of the SAPAP guanylate kinase domain-binding repeats, the upper and lower layers of PSD protein mixtures form two immiscible sub-compartments in a phase-in-phase organization. Phosphorylation of SAPAP leads to fusion of the two sub-compartments into one condensate accompanied with an increased Stargazin density in the condensate. Dephosphorylation of SAPAP can reverse this event. Preventing SAPAP phosphorylation in vivo leads to increased separation of proteins from the lower and upper layers of PSD sub-compartments. Thus, analogous to membrane-based organelles, membraneless organelles can also undergo regulated fusion and fission.

Structure deformation and curvature sensing of PIEZO1 in lipid membranes.

PIEZO channels respond to piconewton-scale forces to mediate critical physiological and pathophysiological processes1-5. Detergent-solubilized PIEZO channels form bowl-shaped trimers comprising a central ion-conducting pore with an extracellular cap and three curved and non-planar blades with intracellular beams6-10, which may undergo force-induced deformation within lipid membranes11. However, the structures and mechanisms underlying the gating dynamics of PIEZO channels in lipid membranes remain unresolved. Here we determine the curved and flattened structures of PIEZO1 reconstituted in liposome vesicles, directly visualizing the substantial deformability of the PIEZO1-lipid bilayer system and an in-plane areal expansion of approximately 300 nm2 in the flattened structure. The curved structure of PIEZO1 resembles the structure determined from detergent micelles, but has numerous bound phospholipids. By contrast, the flattened structure exhibits membrane tension-induced flattening of the blade, bending of the beam and detaching and rotating of the cap, which could collectively lead to gating of the ion-conducting pathway. On the basis of the measured in-plane membrane area expansion and stiffness constant of PIEZO1 (ref. 11), we calculate a half maximal activation tension of about 1.9 pN nm-1, matching experimentally measured values. Thus, our studies provide a fundamental understanding of how the notable deformability and structural rearrangement of PIEZO1 achieve exquisite mechanosensitivity and unique curvature-based gating in lipid membranes.

RIM and RIM-BP Form Presynaptic Active-Zone-like Condensates via Phase Separation.

Both the timing and kinetics of neurotransmitter release depend on the positioning of clustered Ca2+ channels in active zones to docked synaptic vesicles on presynaptic plasma membranes. However, how active zones form is not known. Here, we show that RIM and RIM-BP, via specific multivalent bindings, form dynamic and condensed assemblies through liquid-liquid phase separation. Voltage-gated Ca2+ channels (VGCCs), via C-terminal-tail-mediated direct binding to both RIM and RIM-BP, can be enriched to the RIM and RIM-BP condensates. We further show that RIM and RIM-BP, together with VGCCs, form dense clusters on the supported lipid membrane bilayers via phase separation. Therefore, RIMs and RIM-BPs are plausible organizers of active zones, and the formation of RIM and RIM-BP condensates may cluster VGCCs into nano- or microdomains and position the clustered Ca2+ channels with Ca2+ sensors on docked vesicles for efficient and precise synaptic transmissions.

Nomo1 deficiency causes autism-like behavior in zebrafish.

Patients with neuropsychiatric disorders often exhibit a combination of clinical symptoms such as autism, epilepsy, or schizophrenia, complicating diagnosis and development of therapeutic strategies. Functional studies of novel genes associated with co-morbidities can provide clues to understand the pathogenic mechanisms and interventions. NOMO1 is one of the candidate genes located at 16p13.11, a hotspot of neuropsychiatric diseases. Here, we generate nomo1-/- zebrafish to get further insight into the function of NOMO1. Nomo1 mutants show abnormal brain and neuronal development and activation of apoptosis and inflammation-related pathways in the brain. Adult Nomo1-deficient zebrafish exhibit multiple neuropsychiatric behaviors such as hyperactive locomotor activity, social deficits, and repetitive stereotypic behaviors. The Habenular nucleus and the pineal gland in the telencephalon are affected, and the melatonin level of nomo1-/- is reduced. Melatonin treatment restores locomotor activity, reduces repetitive stereotypic behaviors, and rescues the noninfectious brain inflammatory responses caused by nomo1 deficiency. These results suggest melatonin supplementation as a potential therapeutic regimen for neuropsychiatric disorders caused by NOMO1 deficiency.

M6AREG: m6A-centered regulation of disease development and drug response.

As the most prevalent internal modification in eukaryotic RNAs, N6-methyladenosine (m6A) has been discovered to play an essential role in cellular proliferation, metabolic homeostasis, embryonic development, etc. With the rapid accumulation of research interest in m6A, its crucial roles in the regulations of disease development and drug response are gaining more and more attention. Thus, a database offering such valuable data on m6A-centered regulation is greatly needed; however, no such database is as yet available. Herein, a new database named 'M6AREG' is developed to (i) systematically cover, for the first time, data on the effects of m6A-centered regulation on both disease development and drug response, (ii) explicitly describe the molecular mechanism underlying each type of regulation and (iii) fully reference the collected data by cross-linking to existing databases. Since the accumulated data are valuable for researchers in diverse disciplines (such as pathology and pathophysiology, clinical laboratory diagnostics, medicinal biochemistry and drug design), M6AREG is expected to have many implications for the future conduct of m6A-based regulation studies. It is currently accessible by all users at: https://idrblab.org/m6areg/.

E3 ubiquitin ligase RNF148 functions as an oncogene in colorectal cancer by ubiquitination-mediated degradation of CHAC2.

We previously reported that RNF148 was involved in the ubiquitination-mediated degradation of CHAC2. However, its molecular mechanism was not determined. In this study, we investigated the role and mechanism of RNF148 in the progression of colorectal cancer (CRC), especially in the process of ubiquitination-mediated degradation of CHAC2. Our results revealed that RNF148 was upregulated in most CRC tissues, and its expression significantly correlated with the 3-year overall survival rate and most clinicopathological parameters of CRC patients. Furthermore, RNF148 served as an independent prognostic biomarker of CRC and promoted CRC cell proliferation and migration while inhibiting cell apoptosis and sensitivity to 5-FU. Mechanistically, RNF148 used its protease-associated domain to bind to the CHAC domain of CHAC2 and target it for degradation. In addition, we identified two phosphorylation and three ubiquitination residues of CHAC2 and identified Y118 and K102 as the critical phosphorylation and ubiquitination residues, respectively. We also identified CHAC2's and RNF148's interacting proteins and discovered their potential interaction network. In conclusion, our current study unveiled the role of RNF148 in CRC and the mechanism of RNF148 in the ubiquitination-mediated degradation of CHAC2, which shed light on providing potential prognostic biomarkers and molecular targets for CRC patients.

Increased expression of REG3A promotes tumorigenic behavior in triple negative breast cancer cells.

BACKGROUND: Identifying new targets in triple negative breast cancer (TNBC) remains critical. REG3A (regenerating islet-derived protein 3 A), a calcium-dependent lectin protein, was thoroughly investigated for its expression and functions in breast cancer. METHODS: Bioinformatics and local tissue analyses were employed to identify REG3A expression in breast cancer. Genetic techniques were employed to modify REG3A expression, and the resulting effects on the behaviors of breast cancer cells were examined. Subcutaneous xenograft models were established to investigate the involvement of REG3A in the in vivo growth of breast cancer cells. RESULTS: Analysis of the TCGA database uncovered increased REG3A levels in human breast cancer tissues. Additionally, REG3A mRNA and protein levels were elevated in TNBC tissues of locally treated patients, contrasting with low expression in adjacent normal tissues. In primary human TNBC cells REG3A shRNA notably hindered cell proliferation, migration, and invasion while triggering caspase-mediated apoptosis. Similarly, employing CRISPR-sgRNA for REG3A knockout showed significant anti-TNBC cell activity. Conversely, REG3A overexpression bolstered cell proliferation and migration. REG3A proved crucial for activating the Akt-mTOR cascade, as evidenced by decreased Akt-S6K1 phosphorylation upon REG3A silencing or knockout, which was reversed by REG3A overexpression. A constitutively active mutant S473D Akt1 (caAkt1) restored Akt-mTOR activation and counteracted the proliferation inhibition and apoptosis induced by REG3A knockdown in breast cancer cells. Crucially, REG3A played a key role in maintaining mTOR complex integrity. Bioinformatics identified zinc finger protein 680 (ZNF680) as a potential REG3A transcription factor. Knocking down or knocking out ZNF680 reduced REG3A expression, while its overexpression increased it in primary breast cancer cells. Additionally, enhanced binding between ZNF680 protein and the REG3A promoter was observed in breast cancer tissues and cells. In vivo, REG3A shRNA significantly inhibited primary TNBC cell xenograft growth. In REG3A-silenced xenograft tissues, reduced REG3A levels, Akt-mTOR inhibition, and activated apoptosis were evident. CONCLUSION: ZNF680-caused REG3A overexpression drives tumorigenesis in breast cancer possibly by stimulating Akt-mTOR activation, emerging as a promising and innovative cancer target.

Saccharin Sodium Coupling Fluorinated Solvent Enabled Stable Interface for High-Voltage Li-Metal Batteries.

Optimizing the electrode/electrolyte interface structure is the key to realizing high-voltage Li-metal batteries (LMBs). Herein, a functional electrolyte is introduced to synergetically regulate the interface layer structures on the high-voltage cathode and the Li-metal anode. Saccharin sodium (NaSH) as a multifunctional electrolyte additive is employed in fluorinated solvent-based electrolyte (FBE) for robust interphase layer construction. On the one hand, combining the results of ex-situ techniques and in-situ electrochemical dissipative quartz crystal microbalance (EQCM-D) technique, it can be seen that the solid electrolyte interface (SEI) layer constructed by NaSH-coupled fluoroethylene carbonate (FEC) on Li-metal anode significantly inhibits the growth of lithium dendrites and improves the cyclic stability of the anode. On the other hand, the experimental results also confirm that the cathode-electrolyte interface (CEI) layer induced by NaSH-coupled FEC effectively protects the active materials of LiCoO2 and improves their structural stability under high-voltage cycling, thus avoiding the material rupture. Moreover, theoretical calculation results show that the addition of NaSH alters the desolvation behavior of Li+ and enhances the transport kinetics of Li+ at the electrode/electrolyte interface. In this contribution, the LiCoO2 ǁLi full cell containing FBE+NaSH results in a high capacity retention of 80% after 530 cycles with a coulombic efficiency of 99.8%.

Fourier metasurface cloaking: unidirectional cloaking of electrically large cylinder under oblique incidence.

The existence of a non-electrically-small scatterer adjacent to the source can severely distort the radiation and lead to a poor electromagnetic compatibility. In this work, we use a conducting hollow cylinder to shield a cylindrical scatterer. The cylinder is shelled with a single dielectric layer enclosed by an electromagnetic metasurface. The relationship between the scattering field and the surface impedance is derived analytically. By optimizing the Fourier expansion coefficients of the surface impedance distribution along ϕ-dimension, the scattering cross-section can be effectively reduced. This unidirectional cloaking method is valid for both TM/TE and non-TM/TE incident field and is not limited to a plane-wave incident field. The accuracy and effectiveness of the method are verified by four cloaking scenarios in microwave regime. We demonstrate that with the surface impedance obtained by the proposed method, a metasurface is designed with physical subwavelength structures. We also show a cloaking scenario under a magnetic dipole radiation, which is closer to the case of a realistic antenna. This method can be further applied to cloaking tasks in terahertz and optical regimes.

Endogenous hydrogen sulphide deficiency and exogenous hydrogen sulphide supplement regulate skin fibroblasts proliferation via necroptosis.

An excessive proliferation of skin fibroblasts usually results in different skin fibrotic diseases. Hydrogen sulphide (H2 S) is regarded as an important endogenous gasotransmitter with various functions. The study aimed to investigate the roles and mechanisms of H2 S on primary mice skin fibroblasts proliferation. Cell proliferation and collagen synthesis were assessed with the expression of α-smooth muscle actin (α-SMA), proliferating cell nuclear antigen (PCNA), Collagen I and Collagen III. The degree of oxidative stress was evaluated by dihydroethidium (DHE) and MitoSOX staining. Mitochondrial membrane potential (ΔΨm) was detected by JC-1 staining. Necroptosis was evaluated with TDT-mediated dUTP nick end labelling (TUNEL) and expression of receptor-interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like protein (MLKL). The present study found that α-SMA, PCNA, Collagen I and Collagen III expression were increased, oxidative stress was promoted, ΔΨm was impaired and positive rate of TUNEL staining, RIPK1 and RIPK3 expression as well as MLKL phosphorylation were all enhanced in skin fibroblasts from cystathionine γ-lyase (CSE) knockout (KO) mice or transforming growth factor-ß1 (TGF-ß1, 10 ng/mL)-stimulated mice skin fibroblasts, which was restored by exogenous sodium hydrosulphide (NaHS, 50 µmol/L). In conclusion, endogenous H2 S production impairment in CSE-deficient mice accelerated skin fibroblasts proliferation via promoted necroptosis, which was attenuated by exogenous H2 S. Exogenous H2 S supplement alleviated proliferation of skin fibroblasts with TGF-ß1 stimulation via necroptosis inhibition. This study provides evidence for H2 S as a candidate agent to prevent and treat skin fibrotic diseases.

Exploring T-cell exhaustion features in Acute myocardial infarction for a Novel Diagnostic model and new therapeutic targets by bio-informatics and machine learning.

BACKGROUND: T-cell exhaustion (TEX), a condition characterized by impaired T-cell function, has been implicated in numerous pathological conditions, but its role in acute myocardial Infarction (AMI) remains largely unexplored. This research aims to identify and characterize all TEX-related genes for AMI diagnosis. METHODS: By integrating gene expression profiles, differential expression analysis, gene set enrichment analysis, protein-protein interaction networks, and machine learning algorithms, we were able to decipher the molecular mechanisms underlying TEX and its significant association with AMI. In addition, we investigated the diagnostic validity of the leading TEX-related genes and their interactions with immune cell profiles. Different types of candidate small molecule compounds were ultimately matched with TEX-featured genes in the "DrugBank" database to serve as potential therapeutic medications for future TEX-AMI basic research. RESULTS: We screened 1725 differentially expressed genes (DEGs) from 80 AMI samples and 71 control samples, identifying 39 differential TEX-related transcripts in total. Functional enrichment analysis identified potential biological functions and signaling pathways associated with the aforementioned genes. We constructed a TEX signature containing five hub genes with favorable prognostic performance using machine learning algorithms. In addition, the prognostic performance of the nomogram of these five hub genes was adequate (AUC between 0.815 and 0.995). Several dysregulated immune cells were also observed. Finally, six small molecule compounds which could be the future therapeutic for TEX in AMI were discovered. CONCLUSION: Five TEX diagnostic feature genes, CD48, CD247, FCER1G, TNFAIP3, and FCGRA, were screened in AMI. Combining these genes may aid in the early diagnosis and risk prediction of AMI, as well as the evaluation of immune cell infiltration and the discovery of new therapeutics.

Robust, Ultrafast and Reversible Photoswitching in Bulk Polymers Enabled by Octupolar Molecule Design.

Improving the photoswitching rate and robustness of photochromic molecules in bulk solids is paramount for practical applications but remains an on-going challenge. Here, we introduce an octupolar design paradigm to develop a new family of visible light organic photoswitches, namely multi-branched octupolar Stenhouse Adducts (MOPSAs) featuring a C3-symmetrical A3-(D-core) architecture with a dipolar donor-acceptor (D-A) photochrome in each branch. Our design couples multi-dimensional geometric and electronic effects of MOPSAs to enable robust ultrafast reversible photoswitching in bulk polymers. Specifically, the optimal MOPSA (4 wt %) in commercial polyurethane films accomplishes nearly 100 % discoloration in 6 s under visible light with ∼ 100 % thermal-recovery in 17.4 s at 60 °C, while the acquired kinetics constants are 3∼7 times that of dipolar DASA counterpart and 1∼2 orders of magnitude higher than those of reported DASAs in polymers. Importantly, the MOPSA-doped polymer films sustain 500 discoloration/recovery cycles with slow degradation, superior to the existing DASAs in polymers (≤30 cycles). We discover that multi-dipolar coupling in MOPSA enables enhanced polarization and electron delocalization, promoting the rate-determining thermal cyclization, while the branched and non-planar geometry of MOPSA induces large free volume to facilitate the isomerization. This design can be extended to develop spiropyran or azobenzene-based ultrafast photochromic films. The superior photoswitching performance of MOPSAs together with their high-yield and scalable synthesis and facile film processing inspires us to explore their versatile uses as smart inks or labels for time-temperature indicators, optical logic encryption and multi-levelled data encryption.

Growth and Local Structures of Single Crystalline Flakes of Three-Dimensional Covalent Organic Frameworks in Water.

Due to the enormous chemical and structural diversities and designable properties and functionalities, covalent organic frameworks (COFs) hold great promise as tailored materials for industrial applications in electronics, biology, and energy technologies. They were typically obtained as partially crystalline materials, although a few single-crystal three-dimensional (3D) COFs have been obtained recently with structures probed by diffraction techniques. However, it remains challenging to grow single-crystal COFs with controlled morphology and to elucidate the local structures of 3D COFs, imposing severe limitations on the applications and understanding of the local structure-property correlations. Herein, we develop a method for designed growth of five types of single crystalline flakes of 3D COFs with controlled morphology, front crystal facets, and defined edge structures as well as surface chemistry using surfactants that can be self-assembled into layered structures to confine crystal growth in water. The flakes enable direct observation of local structures including monomer units, pore structure, edge structure, grain boundary, and lattice distortion of 3D COFs as well as gradually curved surfaces in kinked but single crystalline 3D COFs with a resolution of up to ∼1.7 Å. In comparison with flakes of two-dimensional crystals, the synthesized flakes show much higher chemical, mechanical, and thermal stability.

Novel GSDMD inhibitor GI-Y1 protects heart against pyroptosis and ischemia/reperfusion injury by blocking pyroptotic pore formation.

Activation of gasdermin D (GSDMD) and its concomitant cardiomyocyte pyroptosis are critically involved in multiple cardiac pathological conditions. Pharmacological inhibition or gene knockout of GSDMD could protect cardiomyocyte from pyroptosis and dysfunction. Thus, seeking and developing highly potent GSDMD inhibitors probably provide an attractive strategy for treating diseases targeting GSDMD. Through structure-based virtual screening, pharmacological screening and subsequent pharmacological validations, we preliminarily identified GSDMD inhibitor Y1 (GI-Y1) as a selective GSDMD inhibitor with cardioprotective effects. Mechanistically, GI-Y1 binds to GSDMD and inhibits lipid- binding and pyroptotic pore formation of GSDMD-N by targeting the Arg7 residue. Importantly, we confirmed the cardioprotective effect of GI-Y1 on myocardial I/R injury and cardiac remodeling by targeting GSDMD. More extensively, GI-Y1 also inhibited the mitochondrial binding of GSDMD-N and its concomitant mitochondrial dysfunction. The findings of this study identified a new drug (GI-Y1) for the treatment of cardiac disorders by targeting GSDMD, and provide a new tool compound for pyroptosis research.

5.32 W ultraviolet laser generation at 266†nm using sum-frequency method with CsB3O5 crystal.

Ultraviolet (UV) beam generation at 266 nm using the sum-frequency (SFG) method with CsB3O5 (CBO) crystals was first suggested in 1997 [Opt. Lett.22, 1840 (1997).10.1364/OL.22.001840]; however, there has been no further research in the past 25 years. Herein, by sum-frequency mixing in CBO crystals, we obtained a high conversion efficiency picosecond (ps) and a high-power nanosecond (ns) 266 nm UV beam output. First, a ps laser device with simultaneously radiated wavelengths of 1064 and 355 nm and repetition frequency of 10 Hz was used as the fundamental laser source, and the conversion efficiency from 1064 + 355 nm to 266 nm reached 20.35%. We then used a 1064 nm ns laser with a high output power and repetition frequency of 10 kHz as the pump source. We accurately modified the optimal phase matching direction of the CBO crystal, and the achieved output power at 266 nm reached 5.32 W.

Photo-Assisted Metal-Air Batteries: Recent Progress, Challenges and Opportunities.

To meet the need of high energy density, long durability, safe and cost-efficient energy conversion and storage devices, metal-air batteries like Li-O2 and Zn-O2 batteries have received enormous attention and were subject to exciting development in the past decade. Photo-assisted strategies that enable the effective combination of photo/electric energy conversion/storage render a new dimension for the conventional metal-air batteries techniques with mere electric energy utilization. Therefore, tremendous research is ongoing in search of more efficient and durable devices with photo-assisted strategies. This review provides an overview of photo-assisted Li-O2 batteries, Zn-O2 batteries, and batteries with various metal/air components. The working mechanism, the basic device architecture and practical performances of various photo-assisted systems are summarized and discussed. Furthermore, certain technical challenges and future opportunities for the photo-assisted metal air batteries are emphasized and discussed in the hope of stimulating further research.

Stepwise Stimuli-Responsive, Multicolor-Chromic Perylene Bisimide/Polyvinyl Alcohol Co-assembly System for Information Encryption.

The issue of information security has become a concern in all aspects of daily life, prompting the development of encryption technologies. Therein, optical encryption using color/graphical patterns holds great potential. However, current approaches generally rely on monochromic change upon one or more stimuli, limiting their further application in advanced confidential encryption. Herein, we propose a delicate strategy based on a co-assembly system of perylene bisimides (PBI)/polyvinyl alcohol (PVA) that demonstrates stepwise stimuli response and multicolor changes. The color of the supramolecular system changes from red to purple under the stimulus of UV light, and to orange when exposed to water. The multidimensional chromic response is achieved by an evolution process including the generation, packing rearrangement and quenching of PBI radical anions/dianions. With the virtues of photo- and hydrochromism, this novel co-assembly system was successfully employed for advanced anticounterfeiting and versatile information encryption applications.

HYOU1 promotes cell proliferation, migration, and invasion via the PI3K/AKT/FOXO1 feedback loop in bladder cancer.

BACKGROUND: Hypoxia up-regulated 1 (HYOU1) was identified as a proto-oncogene and involved in tumorigenesis and progression in several cancer. Nonetheless, the biological function and mechanism of HYOU1 in bladder cancer (BCa) remian unclear. METHODS: The HYOU1 level in BCa tissues and cells was examined using RT-qPCR and western blot methods. The relationship between HYOU1 expression and clinicopathologic characteristics of BCa was analyzed. The biological role of HYOU1 on BCa cell proliferation, apoptosis, migration and invasion were analyzed via counting kit-8 (CCK-8), flow cytometry, wound healing and Transwell assays, respectively. The association between HYOU1 and the PI3K/AKT/Forkhead box O1 (FOXO1) signalling was assessed via western blot assay, meanwhile the the association of FOXO1 with HYOU1 was also investigated. RESULTS: HYOU1 was up-regulated in BCa tissues and cell lines, and the high level of HYOU1 was associated with bladder cancer histological grade and pathologic stage. Moreover, patients with high expression of HYOU1 showed poor overall survival from Kaplan-Meier Plotter. HYOU1 depletion impeded cell proliferation, migration and invasion, and induced cell apoptosis, while HYOU1 overexpression promoted cell proliferation, migration and invasion. Mechanically, our results showed that HYOU1 knockdown repressed PI3K/AKT/FOXO1 pathway and HYOU1 was negative regulated by FOXO1 in BCa. Significantly, we confirmed that the HYOU1/PI3K-AKT/FOXO1 negative feedback loop was involved in BCa cell proliferation, migration and invasion. CONCLUSION: These findings revealed that HYOU1 acted as a pro-oncogene on BCa progression, and it will be a possible target for BCa treatment.

Investigating the WNT/TCF pathway and the value of DCE-MRI in predicting and evaluating the efficacy of neoadjuvant radiotherapy and chemotherapy for locally advanced rectal cancer.

The purpose of this research was to Detach the DCE-MRI value in predicting and evaluating the efficacy of neoadjuvant radiotherapy and chemotherapy in middle and low locally advanced rectal cancer (READ). For this purpose, 40 patients with READ were examined by DCE-MRI and DWI before CRT treatment and 4 weeks after CRT treatment, and examined by Avanto1.5T magnetic resonance imaging scanner. According to the comparison of the postoperative pathological T stage and pre-nCRT T stage, the patients with decreased stage were defined as the T-descending group, and those with unchanged or elevated staging were defined as the T-undescending group. The ROC curve was used to evaluate the value of ADC value and Ktrans value to predict the early curative effect of neoadjuvant radiation therapy and chemotherapy for READ. Results showed that The ADC values of the two groups after nCRT were higher than those before nCRT (P<0.05). Compared with the pre-nCRT T-decline group and T-non-decline group, the Ktrans value of the pre-T-decline group was higher than that of the T-non-decline group (P<0.05), and the Ktrans value of both groups after the nCRT was higher than that before nCRT (P<0.05). The difference and the rate of ADC in the T-depression group were higher than in the T-undescending group (P<0.05). Taking the change rate of the ADC value 0.17 as the optimal threshold, the sensitivity and specificity of predicting the T-descending stage of patients with READ after neoadjuvant radiotherapy and chemotherapy were 72.69% and 75.84%, respectively (95%CI:0.608-0.954); taking the pre-nCRTKtrans value 1.18/min as the optimal threshold, the sensitivity and specificity to predict the T-descending stage of READ patients after neoadjuvant radiation therapy and chemotherapy was 78.65% and 80.47%, respectively (95%CI:0.637-0.971). There was no significant difference between the change rate of ADC value and the Ktrans value before nCRT in predicting the early efficacy of neoadjuvant radiotherapy and chemotherapy for READ. In conclusion, ADC value and Ktrans value can reflect the tissue structure changes of READ after neoadjuvant chemotherapy. It can be seen that the change rate of ADC value and pre-nCRTKtrans value can predict the early efficacy of neoadjuvant radiotherapy and chemotherapy for READ. The results showed that Axin2 and ß-catenin factors along with other factors such as APC and CKI proteins are effective at the molecular level along with other factors in the WNT/TCF signaling pathway. These agents start their activity in the cytoplasm and exert their final effect on the genes in the nucleus.