Design, synthesis and biological evaluation of the tumor hypoxia-activated PROTACs bearing caged CRBN E3 ligase ligands.

Tumor hypoxia-activated proteolysis targeting chimeras (ha-PROTACs) 9 and 10 were designed and synthesized by incorporating the hypoxia-activated leaving group (1-methyl-2-nitro-1H-imidazol-5-yl)methyl or 4­nitrobenzyl into the structure of the cereblon (CRBN) E3 ligand of an epidermal growth factor receptor 19 deletions (EGFRDel19-based PROTAC 8. The in vitro protein degradation assay demonstrated that 9 and 10 could effectively and selectively degrade EGFRDel19 in tumor hypoxia. Meanwhile, these two compounds showed higher potency in inhibiting cell viability and migration, as well as in promoting cells apoptosis in tumor hypoxia. Moreover, nitroreductase reductive activation assay indicated that prodrugs 9 and 10 could successfully release the active compound 8. This study confirmed the feasibility to develop ha-PROTACs to enhance the selectivity of PROTACs by caging CRBN E3 ligase ligand.

Boosting Near-Infrared Luminescence of Lanthanide in Cs2 AgBiCl6 Double Perovskites via Breakdown of the Local Site Symmetry.

Currently, lanthanide (Ln3+ )-doped near-infrared (NIR)-emitting double perovskites (DPs) suffer from low photoluminescence quantum yield (PLQY). Herein, we develop a new class of NIR-emitting DPs based on Ln3+ -doped Cs2 (Na/Ag)BiCl6 . Benefiting from the Na+ -induced breakdown of local site symmetry in the Cs2 AgBiCl6 DPs, effective NIR emissions of Ln3+ are realized through Bi3+ sensitization. Specifically, 7.3-fold and 362.9-fold enhanced NIR emissions of Yb3+ and Er3+ are achieved in Cs2 Ag0.2 Na0.8 BiCl6 DPs relative to those in Na-free Cs2 AgBiCl6 counterparts, respectively. The optimal absolute NIR PLQYs for Yb3+ and Er3+ in Cs2 Ag0.2 Na0.8 BiCl6 DPs are determined to be 19.0 % and 4.3 %, respectively. Raman spectroscopy and first-principles density functional theory calculations verify the sublattice distortion in Cs2 (Na/Ag)BiCl6 DPs via Na+ doping. These findings provide fundamental insights into the design of efficient NIR-emitting Ln3+ -doped DPs for versatile optoelectronic applications.

Diagnosis and Grading of Prostate Cancer by Relaxation Maps From Synthetic MRI.

BACKGROUND: The interpretation system for prostate MRI is largely based on qualitative image contrast of different tissue types. Therefore, a fast, standardized, and robust quantitative technique is necessary. Synthetic MRI is capable of quantifying multiple relaxation parameters, which might have potential applications in prostate cancer (PCa). PURPOSE: To investigate the use of quantitative relaxation maps derived from synthetic MRI for the diagnosis and grading of PCa. STUDY TYPE: Prospective. SUBJECTS: In all, 94 men with pathologically confirmed PCa or benign pathological changes. FIELD STRENGTH/SEQUENCE: T1 -weighted imaging, T2 -weighted imaging, diffusion-weighted imaging, and synthetic MRI at 3.0T. ASSESSMENT: Four kinds of tissue types were identified on pathology, including PCa, stromal hyperplasia (SH), glandular hyperplasia (GH), and noncancerous peripheral zone (PZ). PCa foci were grouped as low-grade (LG, Gleason score ≤6) and intermediate/high-grade (HG, Gleason score ≥7). Regions of interest were manually drawn by two radiologists in consensus on parametric maps according to the pathological results. STATISTICAL TESTS: Independent sample t-test, Mann-Whitney U-test, and receiver operating characteristic curve analysis. RESULTS: T1 and T2 values of PCa were significantly lower than SH (P = 0.015 and 0.002). The differences of T1 and T2 values between PCa and noncancerous PZ were also significant (P ≤ 0.006). The area under the curve (AUC) of the apparent diffusion coefficient (ADC) value was significantly higher than T1 , T2 , and proton density (PD) values in discriminating PCa from SH and noncancerous PZ (P ≤ 0.025). T2 , PD, and ADC values demonstrated similar diagnostic performance in discriminating LG from HG PCa (AUC = 0.806 [0.640-0.918], 0.717 [0.542-0.854], and 0.817 [0.652-0.925], respectively; P ≥ 0.535). DATA CONCLUSION: Relaxation maps derived from synthetic MRI were helpful for discriminating PCa from other benign pathologies. But the overall diagnostic performance was inferior to the ADC values. T2 , PD, and ADC values performed similarly in discriminating LG from HG PCa lesions. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;52:552-564.

10-Qubit Entanglement and Parallel Logic Operations with a Superconducting Circuit.

Here we report on the production and tomography of genuinely entangled Greenberger-Horne-Zeilinger states with up to ten qubits connecting to a bus resonator in a superconducting circuit, where the resonator-mediated qubit-qubit interactions are used to controllably entangle multiple qubits and to operate on different pairs of qubits in parallel. The resulting 10-qubit density matrix is probed by quantum state tomography, with a fidelity of 0.668±0.025. Our results demonstrate the largest entanglement created so far in solid-state architectures and pave the way to large-scale quantum computation.

Suppression of Dephasing by Qubit Motion in Superconducting Circuits.

We suggest and demonstrate a protocol which suppresses the low-frequency dephasing by qubit motion, i.e., transfer of the logical qubit of information in a system of n≥2 physical qubits. The protocol requires only the nearest-neighbor coupling and is applicable to different qubit structures. Our analysis of its effectiveness against noises with arbitrary correlations, together with experiments using up to three superconducting qubits, shows that for the realistic uncorrelated noises, qubit motion increases the dephasing time of the logical qubit as √n. In general, the protocol provides a diagnostic tool for measurements of the noise correlations.

Emulating Anyonic Fractional Statistical Behavior in a Superconducting Quantum Circuit.

Anyons are exotic quasiparticles obeying fractional statistics, whose behavior can be emulated in artificially designed spin systems. Here we present an experimental emulation of creating anyonic excitations in a superconducting circuit that consists of four qubits, achieved by dynamically generating the ground and excited states of the toric code model, i.e., four-qubit Greenberger-Horne-Zeilinger states. The anyonic braiding is implemented via single-qubit rotations: a phase shift of π related to braiding, the hallmark of Abelian 1/2 anyons, has been observed through a Ramsey-type interference measurement.

The uncinate fasciculus as observed using diffusion spectrum imaging in the human brain.

INTRODUCTION: The definitive structure and comprehensive role of the uncinate fasciculus (UF) are still obscure. We aimed to map the human UF white matter tractography and investigate the asymmetry, connectivity, and segmentation of the UF. METHODS: Subcomponents of the UF were analyzed in 9 normal subjects and a 30-subject diffusion spectrum imaging (DSI) template (CMU-30). DSI and microdissection were performed to explore the tractography of the UF. RESULTS: Both methods revealed that it connects the anterior part of the temporal lobe (superior temporal gyrus and temporal pole) with the inferior frontal cortex and the orbitofrontal cortex. The UF starts at the temporal gyrus, runs inferiorly to the inferior frontal occipital fasciculus and splits into two branches, terminating in the ventrolateral frontal cortex and the rostral middle frontal cortex. Our study showed that the cortical areas of termination in the frontal lobe of the UF are the pars triangularis and pars orbitalis. The relative volume of the UF in both hemispheres was calculated. An independent t test was used to determine variances in the value of tract volume between the left and right hemispheres. The volume and the length showed a significant statistical difference in the total volume of the UF. We suggest the UF is leftward asymmetry. CONCLUSIONS: The two parts of the UF were divided, but the conclusion is not consistent with the previous published articles which have shown that the UF is segmented into three parts. Our research facilitates a better understanding of the UF.

Quantum Delayed-Choice Experiment with a Beam Splitter in a Quantum Superposition.

A quantum system can behave as a wave or as a particle, depending on the experimental arrangement. When, for example, measuring a photon using a Mach-Zehnder interferometer, the photon acts as a wave if the second beam splitter is inserted, but as a particle if this beam splitter is omitted. The decision of whether or not to insert this beam splitter can be made after the photon has entered the interferometer, as in Wheeler's famous delayed-choice thought experiment. In recent quantum versions of this experiment, this decision is controlled by a quantum ancilla, while the beam splitter is itself still a classical object. Here, we propose and realize a variant of the quantum delayed-choice experiment. We configure a superconducting quantum circuit as a Ramsey interferometer, where the element that acts as the first beam splitter can be put in a quantum superposition of its active and inactive states, as verified by the negative values of its Wigner function. We show that this enables the wave and particle aspects of the system to be observed with a single setup, without involving an ancilla that is not itself a part of the interferometer. We also study the transition of this quantum beam splitter from a quantum to a classical object due to decoherence, as observed by monitoring the interferometer output.

Demonstration of geometric Landau-Zener interferometry in a superconducting qubit.

Geometric quantum manipulation and Landau-Zener interferometry have been separately explored in many quantum systems. In this Letter, we combine these two approaches to study the dynamics of a superconducting phase qubit. We experimentally demonstrate Landau-Zener interferometry based on the pure geometric phases in this solid-state qubit. We observe the interference caused by a pure geometric phase accumulated in the evolution between two consecutive Landau-Zener transitions, while the dynamical phase is canceled out by a spin-echo pulse. The full controllability of the qubit state as a function of the intrinsically robust geometric phase provides a promising approach for quantum state manipulation.

Neuroprotective Effects of Bifidobacterium animalis subsp. lactis NJ241 in a Mouse Model of Parkinson's Disease: Implications for Gut Microbiota and PGC-1α.

Intestinal dysbiosis plays a critical role in the pathogenesis of Parkinson's disease (PD), and probiotics have emerged as potential modulators of central nervous system function through the microbiota-gut-brain axis. This study aimed to elucidate the anti-inflammatory effects and underlying mechanisms of the probiotic strain Bifidobacterium animalis subsp. lactis NJ241 (NJ241) in a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The impact of NJ241 was comprehensively assessed in PD mice through behavioral tests, immunofluorescence, Western blotting, enzyme-linked immunosorbent assay (ELISA), 16S rRNA sequencing, and short-chain fatty acid (SCFA) detection. NJ241 exhibited notable efficacy in mitigating MPTP-induced weight loss, gastrointestinal dysfunction, and behavioral deficits in mice. Furthermore, it demonstrated protected against MPTP-induced dopaminergic neuron death and inhibited the activation of glial cells in the substantia nigra (SN). NJ241 demonstrated the ability to normalized dysbiosis in the intestinal microbiota and elevate SCFA levels in PD mice. Additionally, NJ241 reversed MPTP-induced reductions in colonic GLP-1 levels and the expression of GLP-1R and PGC-1α in the SN. Notably, GLP-1R antagonists partially reversed the inhibitory effects of NJ241 on the activation of glial cells in the SN. In summary, NJ241 exerts a neuroprotective effect against MPTP-induced neuroinflammation by enhancing intestinal GLP-1 levels and activating nigral PGC-1α signaling. These findings provide a rationale for the exploration and development of probiotic-based therapeutic strategies for PD.

Electrochemical aerobic Wacker-type oxygenation of triaryl substituted alkenes to 1,2,2-triarylethanones.

An effective synthetic approach for various 1,2,2-triarylethanones from triaryl substituted alkenes has been developed via an electrochemical Wacker-type oxygenation with O2 as the sole oxygen source. It presents the first instance of the Wacker-type oxidation expanding its substrate scope to trisubstituted alkenes. The approach is transition-metal-free, compatible with various functional groups, and can be carried out under mild conditions resulting in satisfactory yields. Mechanistic experiments suggest the CO bond formation occurs through reactions between cationic carbon species and the superoxide radical, which involves the 1,2-shift of the electron-rich substituent.

Amphiphilic poly(L-aspartic acid) copolymer nanoparticles for cyclosporine A delivery.

In this paper, novel cyclosporine A (CsA)-loaded amphiphilic poly(L-aspartic acid-co-L-lactic acid) (PAL)-1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE) copolymer nanoparticles (NPs) were successfully fabricated using an emulsion/solvent evaporation technique. The CsA-loaded NPs were characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The CsA-loaded NPs size, size distribution, encapsulation efficiency (EE) and drug-loading content (LC) were influenced by polyvinyl alcohol (PVA) concentration and the weight ratio of the copolymer to CsA. In vitro release behavior of CsA-loaded NPs showed a sustained release. With the increasing of copolymer/CsA weight ratio, the release of CsA from NPs is rapid. The poly(L-aspartic acid) derivatives NPs have a promising potential in hydrophobic drug delivery system.

Huangkui capsule alleviates doxorubicin-induced proteinuria via protecting against podocyte damage and inhibiting JAK/STAT signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Huangkui capsule (HKC), a Chinese patent medicine, has been widely used in China as adjuvant therapy for chronic kidney disease (CKD). It displays superior anti-proteinuria efficacy than losartan in patients with CKD at stages 1-2, however, the mechanism of HKC alleviating proteinuria has not been well elucidated. AIM OF THE STUDY: This study aims to confirm the therapeutic effect and investigate associated underlying mechanism of HKC against proteinuria by in vivo and in vitro experiments. MATERIALS AND METHODS: We established a doxorubicin (DOX) induced proteinuria mouse model to evaluate kidney function by biochemical markers measurement and to observe histopathological alterations by hematoxylin and eosin (H&E), Masson's trichrome and Periodic Acid-Schiff (PAS)-stained sections of renal, respectively. Moreover, the expressions of Nephrin and Podocin were measured by immunohistochemistry (IHC) and western blotting analysis to investigate podocyte damage. Furthermore, we established Mouse Podocyte Clone-5 (MPC-5) injury model to identify the active components of HKC against podocyte damage by detecting the expressions of Nephrin, Podocin, and ZO-1 proteins. At last, the key protein levels of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway were assessed by western blotting analysis to explore the underlying mechanism of HKC against proteinuria. RESULTS: Our results showed that HKC administration for three consecutive weeks dose-dependently ameliorated both renal function and histopathological damages, elevated the expressions of Nephrin and Podocin, the pivotal molecules maintaining filtration function of the podocyte, indicating the promising protective effect against podocyte injury under DOX exposure. Consistently, in vitro experiments showed HKC administration effectively reversed the abnormal expressions of Nephrin and Podocin in MPC-5 cells treated with DOX, suggesting its protective effect against podocyte injury to maintain filtration barrier integrity. In addition, Hibifolin was identified as the most active ingredients in HKC, which suppressed upstream JAK2/STAT3 and PI3K/Akt pathway phosphorylation to maintain the structural and functional integrity of podocyte filtration barrier. Of note, AG490, a selective JAK2 inhibitor, was used to further affirm the role of Hibifolin involving in regulation JAK2/STAT3. CONCLUSIONS: Our study suggested that HKC may protect podocytes via JAK2/STAT3 and PI3K/Akt pathway to display its effects of ameliorating proteinuria.

Macrophages and fibroblasts in foreign body reactions: How mechanical cues drive cell functions?

Biomaterials, when implanted in the human body, can induce a series of cell- and cytokine-related reactions termed foreign body reactions (FBRs). In the progression of FBRs, macrophages regulate inflammation and healing by polarizing to either a pro-inflammatory or pro-healing phenotype and recruit fibroblasts by secreting cytokines. Stimulated by the biomaterials, fibrotic capsule is formed eventually. The implant, along with its newly formed capsule, introduces various mechanical cues that influence cellular functions. Mechanosensing proteins, such as integrins or ion channels, transduce extracellular mechanical signals into cytoplasm biochemical signals in response to mechanical stimuli. Consequently, the morphology, migration mode, function, and polarization state of the cells are affected. Modulated by different intracellular signaling pathways and their crosstalk, the expression of fibrotic genes increases with fibroblast activation and fibroblast to myofibroblast transition under stiff or force stimuli. However, summarized in most current studies, the outcomes of macrophage polarization in the effect of different mechanical cues are inconsistent. The underlying mechanisms should be investigated with more advanced technology and considering more interfering aspects. Further research is needed to determine how to modulate the progression of fibrotic capsule formation in FBR artificially.

Multicellular tumor spheroids as an in vivo-like tumor model for three-dimensional imaging of chemotherapeutic and nano material cellular penetration.

We present a flexible and highly reproducible method using three-dimensional (3D) multicellular tumor spheroids to quantify chemotherapeutic and nanoparticle penetration properties in vitro. We generated HeLa cell-derived spheroids using the liquid overlay method. To properly characterize HeLa spheroids, scanning electron microscopy, transmission electron microscopy, and multiphoton microscopy were used to obtain high-resolution 3D images of HeLa spheroids. Next, pairing high-resolution optical characterization techniques with flow cytometry, we quantitatively compared the penetration of doxorubicin, quantum dots, and synthetic micelles into 3D HeLa spheroid versus HeLa cells grown in a traditional two-dimensional culturing system. Our data revealed that 3D cultured HeLa cells acquired several clinically relevant morphologic and cellular characteristics (such as resistance to chemotherapeutics) often found in human solid tumors. These characteristic, however, could not be captured using conventional two-dimensional cell culture techniques. This study demonstrated the remarkable versatility of HeLa spheroid 3D imaging. In addition, our results revealed the capability of HeLa spheroids to function as a screening tool for nanoparticles or synthetic micelles that, due to their inherent size, charge, and hydrophobicity, can penetrate into solid tumors and act as delivery vehicles for chemotherapeutics. The development of this image-based, reproducible, and quantifiable in vitro HeLa spheroid screening tool will greatly aid future exploration of chemotherapeutics and nanoparticle delivery into solid tumors.

CSMD1 exhibits antitumor activity in A375 melanoma cells through activation of the Smad pathway.

In this work, we studied the effects of CUB and Sushi multiple domains 1 gene (CSMD1) expression in A375 melanoma cells in vivo and in vitro. CSDM1 expression decreased proliferation and migration, and increased apoptosis and G(1) arrest in A375 cells in vitro. Expression of CSDM1 in established xenografted tumors decreased tumor size and weight, and decreased the density of intratumor microvessels. The survival rate of mice with tumors expressing CSMD1 was significantly higher than mice with tumors that did not express CSDM1. These results confirm the role of CSDM1 as a tumor suppressor gene in melanoma cells. Furthermore, we found that CSMD1 can interact with Smad3, activate Smad1, Smad2, and Smad3, and increase the expression of Smad4. These results might prove helpful for the development of novel therapies for melanoma treatment.

Efficient delivery of antitumor drug to the nuclei of tumor cells by amphiphilic biodegradable poly(L-aspartic acid-co-lactic acid)/DPPE co-polymer nanoparticles.

The use of biodegradable polymeric nanoparticles (NPs) for controlled drug delivery has shown significant therapeutic potential. Polyaspartic acid and polylactic acid are the most intensively studied biodegradable polymers. In the present study, novel amphiphilic biodegradable co-polymer NPs, poly(L-aspartic acid-co-lactic acid) with 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE) (poly(AA-co-LA)/DPPE) is synthesized and subsequently used to encapsulate an antitumor drug doxorubicin (DOX). The formulation parameters of the NPs are optimized to improve encapsulation efficiency. The resulting drug-loaded NPs possess better size homogeneity (polydispersity) and exhibit pH-responsive drug release profiles. Cellular viability assays indicate that the poly(AA-co-LA)/DPPE NPs did not induce cell death, whereas doxorubicin encapsulated NPs were cytotoxic to various types of tumor cells. In addition, the free NPs could not enter the cell nuclei after internalized in tumor cells. The DOX-loaded NPs exhibit efficient intracellular delivery in tumor cells with co-localization in lysosome and delay entering into the nucleus, which suggests a time- and pH-dependent drug release profile within cells. When applied to deliver chemotherapeutics to a mouse xenograft model of human lung adenocarcinoma, DOX-loaded NPs have a comparable antitumor activity with free DOX, and greatly reduce systemic toxicity and mortality. The delivery of cytotoxic drugs directly to the nucleus specifically within tumor cells is of great interest. These results demonstrate the feasibility of the application of the amphiphilic polyaspartic acid derivative, poly(AA-co-LA)/DPPE, as a nanocarrier for cell nuclear delivery of potent antitumor drugs.

Impact of Foreign Language Classroom Anxiety on Higher Education Students Academic Success: Mediating Role of Emotional Intelligence and Moderating Influence of Classroom Environment.

The current study aimed to investigate the impact of foreign language classroom anxiety (FLCA) on academic success through mediating role of emotional intelligence communication (EIC) and moderating role of class room environment. Due to the disruptive impacts of the COVID-19 pandemic, teaching and learning were moved online nation-wide. The convenient sampling technique was used, for data collection from Chinese university students. There was a total of 615 students that participated in the survey and data gathered in 5 months from November 2021 till March 2022. Covariance-based structural equation modeling (CB-SEM) in SPSS V.25 and AMOS V.22 was used to assess model fitness and hypotheses, as well as construct reliability and validity of the measurement model. The results revealed that FLCA is negatively and significantly influence students' academic success. Furthermore, EIC as a mediator significantly and positively mediates the relationship between FLCA and academic success. The current study shows that emotional intelligence has the ability to reduce students' foreign language anxiety and so improve their language skills. Lastly, classroom environment positively and significantly moderates the relationship between FLCA and emotional intelligence communication.

Case report: Lymph node metastases of breast cancer and thyroid cancer encountered in axilla.

Occurrences of breast cancer and thyroid cancer metachronously or synchronously are common for women, but axillary lymph node metastasis from both cancers is rarely seen. We report a patient who had two metastatic lymph nodes from papillary thyroid carcinoma after axillary lymph node dissection with mastectomy. Papillary thyroid carcinoma diagnosis was ensured after thyroidectomy. A literature review revealed that even the co-occurrence of breast cancer and thyroid cancer is not rare, but the etiology behind this phenomenon is not elucidated well. Genetic disorders, thyroid dysfunction, and hormone receptors may be relevant. Considering the rareness of axillary lymph node metastasis of thyroid cancer, adjuvant therapy and surgery treatment for this kind of case should be considered elaborately.

Highly efficient NIR-II luminescent I-III-VI semiconductor nanoprobes based on AgInTe2:Zn/ZnS nanocrystals.

Highly efficient luminescence of AgInTe2:Zn/ZnS nanocrystals with the maximum NIR-II quantum yield of 25.2% has been designed through elaborately manipulating the structure to reduce their internal and surface defects. These AgInTe2:Zn/ZnS nanoprobes were employed for sensitive homogeneous biodetection of xanthine oxidase with the limit of detection down to 25 nU L-1.