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Ir/Cu dual-catalysed allylation constructs vicinal tertiary and N-substituted quaternary stereogenic centres of two alkaloids in a single operation.

Habitat degradation and fragmentation are crucial factors which result in biodiversity loss among the world. Understanding how species respond to the habitat change is helpful and essential for the conservation of the endangered ones. Therefore, the aim of current study is to explore how to carry out biodiversity conservation from the perspective of the habitat selection of species. We studied the microhabitat selection of blue eared pheasant ( Crossoptilon auritum) during its breeding time (including mating, incubation, and feeding periods). The field research was carried out from April to August in 2014 at Helan Mountains, China. Six nests of blue eared pheasants were found; 323 used plots and 171 control plots were recorded. Results indicated that blue eared pheasants prefer mountainous coniferous forest at shady slope with domination of Picea crassifolia, and its habitat selection was mainly influenced by shrub density, tree density, altitude, slope degree, hiding cover, water resource, and human disturbance. However, there were slight differences among the three periods. Our study firstly compared factors that affect the microhabitat selection of blue eared pheasants among the three periods of its breeding time. Meanwhile, combining the current study with the previous ones, specific strategies could be applied on the works of endangered species and biodiversity conservation.

Objective: Our study will explore the function and regulatory mechanism of USP36 in hepatocellular carcinoma (HCC). Methods: USP36-overexpressed and USP36-knockdown cells were established. The USP36 and Myc level were checked by Western blotting and the cell viability was checked by the MTT method. The apoptotic rate was checked by flow cytometry, while the migration was detected by the Transwell assay. A xenograft model was constructed in nude mice to explore the function of USP36 in HCC. USP36-overexpressed and USP-knockdown cells were constructed by transfecting pcDNA3.1-USP36 and siRNA-USP36 (si-USP36), respectively. Myc-overexpressed cells were constructed by transfecting pcDNA3.1-Myc. Results: Significantly declined cell viability, increased apoptotic rate, elevated number of migrated cells, downregulated Myc, and repressed tumor growth were observed in USP36-knockdown HepG2 and HUH7 cells, while opposite results were observed in USP36-overexpressed HepG2 and HUH7 cells. The expression level of Myc was positively regulated by USP36. However, the USP36 level was not regulated by Myc. Lastly, the declined cell viability, increased apoptotic rate, and elevated number of migrated cells in USP36-knockdown HepG2 cells were dramatically abrogated by the overexpression of Myc. Conclusion: USP36 facilitated the progression of hepatocellular carcinoma by upregulating Myc.

Cluster of differentiation (CD) antigens are cell surface molecules expressed on leukocytes and other cells associated with the immune system. Antibodies that react with CD antigens are known to be one of the most essential tools for identifying leukocyte subpopulations. T lymphocytes, as an important population of leukocytes, play essential roles in the adaptive immune system. Many of the CD antigens expressed on T lymphocytes are used as surface markers for T lymphocyte classification, including CD3, CD4 and CD8 molecules. In this review, we summarize the recent advances in the identification of CD molecules on T lymphocytes in teleosts, with emphasis on the functions of CD markers in the classification of T lymphocyte subsets. We notice that genes encoding CD3, co-receptors CD4 and CD8 have been cloned in several fish species and antibodies have been developed to study protein expression in morphological and functional contexts. T lymphocytes can be divided into CD4+and CD8+cells discriminated by the expression of CD4 and CD8 molecules in teleost, which are functionally similar to mammalian helper T cells (Th) and cytotoxic T cells (Tc), respectively. Further studies are still needed on the particular characteristics of teleost T cell repertoires and adaptive responses, and results will facilitate the health management and development of vaccines for fish.

Gauge theories form the foundation of modern physics, with applications ranging from elementary particle physics and early-universe cosmology to condensed matter systems. We perform quantum simulations of the unitary dynamics of a U(1) symmetric gauge field theory and demonstrate emergent irreversible behavior. The highly constrained gauge theory dynamics is encoded in a one-dimensional Bose--Hubbard simulator, which couples fermionic matter fields through dynamical gauge fields. We investigate global quantum quenches and the equilibration to a steady state well approximated by a thermal ensemble. Our work may enable the investigation of elusive phenomena, such as Schwinger pair production and string-breaking, and paves the way for simulating more complex higher-dimensional gauge theories on quantum synthetic matter devices., Accepted version, 6+6 pages, 4+5 figures

The topological $\theta$-angle is central to the understanding of a plethora of phenomena in condensed matter and high-energy physics such as the strong CP problem, dynamical quantum topological phase transitions, and the confinement--deconfinement transition. Difficulties arise when probing the effects of the topological $\theta$-angle using classical methods, in particular through the appearance of a sign problem in numerical simulations. Quantum simulators offer a powerful alternate venue for realizing the $\theta$-angle, which has hitherto remained an outstanding challenge due to the difficulty of introducing a dynamical electric field in the experiment. Here, we report on the experimental realization of a tunable topological $\theta$-angle in a Bose--Hubbard gauge-theory quantum simulator, implemented through a tilted superlattice potential that induces an effective background electric field. We demonstrate the rich physics due to this angle by the direct observation of the confinement--deconfinement transition of $(1+1)$-dimensional quantum electrodynamics. Using an atomic-precision quantum gas microscope, we distinguish between the confined and deconfined phases by monitoring the real-time evolution of particle--antiparticle pairs, which exhibit constrained (ballistic) propagation for a finite (vanishing) deviation of the $\theta$-angle from $\pi$. Our work provides a major step forward in the realization of topological terms on modern quantum simulators, and the exploration of rich physics they have been theorized to entail., Comment: $7+7$ pages, $4+7$ figures, $1+0$ table

Aiming at the problem of silo design, the silo ejector model and ejector function were proposed. The properties of the static pressure matching function were studied. The critical conditions were a...

Wepropose and experimentally demonstrate the ultra-compact mode (de)multiplexers and polarization beam splitter (PBS) based on tapered bent asymmetric directional couplers. The strong coupling strength introduced by tapered bent waveguides significantly shortens the coupling length. As a result, high coupling and conversion efficiencies over a broad bandwidth can be obtained with small footprint. The coupling length of the fabricated PBS and mode (de)multiplexers are less than 4.9 μm and 8.7 μm, respectively. From 1534-1600 nm, the measured insertion loss (IL) is less than 1.4 and 1.55 dB for the TE1-TE0 and TE2-TE0 mode (de)multiplexers, respectively, and the crosstalk (CT) is less than −10 dB. The fabricated PBS shows low insertion loss of 0.55 dB and decent crosstalk of < −14 dB for both polarizations over an 85 nm wavelength range from 1505-1590 nm. Meanwhile, the larger fabrication tolerance ensures that the proposed devices can be readily fabricated with the standard complementary metal-oxide-semiconductor (CMOS) process.

Supplementary Figures and Figure Legends

Purpose:Cancer stem-like cells (CSCs) contribute to bladder cancer chemotherapy resistance and progression, but the associated mechanisms have not been elucidated. This study determined whether blocking an autocrine signaling loop in CSCs improves the therapeutic effects of cis-platinum on bladder cancer.Experimental Design:The expression of the epithelial marker OV6 and other markers in human bladder cancer specimens was examined by IHC. The CSC properties of magnetic-activated cell sorting (MACS)-isolated OV6+ and OV6− bladder cancer cells were examined. Molecular mechanisms were assessed through RNA-Seq, cytokine antibody arrays, co-immunoprecipitation (co-IP), chromatin immunoprecipitation (ChIP) and other assays. An orthotopic bladder cancer mouse model was established to evaluate the in vivo effects of a YAP inhibitor (verteporfin) and a PDGFR inhibitor (CP-673451) on the cis-platinum resistance of OV6+ CSCs in bladder cancer.Results:Upregulated OV6 expression positively associated with disease progression and poor prognosis for bladder cancer patients. Compared with OV6− cells, OV6+ bladder cancer cells exhibited strong CSC characteristics, including self-renewal, tumor initiation in NOD/SCID mice, and chemotherapy resistance. YAP, which maintains the stemness of OV6+ CSCs, triggered PDGFB transcription by recruiting TEAD1. Autocrine PDGF-BB signaling through its receptor PDGFR stabilized YAP and facilitated YAP nuclear translocation. Furthermore, blocking the YAP/TEAD1/PDGF-BB/PDGFR loop with verteporfin or CP-673451 inhibited the cis-platinum resistance of OV6+ bladder cancer CSCs in an orthotopic bladder cancer model.Conclusions:OV6 could be a helpful indicator of disease progression and prognosis for patients with bladder cancer, and targeting the autocrine YAP/TEAD1/PDGF-BB/PDGFR loop might serve as a remedy for cis-platinum resistance in patients with advanced bladder cancer.

The topological $θ$-angle is central to the understanding of a plethora of phenomena in condensed matter and high-energy physics such as the strong CP problem, dynamical quantum topological phase transitions, and the confinement--deconfinement transition. Difficulties arise when probing the effects of the topological $θ$-angle using classical methods, in particular through the appearance of a sign problem in numerical simulations. Quantum simulators offer a powerful alternate venue for realizing the $θ$-angle, which has hitherto remained an outstanding challenge due to the difficulty of introducing a dynamical electric field in the experiment. Here, we report on the experimental realization of a tunable topological $θ$-angle in a Bose--Hubbard gauge-theory quantum simulator, implemented through a tilted superlattice potential that induces an effective background electric field. We demonstrate the rich physics due to this angle by the direct observation of the confinement--deconfinement transition of $(1+1)$-dimensional quantum electrodynamics. Using an atomic-precision quantum gas microscope, we distinguish between the confined and deconfined phases by monitoring the real-time evolution of particle--antiparticle pairs, which exhibit constrained (ballistic) propagation for a finite (vanishing) deviation of the $θ$-angle from $π$. Our work provides a major step forward in the realization of topological terms on modern quantum simulators, and the exploration of rich physics they have been theorized to entail., $7+7$ pages, $4+7$ figures, $1+0$ table

Optical lattices for coherently manipulating ultracold atoms demand high-power, low-noise, narrow-line-width, and continuous-wave lasers. Here, we report the implementation of a 30 W 532 nm low-noise laser by second harmonic generation from a 1064 nm fiber laser, which is capable to generate optical lattices for a quantum gas microscope of [Formula: see text] atoms. The overall conversion efficiency is 59% at an input power of 51 W with a lithium triborate crystal coupled to a ring cavity. The relative intensity noise of the output laser is suppressed to −120 dBc/Hz in the range of 10 Hz–100 kHz with a high dynamic range of over 50 dB, which is suitable for long-term trapping and coherent manipulation of the quantum gases.

3D doping structure has significant advantages in modulation efficiency and loss compared with 2D modulator doping profiles. However, to the best of our knowledge, previous work on 3D simulation methods for interdigitated doping designs applied simplified models, which prohibited complex 3D doping. In this work, innovative omni junctions, based on the effective 3D Monte-Carlo method, are believed to be the first proposed for high-performance modulators. Simulation results show that the modulation efficiency reaches 0.88 V·cm, while the loss is only 16 dB/cm, with capacitance below 0.42 pF/mm. This work provides a modulator design with superior modulation efficiency and serviceability for high-speed datacom.

Background and Objective: Although growing evidence indicates that non-alcoholic fatty liver disease is related to diabetic retinopathy (DR), research results significantly vary. Therefore, we conducted a meta-analysis to assess the association between the progression of non-alcoholic fatty liver disease and the onset of DR.Methods: PubMed, Embase, and Cochrane databases were searched until 7 November 2021. Combined odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the association.Results: We identified 18 studies involving 12,757 patients. The pooled effect assessment showed that liver fibrosis was positively correlated with DR (OR = 1.69, 95%CI 1.30–2.20; p < 0.0001); non-alcoholic fatty liver disease was not associated with the risk of DR (OR = 1.15, 95%CI 0.75-1.76; p = 0.51); non-alcoholic fatty liver disease was positively correlated with DR in patients with type 1 diabetes (OR = 2.96, 95%CI 1.48–5.94; p = 0.002). In patients with type 2 diabetes, there was no association between non-alcoholic fatty liver disease and DR (OR = 0.92, 95%CI 0.59–1.43; p = 0.70). Subgroup analysis showed no correlation in both Asian and Caucasian races.Conclusion: There is a significant correlation between liver fibrosis and DR. This suggests that the ocular examination of DR could be helpful in predicting whether patients with non-alcoholic fatty liver disease would progress to liver fibrosis.

Nonequilibrium dynamics of many-body systems is challenging for classical computing, providing opportunities for demonstrating practical quantum computational advantage with analogue quantum simulators. It is proposed to be classically intractable to sample driven thermalized many-body states of Bose-Hubbard systems, and further extract multi-point correlations for characterizing quantum phases. Here, leveraging dedicated precise manipulations and number-resolved detection through a quantum gas microscope, we implement and sample a 32-site driven Hubbard chain in the thermalized phase. Multi-point correlations of up to 14th-order extracted from experimental samples offer clear distinctions between the thermalized and many-body-localized phases. In terms of estimated computational powers, the quantum simulator is comparable to the fastest supercomputer with currently known best algorithms. Our work paves the way towards practical quantum advantage in simulating Floquet dynamics of many-body systems., 18 pages, 14 figures

Featuring excellent coherence and operated parallelly, ultracold atoms in optical lattices form a competitive candidate for quantum computation. For this, a massive number of parallel entangled atom pairs have been realized in superlattices. However, the more formidable challenge is to scale-up and detect multipartite entanglement due to the lack of manipulations over local atomic spins in retro-reflected bichromatic superlattices. Here we developed a new architecture based on a cross-angle spin-dependent superlattice for implementing layers of quantum gates over moderately-separated atoms incorporated with a quantum gas microscope for single-atom manipulation. We created and verified functional building blocks for scalable multipartite entanglement by connecting Bell pairs to one-dimensional 10-atom chains and two-dimensional plaquettes of $2\times4$ atoms. This offers a new platform towards scalable quantum computation and simulation.

Background To evaluate the safety and effectiveness of posterior closed-open wedge osteotomy for treatment of congenital kyphosis in children. Methods Imaging and clinical data from January 2010 to December 2019 of posterior closed-open wedge osteotomy of congenital kyphosis with at least 2-year follow up was analyzed retrospectively. Perioperative indicators such as operation time, osteotomy site, osteotomy method and occurrence of complications, and imaging indicators were observed. The 3D printed models were used to measure the expanded distance of anterior edge vertebra and closed length of spinal canal line. The clinical effect was evaluated through SRS-22 questionnaires. Results There were 15 CK patients in this study. The osteotomy segments and details are as follows: 1 case each for T6-9 and L2, 2 cases at T11, 3 cases at T12, and 6 cases at L1. The average operation time was 314 min, the average blood loss was 970 mL, the average fusion range was 6.3 segments, and the average time of follow up was 70.5 months. The Cobb angle of local kyphosis was corrected from 65.6 ± 18.8° to 11.3 ± 7.1°( p < .001). The range of kyphosis correction was 40–90°, and average correction rate was 83.2% (67.7–95.7%). The correction was stable in follow-up, and the kyphotic angle was 11.0 ± 7.6 ( p = .68). The preoperative SVA was 31.5 ± 21.8 mm, and the postoperative recovery was 18.0 ± 15.5, while the last follow-up was 9.1 ± 7.9. The p values were 0.02 and 0.07 respectively. By using 3D printed models, the expanded distance of anterior edge vertebra and closed length of spinal canal line were 14.5 ± 7.5 mm and 24.5 ± 8.0 mm respectively. Self-image and satisfaction in SRS-22 improved significantly. There was no recurrence of deformity and junctional kyphosis. Conclusions The posterior closing-opening wedge osteotom for treatment of congenital kyphosis in children is satisfactory, if selected appropriately. During the longitudinal follow-up, the patients could achieve solid fusion and the correction could be well maintained. Evidence of Confidence: IVa

To achieve scalable quantum information processing, great efforts have been devoted to the creation of large-scale entangled states in various physical systems. Ultracold atom in optical lattice is considered as one of the promising platforms due to its feasible initialization and parallel manipulation. In this work, we propose an efficient scheme to generate and characterize global entanglement in the optical lattice. With only two-layer quantum circuits, the generation utilizes two-qubit entangling gates based on the superexchange interaction in double wells. The parallelism of these operations enables the generation to be fast and scalable. To verify the entanglement of this non-stabilizer state, we mainly design three complementary detection protocols which are less resource-consuming compared to the full tomography. In particular, one just needs two homogenous local measurement settings to identify the entanglement property. Our entanglement generation and verification protocols provide the foundation for the further quantum information processing in optical lattice., 13 pages, 5 figures

We present a compact and gain-enhanced microwave helical antenna for manipulating ultracold

Herein, we describe a highly effective 1,8-conjugate-addition-mediated formal (3+3)-annulation of (aza)-para-quinone methides in situ generated from propargylic alcohols with 4-hydroxycoumarins and 1,3-dicarbonyl compounds under the catalysis of a Bronsted acid. This methodology affords efficient and practical access to synthetically important and highly functionalized pyranocoumarins and pyrans in excellent yields under mild conditions. Importantly, these products exhibit impressive inhibitory activity toward α-glucosidase.

An ultra-broadband, compact and CMOS-compatible arbitrary ratio power splitter that is based on a directional coupler is proposed on the silicon-on-insulator (SOI) platform. The proposed device consists of an adiabatic sub-wavelength grating (ASWG) and a conventional directional coupler. The wavelength dependence is greatly reduced by introducing an ASWG in the coupling region of the directional coupler. Simulation results show that our proposed device has an operating bandwidth of 250 nm for arbitrary power splitting ratios, with a transmission power variation of less than 8.5%, covering the wavelength range from 1400 nm to 1650 nm. Meanwhile, the device footprint has been narrowed to less than 46 μm. In addition, the power splitters also exhibit a low excess loss of below 0.24 dB. Our proposed ASWG-assisted power splitters show excellent potential for application in large-scale photonic integrated circuits.

A 32×32 100 GHz silicon photonic integrated arrayed waveguide grating router (AWGR) is experimentally demonstrated for dense wavelength division multiplexing (DWDM) applications. The dimension of the AWGR is 2.57 mm×1.09 mm with a core size of 1.31 mm×0.64 mm. It exhibits 6.07 dB maximum channel loss non-uniformity with −1.66 dB best-case insertion loss and average channel crosstalk of −15.74 dB. In addition, in the case of 25 Gb/s signals, the device successfully realizes high-speed data routing. The AWG router provides clear optical eye diagrams and low power penalty at bit-error-rates of 10−9.

BACKGROUND: Teleradiology has become one of the most important approaches to virtual clinical diagnosis; its importance has only grown during the coronavirus 2019 pandemic. In developing countries, asking patients to take photographs of their images using a smartphone can facilitate the process and help keep its costs down. However, the images taken by patients with smartphones often are of poor quality, and there is no regulation or standard instruction about how to use smartphones to take photographs of medical examination images effectively. These problems limit the use of smartphones in remote diagnosis and treatment. QUESTIONS/PURPOSES: To formulate a set of guidelines for the most appropriate and effective use of smartphones to capture images (radiographs, CT images, and MR images), and to determine whether these guidelines are more effectively adopted by patients of differing ages and genders. METHODS: In this prospective study, a set of step-by-step instructions was created with the goal of helping patients take better smartphone photographs of orthopaedic diagnostic images for transfer to telemedicine services. Following the advice of surgeons, experts in smartphone technology, imaging experts, and suggestions from patients, the instructions were modified based on clinical experience and finalized with the goals of simplicity, clarity, and convenience. Potentially eligible patients were older than 18 years, had no cognitive impairment, and used smart phones. Based on that, 256 participants (patients or their relatives and friends) who visited the orthopaedic department of our hospital from June to October 2020 potentially qualified for this study. A total of 11% (29) declined to participate, leaving 89% (227) for analysis here. Their mean age was 36 ± 11 years, 50% were women (113 of 227), and the patient himself/herself represented in 34% (78 of 227) of participants while relatives or friends of patients made up 66% (149 of 227) of the group. In this study, the diagnoses included spinal stenosis (47% [107 of 227]), disc herniation without spinal stenosis (31% [71 of 227]), vertebral fractures (14% [32 of 227]), and other (7% [17 of 227]). Each study participant first took photographs of their original medical images based on their own knowledge of how to use the smartphone camera function; each participant then took pictures of their original images again after receiving our instructional guidance. Three senior spine surgeons (YZ, TQL, TCM) in our hospital analyzed, in a blinded manner, the instructed and uninstructed imaging files based on image clarity (the content of the image is complete, the text information in the image is clearly visible, there is neither reflection nor shadow in the image) and image position (it is not tilted, curled, inverted, or reversed). If either of these conditions was not satisfied, the picture quality was deemed unacceptable; two of three judges' votes determined the outcome. Interobserver reliability with kappa values for the three judges were 0.89 (YZ versus TQL), 0.92 (YZ versus TCM), and 0.90 (TQL versus TCM). RESULTS: In this study, the overall proportion of smartphone medical images deemed satisfactory increased from 40% (91 of 227) for uninstructed participants to 86% (196 of 227) for instructed participants (risk ratio 2.15 [95% CI 1.82 to 2.55]; pi¼œ0.001). The proportion of acceptable-quality images in different age groups improved after instruction, except for in patients aged 51 years or older (3 of 17 uninstructed participants versus 8 of 17 instructed participants; RR 2.67 [95% CI 0.85 to 8.37]; p = 0.07). The proportion of acceptable-quality images in both genders improved after instruction, but there was no difference between the genders. CONCLUSION: We believe our guidelines for patients who wish to take smartphone photographs of their medical images will decrease image transmission cost and facilitate orthopaedic telemedicine consultations. However, it appears that patients older than 50 years are more likely to have difficulty with this approach, and if so, they may benefit from more hands-on assistance from clinic staff or younger relatives or friends. The degree to which our findings are culture-specific should be verified by other studies in other settings, but on the face of it, there is little reason to believe our findings would not generalize to a reasonable degree. Other studies in more heterogeneous populations should also evaluate factors related to levels of educational attainment and wealth differences, but in the meantime, our findings can give clinical teams an idea of which patients may need a little extra assistance. LEVEL OF EVIDENCE: Level II, therapeutic study.

Introduction Blinatumomab, a bi-specific T cell engager (BiTE®) combining the VH and VL domains of two antibodies against human CD19 and CD3, has been approved by U.S. Food and Drug Administration (FDA) for the treatment of patients with relapsed or refractory B precursor ALL (r/r B-ALL) for its clinical benefit demonstrated in different clinical trials. Clinical trials have also shown that there are still patients refractory to blinatumomab. It is thus important to understand the resistance mechanisms. Blinatumomab connects patients' autologous T cells and target cells to form immunologic synapse which potently triggers the activation signaling cascades in T cells and guides T cells to recognize and induce perforin/granzyme-mediated lysis of CD19+ B-ALL cells. Previous studies showed blinatumomab-mediated cytotoxicity involves different T cell subpopulations. But response of each T cell subpopulation to blinatumomab treatment remained largely unknown. Methods and Results In this study, we used 10X Genomics based single cell RNA sequencing to analyze the transcriptome of single T cells before and after blinatumomab treatment. First, ex vivo blinatumomab cytotoxicity model was established, in which healthy PBMCs were used as effector cells and cocultured with target cells (RS4;11 cells or SUP-B15 cells) at an effector-to-target cell ratio of 10:1 with 0.1 ng/mL blinatumomab. Then, PBMCs and BMMCs from 2 B-ALL patients were cultured with 10 ng/mL blinatumomab. Cells from both ex vivo model and patient samples were sequenced using 10X Genomics platform. In total, transcriptome of 17920 single T cells from the ex vivo model and 2271 single T cells from patient sample were analyzed. Based on T cell trajectory analysis, we identified four distinct populations of blinatumomab-activated T cells, which were derived from CD8+ effector memory T (TEM) cells, CD4+ central memory (TCM) cells, naïve T cells and Tregs, respectively. The differentially expressed genes in activated clusters were analyzed to reflect T cell activation mechanisms. The result showed blinatumomab induced the upregulation of aerobic glycolysis pathway (PKM, PGAM1, ENO1, GAPDH and LDHA), cytoskeleton dynamics pathway (ACTD1, ACTB, NME1 and TUBA1B), IFN-responsive pathway (GBP1, PSME2, WARS, CXCL10 and STAT1), and the upregulation of well-known immune-related genes (TNFRSF4, TNFRSF18, LAG3, CD69, IL2RA, MIR155HG, BATF, SH2D2A, LTA, NFKBIA and NDFIP2). We found blinatumomab-activated CD8+ TEM cells showed stronger cytotoxic capability than other activated populations with specific production of cytotoxic factors (PRF1, IFNG and FASLG) and cytokines (CCL2, CCL3, CCL3L1, CCL4, CCL4L2, CCL8, XCL1, XCL2, TNFSF9 and TNFSF14). Last, differential gene expression analysis revealed that co-stimulatory (TNFRSF4,TNFRSF9 and TNFRSF18) and co-inhibitory receptors (LAG3 and TIGIT) were similarly up-regulated in clusters activated from memory and naïve T cells, indicating ligand dependent T cell functional outcomes induced by blinatumomab. Conclusion In summary, we used single cell sequencing to map the blinatumomab-mediated T cell activation state transition and reveal the molecular changes in different T cell subpopulations. Memory T cells, naïve T cells and Tregs were identified functional populations after blinatumomab treatment. CD8+ TEM accounted for the majority of blinatumomab-induced cytotoxicity. Furthermore, T cell co-regulatory receptors were identified as potential targets accountable for blinatumomab sensitivity or resistance mechanisms. The study demonstrated that the collected cellular transcriptional profiles can serve as resource to explore novel strategies to enhance the efficacy of blinatumomab. Disclosures Yin: Amgen: Employment. Huo:Amgen: Employment. Sheng:Amgen: Employment. Li:Amgen: Employment. Ellwanger:Amgen: Employment. Lu:Amgen: Employment. Homann:Amgen: Employment. Wang:Amgen: Employment. Ren:Ruijin hospital: Employment.

The phenotypic transformation of hepatic myofibroblasts (MFs) is involved in the whole process of the progression and regression of liver fibrosis. Notch signaling has been demonstrated to modulate the fibrosis. In this study, we found that Notch signaling in MFs was overactivated and suppressed with the progression and regression of hepatic fibrosis respectively, by detecting Notch signaling readouts in MFs. Moreover, we inactivated Notch signaling specifically in MFs with Sm22αCreER-RBPjflox/flox mice (RBPjMF-KO), and identified that MFs-specific down-regulation of Notch signaling significantly alleviated CCl4-induced liver fibrosis during the progression and regression. During the progression of liver fibrosis, MFs-specific blockade of Notch signaling inhibited the activation of HSCs to MFs and increases the expression of MMPs to reduce the deposition of ECM. During the regression of fibrosis, blocking Notch signaling in MFs increased the expression of HGF to promote proliferation in hepatocytes and up-regulated the expression of pro-apoptotic factors, Ngfr and Septin4, to induce apoptosis of MFs, thereby accelerating the reversal of fibrosis. Collectively, the MFs-specific disruption of Notch signaling attenuates liver fibrosis by modulating fibrosis progression and regression, which suggests a promising therapeutic strategy for liver fibrosis.

Unruptured intracranial vertebral artery dissecting aneurysms (IVADAs) with mass effect have an extremely poor natural course, and treatment of these aneurysms remains a challenge for endovascular and surgical strategies. The aim of this study was to analyze the role of double-stent-assisted coil embolization in preventing rupture and bleeding of intracranial vertebral artery dissecting aneurysm with brainstem compression by reducing mass effect and preventing the recurrence of the aneurysm.A total of 25 patients (mean age, 56.04±13.0 years) with unruptured IVADAs with mass effect received dual-stent-assisted coil embolization. The baseline characteristics, the change of aneurysm size on MR, the rate of retreatment, and the improvement rate of clinical symptoms and signs were analyzed retrospectively.All patients completed the surgical procedures successfully. No aneurysm bleeding or perforating artery occlusion occurred during the perioperative and follow-up periods. The initial maximum diameter of the aneurysm on MR was 17.5 ± 3.6 mm. One year after treatment, the maximum diameter of the aneurysm on MR was 15.8 ± 4.9 mm. The reduction rate of the maximum diameter of the aneurysm was 10.7 ± 12.7%. The change of the maximum diameter before and after treatment of aneurysm was statistically significant (P＜0.001). In terms of the improvement rate of clinical symptoms, 15 cases were completely improved (60.0%), 6 cases were partially improved (24.0%), and the total clinical improvement rate was 84%. Four cases (16.0%) showed no improvement or even had aggravation of clinical symptoms. In 5 cases (20.0%), aneurysms recurred. Among 4 cases involving posterior inferior cerebellar artery origin, 3 cases had the recurrence (75%). 5 recurred cases were treated with single-stent-assisted coil embolization. No residual aneurysm and recurrence were found on the follow-up angiography.The double-stent-assisted coil embolization procedure is very safe and reliable. It can effectively prevent the aneurysm from continuing to grow and rupture and thereby reduce the clinical symptoms caused by the mass effect.

Of the known regulators of atherosclerosis, miRNAs have been demonstrated to play critical roles in lipoprotein homeostasis and plaque formation. Here, we generated a novel animal model of atherosclerosis by knocking in LDLR(W483X) in C57BL/6 mice, as the W483X mutation in LDLR is considered the most common newly identified pathogenic mutation in Chinese familial hypercholesterolemia (FH) individuals. Using the new in vivo mouse model combined with a well-established atherosclerotic in vitro human cell model, we identified a novel atherosclerosis-related miRNA, miR-23a-3p, by microarray analysis of mouse aortic tissue specimens and human aortic endothelial cells (HAECs). miR-23a-3p was consistently downregulated in both models, which was confirmed by qPCR. Bioinformatics analysis and further validation experiments revealed that the TNFα-induced protein 3 (TNFAIP3) gene was the key target of miR-23a-3p. The miR-23a-3p-related functional pathways were then analyzed in HAECs. Collectively, the present results suggest that miR-23a-3p regulates inflammatory and apoptotic pathways in atherogenesis by targeting TNFAIP3 through the NF-κB and p38/MAPK signaling pathways.

Objective: To investigate the expression of RNF187 in hepatocellular carcinoma (HCC) and its relationship with prognosis. Methods: The mRNA and protein expressions in hepatocellular carcinoma and tumor-adjacent tissues of HCC patients were determined by qRT-PCR and Western blot analysis, and RNF187 expressions in HCC were detected by immunohistochemistry. The relationship of RNF187 expression with clinicopathologic factors and prognosis in HCC patients were analyzed. Results: RNF187 expressed highly in HCC tissues compared with the corresponding adjacent liver tissues both in mRNA and protein level, and significantly higher in HCC tissue from patients with intrahepatic metastases or vascular invasion than those in HCC tissue from patients without intrahepatic metastases and vascular invasion (all P

Collective total synthesis of five tetrahydroisoquinoline alkaloids including the first total synthesis of (-)-fennebricin A and (-)-renieramycin J has been accomplished. The synthesis features employing a single common amino acid to symmetrically construct the pentacycle of title alkaloids. The palladium-catalyzed arylation of alanine-derived amide developed by Yu was tactically utilized to afford unnatural amino acid building block rapidly and practically. The structure of synthetic (-)-renieramycin M has been confirmed by single crystal X-ray analysis for the first time.