Deep mutational scanning of influenza A virus NEP reveals pleiotropic mutations in its N-terminal domain.

The influenza A virus nuclear export protein (NEP) is a multifunctional protein that is essential for the viral life cycle and has very high sequence conservation. However, since the open reading frame of NEP largely overlaps with that of another influenza viral protein, non-structural protein 1, it is difficult to infer the functional constraints of NEP based on sequence conservation analysis. Besides, the N-terminal of NEP is structurally disordered, which further complicates the understanding of its function. Here, we systematically measured the replication fitness effects of >1,800 mutations of NEP. Our results show that the N-terminal domain has high mutational tolerance. Additional experiments demonstrate that N-terminal domain mutations pleiotropically affect viral transcription and replication dynamics, host cellular responses, and mammalian adaptation of avian influenza virus. Overall, our study not only advances the functional understanding of NEP, but also provides insights into its evolutionary constraints.

Inhibition of GLUD1 mediated by LASP1 and SYVN1 contributes to hepatitis B virus X protein-induced hepatocarcinogenesis.

Glutamate dehydrogenase 1 (GLUD1) is implicated in oncogenesis. However, little is known about the relationship between GLUD1 and hepatocellular carcinoma (HCC). In the present study, we demonstrated that the expression levels of GLUD1 significantly decreased in tumors, which was relevant to the poor prognosis of HCC. Functionally, GLUD1 silencing enhanced the growth and migration of HCC cells. Mechanistically, the upregulation of interleukin-32 through AKT activation contributes to GLUD1 silencing-facilitated hepatocarcinogenesis. The interaction between GLUD1 and AKT, as well as α-ketoglutarate regulated by GLUD1, can suppress AKT activation. In addition, LIM and SH3 protein 1 (LASP1) interacts with GLUD1 and induces GLUD1 degradation via the ubiquitin-proteasome pathway, which relies on the E3 ubiquitin ligase synoviolin (SYVN1), whose interaction with GLUD1 is enhanced by LASP1. In hepatitis B virus (HBV)-related HCC, the HBV X protein (HBX) can suppress GLUD1 with the participation of LASP1 and SYVN1. Collectively, our data suggest that GLUD1 silencing is significantly associated with HCC development, and LASP1 and SYVN1 mediate the inhibition of GLUD1 in HCC, especially in HBV-related tumors.

Hepatitis B virus core protein stabilizes RANGAP1 to upregulate KDM2A and facilitate hepatocarcinogenesis.

PURPOSE: As a vital component of the hepatitis B virus (HBV) nucleocapsid, HBV core protein (HBC) contributes to hepatocarcinogenesis. Here, we aimed to assess the effects of RANGAP1 and KDM2A on tumorigenesis induced by HBC. METHODS: Co-immunoprecipitation (Co-IP) combined with mass spectrometry were utilized to identify the proteins with the capacity to interact with HBC. The gene and protein levels of RANGAP1 and KDM2A in hepatocellular carcinoma (HCC) and HBV-positive HCC tissues were evaluated using different cohorts. The roles of RANGAP1 and KDM2A in HCC cells mediated by HBC were investigated in vitro and in vivo. Co-IP and western blot were used to estimate the interaction of HBC with RANGAP1 and KDM2A and assess RANGAP1 stabilization regulated by HBC. RESULTS: We discovered that HBC could interact with RANGAP1 and KDM2A, the levels of which were markedly elevated in HCC tissues. Relying on RANGAP1 and KDM2A, HBC facilitated HCC cell growth and migration. The increased stabilization of RANGAP1 mediated by HBC was relevant to the disruption of the interaction between RANGAP1 and an E3 ligase SYVN1. RANGAP1 interacted with KDM2A, and it further promoted KDM2A stabilization by disturbing the interaction between KDM2A and SYVN1. HBC enhanced the interaction of KDM2A with RANGAP1 and upregulated the expression of KDM2A via RANGAP1 in HCC cells. CONCLUSIONS: These findings demonstrate a novel mechanism by which HBC facilitates hepatocarcinogenesis. RANGAP1 and KDM2A could act as potential molecular targets for treating HBV-associated malignancy.

MAS-Net:Multi-modal Assistant Segmentation Network For Lumbar Intervertebral Disc.

Objective.Despite advancements in medical imaging technology, the diagnosis and positioning of lumbar disc diseases still heavily rely on the expertise and experience of medical professionals. This process is often time-consuming, labor-intensive, and susceptible to subjective factors. Achieving automatic positioning and segmentation of lumbar intervertebral disc (LID) is the first and critical step in intelligent diagnosis of lumbar disc diseases. However, due to the complexity of the vertebral body and the ambiguity of the soft tissue boundaries of the LID, accurate and intelligent segmentation of LIDs remains challenging. The study aims to accurately and intelligently segment and locate LIDs by fully utilizing multi-modal lumbar magnetic resonance Images (MRIs).Approach.A novel multi-modal assistant segmentation network (MAS-Net) is proposed in this paper. The architecture consists of four key components: the multi-branch fusion encoder (MBFE), the cross-modality correlation evaluation (CMCE), the channel fusion transformer (CFT), and the selective Kernel (SK) based decoder. The MBFE module captures and integrates various modal features, while the CMCE module facilitates the fusion process between the MBFE and decoder. The CFT module selectively guides the flow of information between the MBFE and decoder and effectively utilizes skip connections from multiple layers. The SK module computes the significance of each channel using global pooling operations and applies weights to the input feature maps to improve the models recognition of important features.Main results.The proposed MAS-Net achieved a dice coefficient of 93.08% on IVD3Seg and 93.22% on DualModalDisc dataset, outperforming the current state-of-the-art network, accurately segmenting the LIDs, and generating a 3D model that can precisely display the LIDs.Significance.MAS-Net automates the diagnostics process and addresses challenges faced by doctors. Simplifying and enhancing the clarity of visual representation, multi-modal MRI allows for better information complementation and LIDs segmentation. By successfully integrating data from various modalities, the accuracy of LID segmentation is improved.

Molecular characterization of TNF-ß and IFN-γ in yellowfin seabream (Acanthopagrus latus, Hottuyn, 1782) and their immune responses to density stress during transport.

The inflammatory cytokines TNF-ß and IFN-γ are important mediators of the vertebrate inflammatory response and coordinators of the immune system in regard to NF-κB signalling pathways. In this study, the TNF-ß and IFN-γ genes of yellowfin seabream, Acanthopagrus latus were identified, and the multiple sequence alignments, evolutionary relationships and gene expressions of the two genes were also determined. AlTNF-ß contained a 762 bp open reading frame (ORF) encoding 253 amino acids, while AlIFN-γ contained a 582 bp ORF encoding 193 amino acids. An amino-acid sequence alignment analysis showed that these proteins have highly conserved transmembrane structural domains among teleosts. Moreover, AlTNF-ß has a close affinity with TNF-ß of yellowfin seabream while AlIFN-γ has a high evolutionary correlation with A. regius and Sparus aurata. In addition, the mRNAs of AlTNF-ß and AlIFN-γ are widely expressed in various tissues. AlTNF-ß is highly expressed in gill and intestinal tissues, and the mRNA levels of AlIFN-γ are higher in spleen, skin, and gill tissues than in other tissues. Under transportation density stress, the mRNA level of AlTNF-ß was significantly elevated in the intestine of the high-density group, while AlTNF-ß transcription in the gills did not vary significantly among the density groups. Furthermore, AlIFN-γ expression was increased in liver, intestinal, and gill tissues under high transportation density. The results of this study show that TNF-ß and IFN-γ expression in yellowfin seabream is greatly affected by density stress. The density of 125 per bag for 4-5 cm fry or 1200 per bag for 1-2 cm fry is most suitable for the transportation of live fish. These results might provide a reference for further studies on the immunomodulatory response process and auxiliary function of immune stress of TNF and IFN genes in fish under density stress.

Tail-Engineered Phage P2 Enables Delivery of Antimicrobials into Multiple Gut Pathogens.

Bacteriophages can be reprogrammed to deliver antimicrobials for therapeutic and biocontrol purposes and are a promising alternative treatment to antimicrobial-resistant bacteria. Here, we developed a bacteriophage P4 cosmid system for the delivery of a Cas9 antimicrobial into clinically relevant human gut pathogens Shigella flexneri and Escherichia coli O157:H7. Our P4 cosmid design produces a high titer of cosmid-transducing units without contamination by a helper phage. Further, we demonstrate that genetic engineering of the phage tail fiber improves the transduction efficiency of cosmid DNA in S. flexneri M90T as well as allows recognition of a nonnative host, E. coli O157:H7. We show that the transducing units with the chimeric tails enhanced the overall Cas9-mediated killing of both pathogens. This study demonstrates the potential of our P4 cas9 cosmid system as a DNA sequence-specific antimicrobial against clinically relevant gut pathogenic bacteria.

An adenine/thymidine-rich region is integral to RepL-mediated DNA replication.

The lytic replication of bacteriophage P1 requires RepL expression and the lytic stage origin, oriL, which is postulated to be located within repL gene sequence. The exact sequence of P1 oriL and the mechanism(s) of RepL-mediated DNA replication, however, are not fully understood. By using repL gene expression to induce DNA replication of a gfp and a rfp reporter plasmids, we demonstrated that synonymous base substitution in an adenine/thymidine-rich region of repL gene sequence, termed AT2, significantly inhibited the RepL-mediated signal amplification. Contrastingly, mutations in an IHF and two DnaA binding sites did not affect the RepL-mediated signal amplification significantly. A truncated repL sequence with the AT2 region allowed RepL-mediated signal amplification in trans therefore verifying a significant role of the AT2 region in RepL-mediated DNA replication. A combination of repL gene expression and a non-protein-coding copy of repL gene sequence (termed nc-repL) was able to amplify the output of an arsenic biosensor. Furthermore, mutation(s) at single or multiple positions within the AT2 region produced varying levels of RepL-mediated signal amplification. Overall, our results provide novel insights into the identity and location of P1 oriL as well as demonstrating the potential of using repL constructs to amplify and modulate the output of genetic biosensors.

P1 Bacteriophage-Enabled Delivery of CRISPR-Cas9 Antimicrobial Activity Against Shigella flexneri.

The discovery of clustered, regularly interspaced, short palindromic repeats (CRISPR) and the Cas9 RNA-guided nuclease provides unprecedented opportunities to selectively kill specific populations or species of bacteria. However, the use of CRISPR-Cas9 to clear bacterial infections in vivo is hampered by the inefficient delivery of cas9 genetic constructs into bacterial cells. Here, we use a broad-host-range P1-derived phagemid to deliver the CRISPR-Cas9 chromosomal-targeting system into Escherichia coli and the dysentery-causing Shigella flexneri to achieve DNA sequence-specific killing of targeted bacterial cells. We show that genetic modification of the helper P1 phage DNA packaging site (pac) significantly enhances the purity of packaged phagemid and improves the Cas9-mediated killing of S. flexneri cells. We further demonstrate that P1 phage particles can deliver chromosomal-targeting cas9 phagemids into S. flexneri in vivo using a zebrafish larvae infection model, where they significantly reduce the bacterial load and promote host survival. Our study highlights the potential of combining P1 bacteriophage-based delivery with the CRISPR chromosomal-targeting system to achieve DNA sequence-specific cell lethality and efficient clearance of bacterial infection.

Flow mechanism and axial force distribution characteristics of multistage pump cavity.

The gap leakage between the impeller ring leads to the change of the pump cavity flow characteristics, resulting in the uneven pressure distribution of shroud, which causes the axial force of the cavity to change. In this paper, the flow in the front and the rear cavity of the multistage centrifugal pump was taken as the research object. Through the numerical method, the radial flow velocity, the leakage flow size and its direction, the core zone rotation factor of the front and the rear cavity of the multistage pump impeller at all stages and the axial force of pump cavity were studied. The results show that the leakage in the front cavity of multistage pump impeller at all stages flows inward along radial direction (i.e. it flows from the inlet of pump cavity to the front ring clearance). The rotation factor in core zone is higher than 0.5, and with the increase of rotation factor, the axial force of the front pump cavity increased. The leakage in the rear pump cavity flows outward along radial direction (i.e. it flows from the rear ring to the inlet of pump cavity). The rotation factor in core zone is less than 0.5, and with the increase of rotation factor, the axial force decreased gradually. Besides, the radial velocity and rotation factor in the front and the rear multistage pump of impellers were obviously along the axial direction at three regions, the regions are pump case boundary layer, core zone and impeller boundary layer. The flow in the core zone is dominated by circumferential circular motion, and the radial velocity in the core zone is 0. It is shown that the direction of the leakage in the pump cavity and the rotation effect of the flow micelle in the mainstream core zone are the main factors affecting the axial force of the pump cavity, and the research results can provide theoretical guidance for the calculation and suppression of axial force of multistage pumps.

The Role of O-antigen in P1 Transduction of Shigella flexneri and Escherichia coli with its Alternative S' Tail Fibre.

Enterobacteria phage P1 expresses two types of tail fibre, S and S'. Despite the wide usage of phage P1 for transduction, the host range and the receptor for its alternative S' tail fibre was never determined. Here, a ΔS-cin Δpac E. coli P1 lysogenic strain was generated to allow packaging of phagemid DNA into P1 phage having either S or S' tail fibre. P1(S') could transduce phagemid DNA into Shigella flexneri 2a 2457O, Shigella flexneri 5a M90T and Escherichia coli O3 efficiently. Mutational analysis of the O-antigen assembly genes and LPS inhibition assays indicated that P1(S') transduction requires at least one O-antigen unit. E. coli O111:B4 LPS produced a high neutralising effect against P1(S') transduction, indicating that this E. coli strain could be susceptible to P1(S')-mediated transduction. Mutations in the O-antigen modification genes of S. flexneri 2a 2457O and S. flexneri 5a M90T did not cause significant changes to P1(S') transduction efficiency. A higher transduction efficiency of P1(S') improved the delivery of a cas9 antimicrobial phagemid into both S. flexneri 2457O and M90T. These findings provide novel insights into P1 tropism-switching, by identifying the bacterial strains which are susceptible to P1(S')-mediated transduction, as well as demonstrating its potential for delivering a DNA sequence-specific Cas9 antimicrobial into clinically relevant S. flexneri.

Concurrent Tuberculous Meningoencephalitis and Anti-NMDAR Encephalitis: A Case Report.

Background: Cases of tuberculosis triggering the development of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis are absent. Case Presentation: Herein, we report, for the first time, the case of a patient who developed anti-NMDAR encephalitis likely due to tuberculosis. The patient, a 33-year-old man, experienced weight loss during the previous 2 years, along with acute headache, fever, cognitive deficits, and right ophthalmoplegia. Based on these findings and on data from magnetic resonance imaging and cerebrospinal fluid antibody analysis, tuberculous meningoencephalitis combined with anti-NMDAR encephalitis was diagnosed. Marked clinical and brain imaging improvement were observed after antituberculosis and high-dose corticosteroid treatment initiation, which persisted during the 3 months of follow-up. Conclusions: This case suggests that anti-NMDAR encephalitis may arise after tuberculosis infection. Therefore, clinicians must be aware of this possibility, especially when cognitive and new neurological symptoms suddenly occur.

A multicenter study to evaluate the disease burden and health economics of inpatients with multiple sclerosis in China.

OBJECTIVE: To assess the disease burden and health economics of inpatients with multiple sclerosis (MS) in China by evaluating the direct, indirect, and intangible costs. METHODS: A total of 863 patients were included for a cross-sectional retrospective study in 50 centers. The direct economic burden was measured by the cost of hospitalization and out-of-hospital application drugs, and the indirect economic burden was measured by the human capital method. The disability-adjusted life year (DALY) was used to express the intangible economic burden. Cost-utility analysis (CUA) using DALYs as indicators of health benefits was performed by calculating the incremental cost-utility ratio. RESULTS: The mean direct economic burden/year, daily medication expenses/year, DALY, indirect economic burden, and indirect economic burden/year were 27,655.57 Yuan, 17,944.97 Yuan, 10.89 Yuan, 512,041.7 Yuan, and 11,299.85 Yuan, respectively. For the study period of two years, the direct economic burden, daily medication expense, and indirect economic burden were 48.6%, 31.5%, and 19.85% of the total economic burden, respectively. Disease burden and the number of episodes of remission were not statistically significant (p>0.001). The direct economic burden and total economic burden of the disease-modifying therapy (DMT) group were higher than those of the non-DMT group, but DALYs had no statistical significance (p>0.001). CUA showed that inpatients with MS in the DMT group received a DALY every time compared with the non-DMT group. CONCLUSION: The DALY losses are concentrated in young and middle-aged Chinese people. In this two-year study, CUA prompted the application of DMT drugs to increase the economic burden and DALYs. However, follow-up time is still short, and further follow-up observation is required.

Ultra-compact reconfigurable device for mode conversion and dual-mode DPSK demodulation via inverse design.

The mode multiplexing/de-multiplexing devices are key components for mode-division multiplexing (MDM) technology. Here, we propose an ultra-compact and reconfigurable mode-conversion device via inverse design, which can selectively implement multichannel mode conversion controlled by input phase shifts (Δφ). The device can transform input TE0 (TE1) mode to TE4 (TE3) mode at Δφ=0, or from TE0 (TE1) to TE1 (TE2) at Δφ=π spanning the wavelength range of 1525-1565 nm. We further demonstrate an integrated monolithic module based on the mode conversions to directly demodulate the dual-mode difference phase shift keying (DPSK) signal which significantly reduces the device size and benefits for future dense integrations in MDM systems.

The preparation and characterization of TiO2/r-GO/Ag nanocomposites and its photocatalytic activity in formaldehyde degradation.

A series of TiO2-rGO-Ag nanocomposites were prepared in this work via a facile one-pot hydrothermal method utilized for formaldehyde (HCHO) photodegradation; using TiO2, graphene oxide(GO) as well as AgNO3 as the raw materials, and sodium citrate as a reducing agent. Characterization by X-ray diffraction (XRD), Raman spectra, Transmission electron microscopy (TEM) and Field emission scanning electron microscopy (FESEM) demonstrated that GO and Ag+ were reduced during the formation of TiO2-rGO-Ag nanocomposites. X-ray photoelectron spectroscopy(XPS), UV-vis diffuse reflectance spectroscopy (DRS), photoluminescence spectra(PL) and Photocurrent spectrum measurement were applied to quantitatively characterize the bonding between TiO2 and rGO, the band gap energy of catalysts as well as electron-hole pairs recombination rate. The results revealed that the introduction of rGO sheets and Ag nanoparticles reduced the band gap energy of catalysts; it also suppressed the recombination of electron-hole pairs. However, C-O-Ti bond, which played a key role in photocatalysis, was reduced to some extent by the existence of Ag. Photodegradation results showed that, when the Ag loading was 9 mol% of TiO2, the reaction rate constant of formaldehyde (HCHO) removal improved distinctly, by about 22.3 times that of TiO2. The radical scavenger tests and electron paramagnetic resonance(EPR) analysis revealed that superoxide radical (·O2 -), hole (h+), and hydroxylradical (·OH) were reactive species of formaldehyde photodegradation.

Regulatory B Cells and Its Role in Central Nervous System Inflammatory Demyelinating Diseases.

Regulatory B (Breg) cells represent a population of suppressor B cells that participate in immunomodulatory processes and inhibition of excessive inflammation. The regulatory function of Breg cells have been demonstrated in mice and human with inflammatory diseases, cancer, after transplantation, and particularly in autoinflammatory disorders. In order to suppress inflammation, Breg cells produce anti-inflammatory mediators, induce death ligand-mediated apoptosis, and regulate many kinds of immune cells such as suppressing the proliferation and differentiation of effector T cell and increasing the number of regulatory T cells. Central nervous system Inflammatory demyelinating diseases (CNS IDDs) are a heterogeneous group of disorders, which occur against the background of an acute or chronic inflammatory process. With the advent of monoclonal antibodies directed against B cells, breakthroughs have been made in the treatment of CNS IDDs. Therefore, the number and function of B cells in IDDs have attracted attention. Meanwhile, increasing number of studies have confirmed that Breg cells play a role in alleviating autoimmune diseases, and treatment with Breg cells has also been proposed as a new therapeutic direction. In this review, we focus on the understanding of the development and function of Breg cells and on the diversification of Breg cells in CNS IDDs.

Circ_0000144 facilitates the progression of thyroid cancer via the miR-217/AKT3 pathway.

BACKGROUND: Thyroid carcinoma (TC) is the most common malignancy of the endocrine system. Circular RNA (circRNA) is vital in the regulation of tumor progression. Circ_0000144 serves as a novel oncogenic circRNA, and miR-217 is reported to inhibit the malignant phenotypes of cancer cells by targeting AKT3 in TC. The present study aimed to explore the regulatory mechanism of circ_0000144 and miR-217 in the progression of TC. METHODS: Circ_0000144 expression in 32 pairs of TC tissues and different TC cell lines (including BCPAP, K1, H7H83, and TPC-1) was detected by employing a quantitative real-time polymerase chain reaction (qRT-PCR). Circ_0000144 small interfering RNA was used to establish loss-of-function models. Cell counting kit-8 (CCK-8), BrdU (5-bromo-2'-deoxyuridine) and transwell assays were utilized to verify the effects of circ_0000144 on TC cell proliferation, migration and invasion, respectively. Bioinformatics, western blotting, a luciferase reporter experiment and qRT-PCR were employed to confirm the relationships among circ_0000144, miR-217 and AKT3. RESULTS: Circ_0000144 expression was remarkably elevated in TC tissues (p < 0.001) and TC cell lines. The elevation of circ_0000144 expression was markedly linked to tumor size (p = 0.015), TNM stage (p = 0.025) and lymph node metastasis (p = 0.017) of the patients. Functional studies showed that knocking down circ_0000144 repressed the malignancy of TC cells. Furthermore, miR-217 was identified as a downstream target of circ_0000144; inhibition of miR-217 could reverse the effects induced by circ_0000144 knockdown. Moreover, circ_0000144 could regulate AKT3 expression by suppressing miR-217 expression. CONCLUSIONS: Circ_0000144 exerts a cancer-promoting effect on TC cells via the miR-217/AKT3 pathway.

Effectiveness of a machine-assisted healthy physical fitness promotion program for community elderly.

BACKGROUND: Maintaining physical fitness is important for health of the elderly. How to implement an effective and efficient model is a practical issue. A healthy physical fitness promotion program with machine-assisted exercises was designed for elderly and executed in a community in 2015 and 2016. The program was implemented for 10 to 12 weeks with two (group 1) or three (group 2) sessions per week, and functional fitness tests were conducted before, at the end, and 3 months after the training. This study is to investigate the effectiveness of machine-assisted physical fitness promotion program for the community elderly. METHODS: A retrospective analysis was conducted on the participants' data, including sex, age, height, weight, waist-hip ratio, grip strength, back stretch, chair sit-and-reach, 30-second chair stand, 30-second arm curl, 2-minute step, single-leg standing, 8-ft up-and-go, and body composition. The differences in test results before, at the end, and 3 months after the training and the percentage change at different time intervals between the two groups were compared. RESULTS: After training, body mass index in group 2 and the test completion time for 8-ft up-and-go in group 1 decline significantly; furthermore, significant increase was noted in the height and number of times of 2-minute step in both groups, and grip strength, number of times of their 30-second arm curl, and 30-second chair stand in group 2. The training effect sustained 3 months after the training in height and number of times of 2-minute step in both groups, and grip strength, number of times of their 30-second arm curl, and 30-second chair stand in group 2. CONCLUSION: This study discovered that 10 to 12 weeks of machine-assisted exercise training can improve the elderly community members' body composition, muscle strength, muscle endurance, agility, dynamic balance, and cardiorespiratory endurance. Moreover, with three sessions per week, its effects were even maintained for 3 months after the training.

Chimeric antigen receptor-engineered regulatory T lymphocytes: promise for immunotherapy of autoimmune disease.

Regulatory T lymphocytes (Tregs) exist as natural ideal immunosuppressors in the immune system. Autologous or allogeneic Treg transfusion therapy has been carried out in animal models and humans as a new strategy for treating autoimmune disease. Recent studies have shown that Tregs can be engineered with chimeric antigen receptors to be antigen-specific, which are more effective than polyclonal Tregs with fewer target limitations and a lack of major histocompatibility complex restriction. This review describes the potential for applying chimeric antigen receptor-engineered regulatory T cells in autoimmune diseases.

IL-2 gene polymorphisms affect tacrolimus response in myasthenia gravis.

PURPOSE: The IL-2 gene polymorphisms have been reported to be associated with the development of autoimmune disease. However, there are no published studies examining the influence of the IL-2 gene polymorphisms on the response of myasthenia gravis (MG) patients to tacrolimus (Tac). The goal of this study was to investigate the relationship between the polymorphisms of IL-2 and Tac response in MG patients. METHODS: Ninety-two MG patients treated with Tac were studied, including 57 Tac-effective patients and 35 Tac-ineffective patients. Then, we selected four single-nucleotide polymorphisms (SNPs: rs2069776, rs2069772, rs2069762, rs2069763) in the IL-2 gene. Next, we analyzed the distribution of genotypes, allelic frequencies of SNPs, and haplotype frequencies among polymorphisms in the two groups of patients. RESULTS: The distribution of the allelic frequency of the rs2069762 variant differed between the Tac-effective and Tac-ineffective patients (P = 0.02). Genotypes G/T and G/G of rs2069762 were differently distributed between the two groups when the wild genotype T/T was assigned as a reference (P < 0.001 for G/T; P = 0.003 for G/G). Patients with the TAGG haplotype tended to be Tac-ineffective (P < 0.001, OR: 0.15, 95% CI: 0.05-0.43). CONCLUSION: Myasthenia gravis patients with the rs2069762 variant, rs2069762 G/T and G/G genotype, and TAGG haplotype for IL-2 tended to respond poorly to Tac treatment.

Quantum many-body simulation using monolayer exciton-polaritons in coupled-cavities.

Quantum simulation is a promising approach to understanding complex strongly correlated many-body systems using relatively simple and tractable systems. Photon-based quantum simulators have great advantages due to the possibility of direct measurements of multi-particle correlations and ease of simulating non-equilibrium physics. However, interparticle interaction in existing photonic systems is often too weak, limiting the potential for quantum simulation. Here we propose an approach to enhance the interparticle interaction using exciton-polaritons in MoS2 monolayer quantum dots embedded in 2D photonic crystal microcavities. Realistic calculation yields optimal repulsive interaction in the range of 1-10 meV-more than an order of magnitude greater than the state-of-the-art value. Such strong repulsive interaction is found to emerge neither in the photon-blockade regime for small quantum dot nor in the polariton-blockade regime for large quantum dot, but in the crossover between the two regimes with a moderate quantum-dot radius around 20 nm. The optimal repulsive interaction is found to be largest in MoS2 among commonly used optoelectronic materials. Quantum simulation of strongly correlated many-body systems in a finite chain of coupled cavities and its experimental signature are studied via the exact diagonalization of the many-body Hamiltonian. A method to simulate 1D superlattices for interacting exciton-polariton gases in serially coupled cavities is also proposed. Realistic considerations on experimental realizations reveal advantages of transition metal dichalcogenide monolayer quantum dots over conventional semiconductor quantum emitters.