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One could tune a topological double-Weyl semimetal or a topological triple-Weyl semimetal to become a topologically trivial insulator by opening a band gap. This kind of quantum phase transition is characterized by the change of certain topological invariant. A new gapless semimetallic state emerges at each topological quantum critical point. Here we perform a renormalization group analysis to investigate the stability of such critical points against perturbations induced by random scalar potential and random vector potential. We find that the quantum critical point between double-Weyl semimetal and band insulator is unstable and can be easily turned into a compressible diffusive metal by any type of weak disorder. The quantum critical point between triple-Weyl semimetal and band insulator flows to a stable strong-coupling fixed point if the system contains a random vector potential merely along the z-axis, but becomes a compressible diffusive metal when other types of disorders exist.

Acquired drug resistance is a major obstacle in cancer therapy. Recent studies revealed that reprogramming of tRNA modifications modulates cancer survival in response to chemotherapy. However, dynamic changes in tRNA modification were not elucidated. In this study, comparative analysis of the human cancer cell lines and their taxol resistant strains based on tRNA mapping was performed by using UHPLC–MS/MS. It was observed for the first time in all three cell lines that 4-demethylwyosine (imG-14) substitutes for hydroxywybutosine (OHyW) due to tRNA-wybutosine synthesizing enzyme-2 (TYW2) downregulation and becomes the predominant modification at the 37th position of tRNAphe in the taxol-resistant strains. Further analysis indicated that the increase in imG-14 levels is caused by downregulation of TYW2. The time courses of the increase in imG-14 and downregulation of TYW2 are consistent with each other as well as consistent with the time course of the development of taxol-resistance. Knockdown of TYW2 in HeLa cells caused both an accumulation of imG-14 and reduction in taxol potency. Taken together, low expression of TYW2 enzyme promotes the cancer survival and resistance to taxol therapy, implying a novel mechanism for taxol resistance. Reduction of imG-14 deposition offers an underlying rationale to overcome taxol resistance in cancer chemotherapy.

Targeted proteomics has advantages over earlier conventional technologies for protein detection. We developed and validated an LC/MRM-MS-based targeted proteomic method combined with immunoaffinity precipitation for the enrichment and detection of low abundance chemerin isoforms in human biofluids. After tryptic digestion, each chemerin isoform was characterized by isoform-specific peptides, and the absolute quantification was achieved by using stable isotope-labeled peptides as internal standards. In serum, follicular fluid and synovial fluid, a total of 6 chemerin isoforms were identified and quantified, among which a novel natural isoform 153Q was discovered for the first time. The relative content of the six chemerin isoforms in human serum was 157S ≫ 156F ≫ 158K > 154F ≥ 155A > 153Q in the ratio of 25:17:5:2.5:2.2:1, respectively. The absolute contents were in the range of 88–3.5 ng/mL. This distribution remained consistent among the 3 biofluids analyzed. Total chemerin were found to be increased in both polycystic ovary syndrome (serum and follicular fluid) and rheumatoid arthritis (serum) patients. However, chemerin isoform analysis revealed that only 156F & 157S were increased in the former, while 155A, 156F & 157S were increased in the latter. This demonstrates the potential of this method in detailed characterization of changes in chemerin isoforms that may be of clinical relevance.

A new podocarpane type diterpenoid, aculeatusane A (1), and six known diterpenoids (2-7) were isolated from the whole plants of Celastrus aculeatus Merr. (Celastraceae). The structures were identified based on the HRESIMS and NMR spectroscopic data. All diterpenoids were isolated from C. aculeatus for the first time. Antiviral activity assay showed that aculeatusane A (1) is active against A/GZ/GIRD07/09 (H1N1) with the selectivity index (SI) of 6.75 ± 4.38.

The Asclepiadaceae plant is a rich source of C21 steroidal glycosides. The present study aimed to investigate the C21 steroidal glycosides from the whole plants of Tylophora atrofolliculata (Asclepiadaceae). As a result, three new C21 steroidal glycosides named atrofollicosides A-C (1-3) and four known steroidal glycosides (4-7) were isolated. The structures of these compounds were characterized using NMR spectroscopy. Highlighted here is a new disecopregnane-type steroid with a hydroxyl group at the C-18 position that constitutes the aglycone of compound 1.

Due to its relatively small size, homology to humans, and susceptibility to human viruses, the tree shrew becomes an ideal alternative animal model for the study of human viral infectious diseases. However, there is still no report for the comprehensive glycan profile of the respiratory tract tissues in tree shrews. In this study, we characterized the structural diversity of N-glycans in the respiratory tract of tree shrews using our well-established TiO2-PGC chip-Q-TOF-MS method. As a result, a total of 219 N-glycans were identified. Moreover, each identified N-glycan was quantitated by a high sensitivity and accurate MRM method, in which 13C-labeled internal standards were used to correct the inherent run-to-run variation in MS detection. Our results showed that the N-glycan composition in the turbinate and lung was significantly different from the soft palate, trachea, and bronchus. Meanwhile, 28 high-level N-glycans in turbinate were speculated to be correlated with the infection of H1N1 virus A/California/04/2009. This study is the first to reveal the comprehensive glycomic profile of the respiratory tract of tree shrews. Our results also help to better understand the role of glycan receptors in human influenza infection and pathogenesis.

Due to the high mutation rate of influenza virus and the rapid increase of drug resistance, it is imperative to discover host-targeting antiviral agents with broad-spectrum antiviral activity. Considering the discrepancy between the urgent demand of antiviral drugs during an influenza pandemic and the long-term process of drug discovery and development, it is feasible to explore host-based antiviral agents and strategies from antiviral drugs on the market. In the current study, the antiviral mechanism of arbidol (ARB), a broad-spectrum antiviral drug with potent activity at early stages of viral replication, was investigated from the aspect of hemagglutinin (HA) receptors of host cells.

Background Immunotherapy is an emerging cancer therapy with potential great success; however, immune checkpoint inhibitor (e.g., anti-PD-1) has response rates of only 10–30% in solid tumor because of the immunosuppressive tumor microenvironment (TME). This affliction can be solved by vascular normalization and TME reprogramming. Methods By using the single-cell RNA sequencing (scRNAseq) approach, we tried to find out the reprogramming mechanism that the Fc-VEGF chimeric antibody drug (Fc-VFD) enhances immune cell infiltration in the TME. Results In this work, we showed that Fc-VEGF121-VEGF165 (Fc-VEGF chimeric antibody drug, Fc-VFD) arrests excess angiogenesis and tumor growth through vascular normalization using in vitro and in vivo studies. The results confirmed that the treatment of Fc-VFD increases immune cell infiltration including cytotoxic T, NK, and M1-macrophages cells. Indeed, Fc-VFD inhibits Lon-induced M2 macrophages polarization that induces angiogenesis. Furthermore, Fc-VFD inhibits the secretion of VEGF-A, IL-6, TGF-β, or IL-10 from endothelial, cancer cells, and M2 macrophage, which reprograms immunosuppressive TME. Importantly, Fc-VFD enhances the synergistic effect on the combination immunotherapy with anti-PD-L1 in vivo. Conclusions In short, Fc-VFD fusion normalizes intratumor vasculature to reprogram the immunosuppressive TME and enhance cancer immunotherapy.

Background The adherence of oral anticoagulant (OAC) therapy among nonvalvular atrial fibrillation (NVAF) patients with acute ischemic stroke (AIS) in China during recent years was unclear, and the possible factors that influenced the initiation and persistent use of OAC were needed to be explored. Methods A total of 1085 NVAF patients, who experienced new‐onset and nonfatal AIS from August 2011 to December 2020 during follow‐ups in the China Atrial Fibrillation Registry (China‐AF), were enrolled. Information including patients' demographic characteristics, medical history, medication usage, which were collected before and after the index stroke, were used in the analysis. Results OAC was initiated in 40% (434/1085) NVAF patients within 3 months after new‐onset AIS. High‐reimbursement‐rate insurance coverage (odds ratio [OR]: 1.51, 95% confidence interval [CI]: 1.03–2.22, p = .036), 3‐month‐peri‐stroke AF episodes (OR: 2.63, 95% CI: 1.88–3.69, p

Since the pandemic of COVID-19 has intensely struck human society, small animal model for this infectious disease is in urgent need for basic and pharmaceutical research. Although several COVID-19 animal models have been identified, many of them show either minimal or inadequate pathophysiology after SARS-CoV-2 challenge. Here, we describe a new and versatile strategy to rapidly establish a mouse model for emerging infectious diseases in one month by multi-route, multi-serotype transduction with recombinant adeno-associated virus (AAV) vectors expressing viral receptor. In this study, the proposed approach enables profound and enduring systemic expression of SARS-CoV-2-receptor hACE2 in wild-type mice and renders them vulnerable to SARS-CoV-2 infection. Upon virus challenge, generated AAV/hACE2 mice showed pathophysiology closely mimicking the patients with severe COVID-19. The efficacy of a novel therapeutic antibody cocktail RBD-chAbs for COVID-19 was tested and confirmed by using this AAV/hACE2 mouse model, further demonstrating its successful application in drug development., Author summary Upon the emergence of new infectious disease, animal model becomes a pivotal tool for study of disease mechanism and development of therapeutics. In this study, we propose a versatile approach that allows rapid generation of mouse model for novel infectious disease once the receptor of the pathogen is identified. We demonstrated this approach by generating a mouse model for COVID-19 in a month’s time. These mice were capable of recapitulating severe COVID-19 in patients, and successfully applied in the development of a therapeutic antibody cocktail for the disease. This not only suggests the usefulness of this mouse model for the research on COVID-19, but also exhibit the utility of the proposed approach for establishing animal model for infectious disease.

Glycosylation plays an important role in the maintenance of the structure and function of glycoproteins, while aberrant protein glycosylation is correlated with various diseases. Human immunoglobulin G (IgG), which is composed of four subclasses (IgG1, IgG2, IgG3 and IgG4), is one of the most dominant and significant glycoprotein in human serum. The glycosylation on IgG-Fc moiety is known to be alternated with various physiological and pathological states. We herein report an integrated approach for comprehensive profiling and quantitation of IgG-Fc glycopeptides. Firstly, IgG N-glycans were profiled by using mAb-Glyco chip quadrupole time-of-flight mass spectrometry (Q-TOF-MS), resulting characterization of 87 N‑glycans originating from 29 different oligosaccharide compositions. Secondly, subclass-specific glycopeptides were identified on the basis of high-resolution MS and MS/MS data by using ultra high performance liquid chromatography (UHPLC) coupled to Q-TOF-MS. As a result, 83 IgG-Fc glycopeptides from human serum, including 17 sialylated glycopeptides, were identified. In addition, a quantitation method with high sensitivity and repeatability was established by using UHPLC triple quadrupole (QQQ) MS. We applied this approach to carry out quantitative analysis of IgG glycosylation in RA patients. Finally, 36 potential glycopeptide biomarkers, including 13 species from IgG1, 12 species from IgG2/3 and 11 species from IgG4 were identified.

Six oligomeric sesquiterpenoids, aggreganoids A-F (1-6), were isolated from Lindera aggregata. Aggreganoid A (1) and B (2) are two unprecedented methine- or methylene-bridged sesquiterpenoid trimers possessing a unique C46 skeleton. Aggreganoids C-F (3-6) are the first examples of carbon-bridged disesquiterpenoids with a C33 or C31 skeleton in the plant kingdom. Their structures and absolute configurations were elucidated by using spectroscopic methods and electronic circular dichroism calculations. A plausible biosynthetic pathway of these compounds was also proposed.

A phenanthroindolizidine glycoside 6-O-β-D-glucopyranosyl-tylophorinidine (1), the first glycoside of phenanthroindolizidine alkaloid in nature, was isolated from whole plants of Tylophora atrofolliculata (Asclepiadaceae). Its structure was elucidated by means of spectral and chemical evidences. Compound 1 showed potent inhibitory effect (IC50: 69 ± 13 nM) on hypoxia induced factor-1 (HIF-1) activation. It was discovered that glucosylation at C-6 of 1 could lead to reduction in cytotoxicity against normal cells and enhance its selectivity in tumor cells inhibition.

Increasing attention has been directed to Talaromyces marneffei (T. marneffei) infection in HIV-negative patients due to its high mortality rate. However, nonspecific symptoms and biological characteristics similar to those of other common pathogenic fungi complicate the rapid and accurate diagnosis of T. marneffei infection. Sphingolipids (SPLs) are bioactive lipids involved in the regulation of various physiological and pathological processes and have been identified as serum biomarkers for several diseases. This study employed a sphingolipidomic approach established in our previous work to explore the use of serum SPLs in the diagnosis of HIV-negative patients with T. marneffei infection. Additional clinical cohorts of patients infected with other microorganisms were also recruited. We found that sphinganine (Sa) (d16:0) exhibited obvious depletion after infection; moreover, its level in patients with T. marneffei infection was significantly lower than that in patients infected with other microorganisms. Therefore, Sa (d16:0) was considered a specific diagnostic biomarker for T. marneffei infection, and 302.71 nM was selected as the optimal cutoff value with a diagnostic sensitivity of 87.5% and specificity of 100%. These results suggested that determination of serum Sa (d16:0) levels can be used as a new alternative tool for the rapid diagnosis of T. marneffei infection in HIV-negative patients.

Pezzini et al. reported an unconventional mass enhancement in topological nodal line semimetal ZrSiS (Nat. Phys. 14, 178 (2018), whose origin remains puzzling. In this material, strong short-range interactions might induce excitonic particle-hole pairs. Here we study the renormalization of fermion velocities and find that the mass enhancement in ZrSiS can be well understood if we suppose that ZrSiS is close to the quantum critical point between semimetal and excitonic insulator. Near this quantum critical point, the fermion velocities are considerably reduced by excitonic quantum fluctuation, leading to fermion mass enhancement. The quasiparticle residue is suppressed as the energy decreases but is finite at zero energy. This indicates that ZrSiS is a strongly correlated Fermi liquid, and explains why the mass enhancement is weaker than non-Fermi liquids. Our results suggest that ZrSiS is a rare example of 3D topological semimetal exhibiting unusual quantum criticality., Comment: 6+11 pages, 4+1 figures, 1 table

This study aimed to explore the prognostic factors for primary gastric diffuse large B-cell lymphoma (PG-DLBCL).This retrospective study analyzed 72 PG-DLBCL patients between January 2012 and December 2017 in the Shanxi Cancer Hospital of Shanxi Medical University to identify the different prognostic factors in PG-DLBCL. The clinical features, treatment, and follow-up information were analyzed.The low CD4:CD8 ratio group (median subsequent overall survival [OS]: 36.06 months; 95% confidence interval [CI]: 25.73-46.40) showed a significant decrease in subsequent OS compared to the normal group among PG-DLBCL patients who were newly diagnosed and did not receive rituximab (median OS: 52.58 months; 95% CI: 44.18-60.97; p=0.029). Event-free survival status 24 months after the date of diagnosis (EFS24) also decreased significantly in the low CD4:CD8 group (median EFS24: 16.27 months; 95% CI: 13.09-19.45) compared to the normal group (median EFS24: 20.34 months; 95% CI: 17.05-23.63; p=0.014). Multivariate analysis showed that low CD4:CD8 at diagnosis was an independent poor prognostic factor for subsequent OS and EFS24.Our data suggest that identifying prognostic factors, especially host immunity, may provide useful information for assessing prognosis or clinical management.Bu çalışmada primer gastrik diffüz büyük B hücreli lenfoma (PG-DLBCL) için prognostik faktörler araştırıldı.Bu retrospektif çalışmada, Shanxi Tıp Üniversitesi’nin Shanxi Kanser Hastanesi’nde Ocak 2012 ile Aralık 2017 arasında 72 PG-DLBCL hastası incelendi ve PG-DLBCL’deki farklı prognostik faktörler incelendi. Klinik özellikler, tedavi ve takip bilgileri analiz edildi.Yeni tanı almış ve rituksimab kullanmamış PG-DLBCL hastalarında, CD4: CD8 oranı düşük olan grupta genel sağkalım (medyan genel sağkalım [OS]: 36,06 ay; %95 güven aralığı [GA]: 25,73-46,40) normal gruba kıyasla (medyan OS: 52,58 ay;% 95 GA: 44,18-60,97; p=0,029) anlamlı olarak düşük bulundu. Tanı tarihinden 24 ay sonraki olaysız sağkalım (EFS24) gene CD4: CD8 düşük olan grupta (ortanca EFS24: 16,27 ay; %95 GA: 13,09-19,45) normal gruba (ortanca EFS24: 20,34; %95 GA: 17,05-23,63; p=0,014) göre önemli ölçüde düşüktü. Çok değişkenli analiz, tanıdaki düşük CD4: CD8 oranının sonraki OS ve EFS24 için bağımsız bir kötü prognostik faktör olduğunu gösterdi.Verilerimiz, özellikle konakçı bağışıklığı olmak üzere prognostik faktörlerin tanımlanmasının, prognozu veya klinik yönetimi değerlendirmek için yararlı bilgiler sağlayabileceğini düşündürmektedir.

Due to its relatively small size, homology to humans, and susceptibility to human viruses, the tree shrew becomes an ideal alternative animal model for the study of human viral infectious diseases. However, there is still no report for the comprehensive glycan profile of the respiratory tract tissues in tree shrews. In this study, we characterized the structural diversity of N-glycans in the respiratory tract of tree shrews using our well-established TiO

Objectives: Ankylosing spondylitis (AS) is a chronic, inflammatory condition that particularly affects the spine. Adalimumab, an anti-TNF-α agent, is frequently used to suppress autoimmune responses in patients with active AS; however, the immune cell subsets change and their states during the course of AS remain unknown. In the present study, we aimed to comprehensively estimate the single-cell level transcriptional changes in peripheral blood mononuclear cells (PBMCs) after adalimumab treatment in the AS patient. Methods: A droplet-based platform was used to perform single-cell multiomics sequencing of PBMCs obtained from patients during the pre-adalimumab or post-adalimumab treatment phase. Multiomics analysis, including single-cell level unbiased transcriptome, surface protein expression (CITE-seq), and T cell receptor repertoire, was performed using the single-cell omics data from the AS patient. Results: TNF-alpha-induced genes, such as Egr1 and FOS, were remarkably decreased after treatment with adalimumab via single-cell profiling of monocytes, which demonstrated the comprehensive impact of adalimumab treatment. Dominant T-cell clonotypes with paired alpha and beta chains, such as the TRAV13-2/TRBV6-5 clones, were identified in patients with AS before adalimumab treatment. Conclusions: Our findings demonstrate the feasibility of applying single-cell level multiomics to identify the detailed inflammatory immune signatures of AS in response to adalimumab. Furthermore, comparative analysis predicted that most differentially expressed genes before and after treatment could potentially be used as novel candidate target genes, which may be beneficial for the AS patient. Funding Statement: Ministry of Science and Technology (MOST-107-2314-B-009-005-MY2, MOST-109-2314-B-009-003-MY3), Center For Intelligent Drug Systems and Smart Bio-devices (IDS2B) of National Chiao Tung University in Taiwan, and University System of Taiwan Joint Research Program (VGHUST108-G2-2-1, VGHUST109-V2-1-2) for their support. Declaration of Interests: None declared. Ethics Approval Statement: This investigation (CE19024B) was approved by the Institutional Review Board and the Ethics Committee of the Taichung Veterans General Hospital, Taichung, Taiwan. Written informed consent was obtained from the subjects or their family members in accordance with the institutional requirements and Declaration of Helsinki principles.

T lymphocytes produced by the thymus are essential mediators of immunity. Accelerated thymic atrophy appears in the patients with administration of glucocorticoids (GCs) which are commonly-used drugs to treat autoimmune and infectious diseases, leading to dysregulation of immunity with manifestation of progressive diminution of new T cell production. However, there is no ideal method to overcome such side effects of GCs. In the current study, we proposed a composition of dexamethasone (DEX) and dihydromyricetin (DMY) derived from a medicinal plant, which could protect from DEX-induced thymus damage and simultaneously enhance the anti-inflammatory effect of DEX. In the current study, we found that DEX-damaged thymic cellularity and architecture, reduced thymocyte numbers, induced thymocyte apoptosis and dropped CD4+ and CD8+ double positive T cell numbers in thymus which was effectively improved by co-treatment with DMY. Quantification of signal joint TCR delta excision circles (TRECs) and Vβ TCR spectratyping analysis were employed to determine the thymus function with indicated treatments. The results showed that DEX-impaired thymus output and decreased TCR cell diversity which was ameliorated by co-treatment with DMY. iTRAQ 2D LC-MS/MS was applied to analyze the proteomic profiling of thymus of mice treated with or without indicated agents, followed by informatics analysis to identify the correlated signaling pathway. After validated by Western blotting and Real-time PCR, we found that PPARγ-associated fatty acid metabolism was increased in the thymic tissues of the animals treated with DMY plus DEX than the animals treated with DEX alone. The agonist and antagonist of PPARγ were further employed to verify the role of PPARγ in the present study. Furthermore, DMY demonstrated a synergistic effect with co-administration of DEX on suppressing inflammation in vivo. Collectively, DMY relieved thymus function damaged by DEX via regulation of PPARγ-associated fatty acid metabolism. Our findings may provide a new strategy on protection of thymus from damage caused by GCs by using appropriate adjuvant natural agents through up-regulation of PPARγ-associated fatty acid metabolism.

Deep profiling of glycosphingolipids and sphingomyelins in wild Cordyceps was carried out by using offline chromatographic enrichment followed by ultrahigh performance liquid chromatography-ultrahigh definition-quadrupole time-of-flight mass spectrometry (UHPLC-UHD-Q-TOF-MS). A total of 119 glycosphingolipids (72 new ones) and 87 sphingomyelins (43 new ones) were identified from wild Cordyceps on the basis of the accurate mass and MS/MS fragmentations, isotope patterns, sphingolipid (SPL) database matching, confirmation by SPL standards, and the reversed-phase liquid chromatographic retention rule. This study is the most comprehensive report on the identification of glycosphingolipids and sphingomyelins from fungus. A subsequent lipopolysaccharide-induced mouse splenic lymphocyte proliferation assay showed that the Cordyceps glycosphingolipid fraction exhibits higher immunosuppressive activity compared to that of Cordyceps sphingomyelins. Our findings provided insight into the chemical diversity of sphingolipids in Cordyceps and chemical evidence for the therapeutic application of wild Cordyceps.

Spheroid-based three-dimensional (3D) liver culture models, offering a desirable biomimetic microenvironment, are useful for recapitulating liver functions in vitro. However, a user-friendly, robust and specially optimized method has not been well developed for a convenient, highly efficient, and safe in situ perfusion culture of spheroid-based 3D liver models. Here, we have developed a biomimetic and reversibly assembled liver-on-a-chip (3D-LOC) platform and presented a proof of concept for long-term perfusion culture of 3D human HepG2/C3A spheroids for building a 3D liver spheroid model. On the basis of a fast and reversible seal of concave microwell-based PDMS-membrane-PDMS sandwich multilayer chips, it enables a high-throughput and parallel perfusion culture of 1080 cell spheroids in a high mass transfer and low fluid shear stress biomimetic microenvironment as well as allowing the convenient collection and analysis of the cell spheroids. In terms of reducing spheroid loss and maintaining cell morphology and viability in long-term perfusion culture, the cell spheroids in the 3D-LOC were more safe and efficient. Notably, the polarisation, liver-specific functions, and metabolic activity of the cell spheroids in 3D-LOC were also remarkably improved and exhibited better long-term maintenance over conventional perfusion methods. Additionally, a robust micromilling method that incorporates secondary PDMS coating techniques (SPCs) for fabricating V-shaped concave microwells was also developed. The V-shaped concave microwell arrays exhibited a higher distribution density and aperture ratio, making it easy to form large-scale and uniform-sized cell spheroids with minimum cell loss. In summary, the proposed 3D-LOC could provide a convenient and robust solution for the long-term safe perfusion culture of hepatic spheroids and be beneficial for a variety of potential applications including development of bio-artificial livers, disease modeling, and drug toxicity screening.

N-linked glycans on immunoglobulin G (IgG) have been associated with pathogenesis of diseases and the therapeutic functions of antibody-based drugs; however, low-abundance species are difficult to detect. Here we show a glycomic approach to detect these species on human IgGs using a specialized microfluidic chip. We discover 20 sulfated and 4 acetylated N-glycans on IgGs. Using multiple reaction monitoring method, we precisely quantify these previously undetected low-abundance, trace and even ultra-trace N-glycans. From 277 patients with rheumatoid arthritis (RA) and 141 healthy individuals, we also identify N-glycan biomarkers for the classification of both rheumatoid factor (RF)-positive and negative RA patients, as well as anti-citrullinated protein antibodies (ACPA)-positive and negative RA patients. This approach may identify N-glycosylation-associated biomarkers for other autoimmune and infectious diseases and lead to the exploration of promising glycoforms for antibody therapeutics., Post-translational modifications can affect antibody function in health and disease, but identification of all variants is difficult using existing technologies. Here the authors develop a microfluidic method to identify and quantify low-abundance IgG N-glycans and show some of these IgGs can be used as biomarkers for rheumatoid arthritis.

We perform a systematic investigation on the effects of Ba and La doping on the lattice and transport properties of Sr2IrO4, which is theoretically predicted to be a host compound of high-temperature superconductivity. We observe a drastic straightening of the Ir–O–Ir bond angle in the Ba-doped samples. The straightening of the bond angle is much weaker in the La-doped samples. It is found that the La doping leads to the introduction of electron-type charge carriers, while the charge carrier concentration does not change too much in the Ba-doped samples. As a result, both the resistivity and the magnetic moments decrease much faster in the La-doped samples, compared to those in the Ba-doped samples. The present results suggest that it is the charge carrier density rather than the Ir–O–Ir bond angle that dominates the magnetic and transport properties of the Sr2IrO4 system.

SmPO4 coated Li1.2Mn0.54Ni0.13Co0.13O2 cathode materials were prepared by the precipitation method and calcined at 450 °C. The crystal structures and electrochemical properties of the pristine and coated samples are studied by X-ray diffraction, scanning electron microscopy, high resolution transmission electron microscopy, electron diffraction spectroscopy, galvanostatic cycling, cyclic voltammetry, and electrochemical impedance spectroscopy (EIS). It has been found that the electrochemical performances of the Li-rich cathode material have been substantially improved by SmPO4 surface coating. Especially, the 2 wt% SmPO4-coated sample demonstrates the best cycling performance, with capacity retention of 88.4% at 1 C rate after 100 cycles, which is much better than that of 72.3% in the pristine sample. The improved electrochemical properties have been ascribed to the SmPO4 coating layer, which not only stabilizes the cathode structure by decreasing the loss of oxygen, but also protects the Li-rich cathode material from side reaction with the electrolyte and increases the Li+ migration rate at the cathode interface.

// Betty Yuen Kwan Law 1 , Flora Gordillo-Martinez 1 , Yuan Qing Qu 1 , Ni Zhang 1 , Su Wei Xu 1 , Paolo Saul Coghi 1 , Simon Wing Fai Mok 1 , Jianru Guo 1 , Wei Zhang 1 , Elaine Lai Han Leung 1 , Xing Xing Fan 1 , An Guo Wu 1 , Wai Kit Chan 1 , Xiao Jun Yao 1 , Jing Rong Wang 1 , Liang Liu 1 , Vincent Kam Wai Wong 1 1 Macau Institute for Applied Research in Medicine and Health, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China Correspondence to: Vincent Kam Wai Wong, email: bowaiwong@gmail.com Liang Liu, email: lliu@must.edu.mo Keywords: thalidezine, AMPK activator, autophagy, autophagic cell death, apoptosis-resistant cancer Received: October 22, 2016 Accepted: January 27, 2017 Published: February 22, 2017 ABSTRACT Cancers illustrating resistance towards apoptosis is one of the main factors causing clinical failure of conventional chemotherapy. Innovative therapeutic methods which can overcome the non-apoptotic phenotype are needed. The AMP-activated protein kinase (AMPK) is the central regulator of cellular energy homeostasis, metabolism, and autophagy. Our previous study showed that the identified natural AMPK activator is able to overcome apoptosis-resistant cancer via autophagic cell death. Therefore, AMPK is an ideal pharmaceutical target for chemoresistant cancers. Here, we unravelled that the bisbenzylisoquinoline alkaloid thalidezine is a novel direct AMPK activator by using biolayer interferometry analysis and AMPK kinase assays. The quantification of autophagic EGFP-LC3 puncta demonstrated that thalidezine increased autophagic flux in HeLa cancer cells. In addition, metabolic stress assay confirmed that thalidezine altered the energy status of our cellular model. Remarkably, thalidezine-induced autophagic cell death in HeLa or apoptosis-resistant DLD-1 BAX-BAK DKO cancer cells was abolished by addition of autophagy inhibitor (3-MA) and AMPK inhibitor (compound C). The mechanistic role of autophagic cell death in resistant cancer cells was further supported through the genetic removal of autophagic gene7 (Atg7). Overall, thalidezine is a novel AMPK activator which has great potential to be further developed into a safe and effective intervention for apoptosis- or multidrug-resistant cancers.

Davidiin, a natural product originating from Polygonum capitatum, has been proven to possess anti-hepatocellular carcinoma activity. To explore the mechanisms underlying the activity of davidiin, sphingolipids (SPLs) in HepG2 human hepatocellular carcinoma cells with or without the treatment of davidiin were comprehensively analyzed using an improved sphingolipidomic approach established in our lab. A total of 133 SPLs were identified and quantified by using the multiple reaction monitoring (MRM) technique. The results revealed an extensive elevation of dihydroceramide (DHCer) and sphinganine (Sa) induced by davidiin in HepG2 cells, which potentially mediate the cytotoxicity of davidiin. Based on the alteration of upstream and downstream products in the biosynthesis and metabolism network of SPLs, the elevated DHCer and Sa are proposed to result from the inhibition effect of davidiin on dihydroceramide desaturase (DES), which was further confirmed by in vitro assay. Given the emerging role of DES as a therapeutic target of cancer, our results not only provided evidence for the mechanisms underlying the cytotoxicity of davidiin, but also underscored the potential of ellagitannin as a new group of aromatic natural products acting on DES.

Ankylosing spondylitis (AS) is a chronic inflammatory disease with poorly defined aetiologies and no curative treatments. The average delay in the diagnosis of AS is 6–8 years.1 Human leukocyte antigen B27 (HLA-B27) is a key laboratory marker for AS presenting in at least 90% of patients with AS.2 However, 63%–90% of patients with reactive arthritis3 and 19.2% of patients with psoriatic arthritis (PsA)4 are also positive for HLA-B27, indicating low specificity of HLA-B27. The risk of development of AS in an HLA-B27-positive individual is only 2%–10%,5 which suggests the limited value of HLA-B27 in supporting an AS diagnosis. Moreover, reported serum biomarkers for AS have generally exhibited low sensitivity or specificity6 (

Resistance of cancer cells to chemotherapy is a significant clinical concern and mechanisms regulating cell death in cancer therapy, including apoptosis, autophagy or necrosis, have been extensively investigated over the last decade. Accordingly, the identification of medicinal compounds against chemoresistant cancer cells via new mechanism of action is highly desired. Autophagy is important in inducing cell death or survival in cancer therapy. Recently, novel autophagy activators isolated from natural products were shown to induce autophagic cell death in apoptosis-resistant cancer cells in a calcium-dependent manner. Therefore, enhancement of autophagy may serve as additional therapeutic strategy against these resistant cancers. By computational docking analysis, biochemical assays, and advanced live-cell imaging, we identified that neferine, a natural alkaloid from Nelumbo nucifera, induces autophagy by activating the ryanodine receptor and calcium release. With well-known apoptotic agents, such as staurosporine, taxol, doxorubicin, cisplatin and etoposide, utilized as controls, neferine was shown to induce autophagic cell death in a panel of cancer cells, including apoptosis-defective and -resistant cancer cells or isogenic cancer cells, via calcium mobilization through the activation of ryanodine receptor and Ulk-1-PERK and AMPK-mTOR signaling cascades. Taken together, this study provides insights into the cytotoxic mechanism of neferine-induced autophagy through ryanodine receptor activation in resistant cancers.

Influence of short-range four-fermion interactions on quadratic and cubic nodal line fermion systems is studied by renormalization group theory. It is found that arbitrarily weak four-fermion interaction could drive quadratic or cubic nodal line fermion system to a new phase. According to the initial conditions and value of fermion flavor, the system may appear three kinds of instabilities. First, quadratic or cubic nodal line is split into conventional nodal lines, thus the system becomes nodal line semimetal. Second, finite excitonic gap is generated, and the system becomes an excitonic insulator. Third, the system is driven into superconducting phase. Thus, quadratic and cubic nodal line fermion systems are rare strong correlated fermion systems in three dimension under the influence of four-fermion interactions. These theoretical results may be verified in the candidates for quadratic and cubic nodal line fermion systems., 19 pages, 10 figures