The novel HLA-DPA1*02:117 allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.

HLA-DPA1*02:117 differs from HLA-DPA1*02:02:02:01 by one nucleotide in exon 2.

The novel HLA-B*38:103N allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.

HLA-B*38:103N differs from HLA-B*38:02:01:01 by one nucleotide in exon 3.

Ferroelectric BaTiO3 Regulating the Local Electric Field for Interfacial Stability in Solid-State Lithium Metal Batteries.

Solid-state Li metal batteries (SSLMBs) are widely investigated since they possess promising energy density and high safety. However, the poor interfacial compatibility between the electrolyte and electrodes limits their promising development. Herein, a robust composite electrolyte (poly(vinyl ethylene carbonate) electrolyte with 3 wt % of BaTiO3, PVEC-3BTO) with excellent interfacial performance is rationally designed by incorporating ferroelectric BaTiO3 (BTO) nanoparticles into the poly(vinyl ethylene carbonate) (PVEC) electrolyte matrix. Benefiting from the high dielectric constant and ferroelectric properties of BTO, the interfacial compatibility between electrolytes and electrodes was significantly improved. The enhanced Li+ transference number (0.64) of solid electrolyte and in situ generated BaF2 inorganic interphase contribute to the enhanced cycling stability of PVEC-3BTO based Li//Li symmetrical batteries. Furthermore, the antioxidation ability of PVEC-3BTO has also been enhanced by modulating the local electric field for good pairing with high-voltage LiCoO2 material. Therefore, in this work, the mechanism of BTO for improving interfacial compatibility is revealed, and also useful methods for addressing the interface issues of SSLMBs have been provided.

The novel HLA-C*17:69 allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.

HLA-C*17:69 differs from HLA-C*17:01:01:02 by one nucleotide in exon 4.

The novel HLA-B*54:01:12 allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.

HLA-B*54:01:12 differs from HLA-B*54:01:01:01 by one nucleotide in exon 2.

The novel HLA-C*01:255 allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.

HLA-C*01:255 differs from HLA-C*01:02:01:01 by one nucleotide in exon 2.

The novel HLA-DPB1*1497:01 allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.

HLA-DPB1*1497:01 differs from HLA-DPB1*05:01:01:01 by one nucleotide in exon 4.

The novel HLA-B*27:267 allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.

HLA-B*27:267 differs from HLA-B*27:04:01 by one nucleotide in exon 2.

Increased α-HB links colorectal cancer and diabetes by potentiating NF-κB signaling.

Sufficient evidence has linked many different types of cancers and T2D through shared risk factors; however, the underlying mechanisms are not fully understood. α-Hydroxybutyrate (α-HB), a byproduct metabolite increased in diabetes and cancer, including colorectal cancer (CRC), triggers lactate dehydrogenase A (LDHA) nuclear translocation. Nuclear LDHA markedly extends NF-κB nuclear retention by interacting with phosphorylated p65, leading to an increase in TNF-α production, impaired insulin secretion and the exacerbation of azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CRC and high-fat diet (HFD)-induced type 2 diabetes. Furthermore, metformin interrupted this process by inhibiting the transcription of FOXM1 and c-MYC, the resultant downregulation of LDHA expression and α-HB-induced LDHA nuclear translocation. Thus, the results reveal the elevated α-HB level could be a novel shared risk factor of linking CRC, diabetes and the use of metformin treatment, as well as highlight the importance of preventing NF-κB activation for protecting against cancer and diabetes.

Screening and oenological property analysis of ethanol-tolerant non-Saccharomyces yeasts isolated from Rosa roxburghii Tratt.

Ethanol tolerance is crucial for the oenological yeasts. Rosa roxburghii Tratt, a Rosaceae plant native to China, is rich in nutritional and medicinal ingredients. In this study, ethanol-tolerant non-Saccharomyces yeasts were screened, and their oenological properties were further evaluated. Three ethanol-tolerant yeast strains (designated as C6, F112, and F15), which could tolerate 12% (v/v) ethanol treatment, were isolated from R. roxburghii, and identified as Candida tropicalis, Pichia guilliermondii, and Wickerhamomyces anomalus, respectively. The winemaking condition tolerances of these ethanol-tolerant yeast strains were similar to those of Saccharomyces cerevisiae X16. However, their growth, sugar metabolic performance and sulphureted hydrogen activities, were different. The ß-glucosidase production ability of strain W. anomalus F15 was lower than that of S. cerevisiae X16, and strains of C. tropicalis C6 and P. guilliermondii F112 were similar to S. cerevisiae X16. Electronic sensory properties of the R. roxburghii wines fermented using ethanol-tolerant yeasts together with S. cerevisiae showed no significant differences. However, the mixed inoculation of the ethanol-tolerant yeast strains with S. cerevisiae could regulate the volatile aroma characteristics of the fermented R. roxburghii wine, enriching and enhancing the aroma flavor. Therefore, the selected ethanol-tolerant yeasts have the potential for application in the production of unique R. roxburghii wine.

Nuclear complement C3b promotes paclitaxel resistance by assembling the SIN3A/HDAC1/2 complex in non-small cell lung cancer.

In addition to the classical role as a serum effector system of innate immunity, accumulating evidence suggests that intracellular complement components have indispensable functions in immune defense, T cell homeostasis, and tumor cell proliferation and metastasis. Here, we revealed that complement component 3 (C3) is remarkably upregulated in paclitaxel (PTX)-resistant non-small cell lung cancer (NSCLC) cells and that knockdown of C3 promoted PTX-induced cell apoptosis, sensitizing resistant cells to PTX therapy. Ectopic C3 decreased PTX-induced apoptosis and induced resistance to PTX treatment in original NSCLC cells. Interestingly, C3b, the activated fragment of C3, was found to translocate into the nucleus and physically associate with the HDAC1/2-containing SIN3A complex to repress the expression of GADD45A, which plays an important role in cell growth inhibition and apoptosis induction. Importantly, C3 downregulated GADD45A by enhancing the binding of the SIN3A complex with the promoter of GADD45A, thus decreasing the H3Ac level to compress chromatin around the GADD45A locus. Subsequently, ectopic GADD45A promoted PTX-induced cell apoptosis, sensitizing resistant cells to PTX therapy, and insufficiency of GADD45A in original cancer cells induced resistance to PTX treatment. These findings identify a previously unknown nucleus location and oncogenic property for C3 in chemotherapy and provide a potential therapeutic opportunity to overcome PTX resistance.

Time-series prediction and detection of potential pathogens in bloodstream infection using mcfDNA sequencing.

Introduction: Next-generation sequencing of microbial cell free DNA (mcfDNA-seq) has emerged as a promising diagnostic method for blood stream infection (BSI) and offers the potential to detect pathogens before blood culture. However, its application is limited by a lack of clinical validation. Methods: We conducted sequential mcfDNA-seq on blood samples from ICU participants at high risk of BSI due to pneumonia, or intravascular catheterization; and explored whether mcfDNA-seq could diagnose and detect pathogens in advance of blood culture positivity. Blood culture results were used as evaluation criteria. Results: A total of 111 blood samples were collected during the seven days preceding and on the day of onset of 16 BSI episodes from 13 participants. The diagnostic and total predictive sensitivity of mcfDNA-seq were 90% and 87.5%, respectively. The proportion of pathogenic bacteria was relatively high in terms of both diagnosis and prediction. The reads per million of etiologic agents trended upwards in the days approaching the onset of BSI. Discussion: Our work found that mcfDNA-seq has high diagnostic sensitivity and could be used to identify pathogens before the onset of BSI, which could help expand the clinical application of mcfDNA-seq.

The novel HLA-C*06:02:105 allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.

HLA-C*06:02:105 differs from HLA-C*06:02:01:01 by one nucleotide in exon 1.

Molecular Self-Assembled Ether-Based Polyrotaxane Solid Electrolyte for Lithium Metal Batteries.

Poly(ethylene oxide) has been widely investigated as a potential separator for solid-state lithium metal batteries. However, its applications were significantly restricted by low ionic conductivity and a narrow electrochemical stability window (<4.0 V vs Li/Li+) at room temperature. Herein, a novel molecular self-assembled ether-based polyrotaxane electrolyte was designed using different functional units and prepared by threading cyclic 18-crown ether-6 (18C6) to linear poly(ethylene glycol) (PEG) via intermolecular hydrogen bond and terminating with hexamethylene diisocyanate trimer (HDIt), which was strongly confirmed by local structure-sensitive solid/liquid-state nuclear magnetic resonance (NMR) techniques. The designed electrolyte has shown an obviously increased room-temperature ionic conductivity of 3.48 × 10-4 S cm-1 compared to 1.12 × 10-5 S cm-1 without assembling polyrotaxane functional units, contributing to the enhanced cycling stability of batteries with both LiFePO4 and LiNi0.8Co0.15Al0.05O2 cathode materials. This advanced molecular self-assembled strategy provides a new paradigm in designing solid polymer electrolytes with demanded performance for lithium metal batteries.

CD59-Regulated Ras Compartmentalization Orchestrates Antitumor T-cell Immunity.

T cell-mediated immunotherapy represents a promising strategy for cancer treatment; however, it has achieved satisfactory clinical responses in only a limited population. Thus, a broader view of the T-cell immune response is required. The Ras/MAPK pathway operates in many important signaling cascades and regulates multiple cellular activities, including T-cell development, proliferation, and function. Herein, we found that the typical membrane-bound complement regulatory protein CD59 is located intracellularly in T cells and that the intracellular form is increased in the T cells of patients with cancer. When intracellular CD59 is abundant, it facilitates Ras transport to the inner plasma membrane via direct interaction; in contrast, when CD59 is insufficient or deficient, Ras is arrested in the Golgi, thus enhancing Ras/MAPK signaling and T-cell activation, proliferation, and function. mCd59ab deficiency almost completely abolished tumor growth and metastasis in tumor-bearing mice, in which CD4+ and CD8+ T cells were significantly increased compared with their proportions in wild-type littermates, and their proportions were inversely correlated with tumor growth. Using bone marrow transplantation and CD4+ and CD8+ T-cell depletion assays, we further demonstrated the critical roles of these cells in the potent antitumor activity induced by mCd59ab deficiency. Reducing CD59 expression also enhanced MAPK signaling and T-cell activation in human T cells. Therefore, the subcellular compartmentalization of Ras regulated by intracellular CD59 provides spatial selectivity for T-cell activation and a potential T cell-mediated immunotherapeutic strategy.

Neutrophils activated by membrane attack complexes increase the permeability of melanoma blood vessels.

The microenvironment of malignant melanomas defines the properties of tumor blood vessels and regulates infiltration and vascular dissemination of immune and cancer cells, respectively. Previous research in other cancer entities suggested the complement system as an essential part of the tumor microenvironment. Here, we confirm activation of the complement system in samples of melanoma patients and murine melanomas. We identified the tumor endothelium as the starting point of the complement cascade. Generation of complement-derived C5a promoted the recruitment of neutrophils. Upon contact with the vascular endothelium, neutrophils were further activated by complement membrane attack complexes (MACs). MAC-activated neutrophils release neutrophil extracellular traps (NETs). Close to the blood vessel wall, NETs opened the endothelial barrier as indicated by an enhanced vascular leakage. This facilitated the entrance of melanoma cells into the circulation and their systemic spread. Depletion of neutrophils or lack of MAC formation in complement component 6 (C6)-deficient animals protected the vascular endothelium and prevented vascular intravasation of melanoma cells. Our data suggest that inhibition of MAC-mediated neutrophil activation is a potent strategy to abolish hematogenous dissemination in melanoma.

Clinical performance of quantitative PCR for the molecular identification of skeletal tuberculosis from formalin-fixed paraffin-embedded tissues.

BACKGROUND: At present, skeletal tuberculosis (TB) diagnosis is mostly by histopathology, but the positivity rate is low. There is a need to develop new methods for the molecular identification of this disorder. Therefore, we aimed to investigate the clinical utility of quantitative PCR (qPCR)-based diagnosis of skeletal TB from formalin-fixed paraffin-embedded (FFPE) tissues and its comparative evaluation with acid-fast bacillus staining (AFS). METHODS: We detected Mycobacterium tuberculosis (M. tuberculosis/MTB) DNA using qPCR and AFS in FFPE tissue samples from 129 patients suspected of having skeletal TB. The sensitivity, specificity as well as area under the curve (AUC) of qPCR and AFS were calculated. Meanwhile, some factors potentially affecting qPCR and AFS results were investigated. RESULTS: Overall, qPCR outperformed AFS in detecting M. tuberculosis. The AUC of qPCR was higher than that of AFS (0.744 vs.0.561, p < 0.001). Furthermore, decalcification of bone tissues did not affect the sensitivity and specificity of qPCR tests. Whereas it impacted the performance of AFS, decalcification increased AFS's specificity and decreased its sensitivity (p < 0.05). Moreover, qPCR had a significantly larger AUC than AFS in decalcified and non-decalcified groups (0.735/0.756 vs. 0.582/0.534, p < 0.001) respectively. Similarly, the AUC of PCR was more extensive than that of AFS regardless of skeletal TB patients with concomitant pulmonary TB or not (0.929 vs. 0.762; 0.688 vs. 0.524, p < 0.01). CONCLUSIONS: Our data demonstrate that qPCR offers superior accuracy for the detection of mycobacteria in FFPE tissues compared to traditional AFS, indicating its clinical value in osteoarticular TB diagnosis.

Intracellular complement C5a/C5aR1 stabilizes ß-catenin to promote colorectal tumorigenesis.

Complement is operative in not only the extracellular but also the intracellular milieu. However, little is known about the role of complement activation inside tumor cells. Here, we report that intracellular C5 is cleaved by cathepsin D (CTSD) to produce C5a in lysosomes and endosomes of colonic cancer cells. After stimulation by C5a, intracellular C5aR1 assembles a complex with KCTD5/cullin3/Roc-1 and ß-catenin to promote the switch of polyubiquitination of ß-catenin from K48 to K63, which enhances ß-catenin stability. Genetic loss or pharmacological blockade of C5aR1 dramatically impedes colorectal tumorigenesis at least by destabilizing ß-catenin. In human colorectal cancer specimens, high levels of C5aR1, C5a, and CTSD are closely correlated with elevated ß-catenin levels and a poor prognosis. Importantly, intracellular C5a/C5aR1-mediated ß-catenin stabilization is also observed ubiquitously in other cell types. Collectively, we identify a machinery for ß-catenin activation and provide a potential target for tumor prevention and treatment.

A thin free-standing composite solid electrolyte film for solid-state lithium metal batteries.

A thin free-standing composite solid electrolyte film (CSE, ∼15 µm) is prepared by a tape casting and solution infusion method, which owns a high ionic conductivity (2.76 × 10-4 S cm-1 at 25 °C) and a wide electrochemical stability window (4.8 V vs. Li+/Li). The CSE-based solid-state lithium metal batteries with the LiCoO2 cathode present good cycling stability and capacity retention with a 4.5 V cut-off voltage.

A Targeted Complement Inhibitor CRIg/FH Protects Against Experimental Autoimmune Myasthenia Gravis in Rats via Immune Modulation.

Antibody-induced complement activation may cause injury of the neuromuscular junction (NMJ) and is thus considered as a primary pathogenic factor in human myasthenia gravis (MG) and animal models of experimental autoimmune myasthenia gravis (EAMG). In this study, we tested whether CRIg/FH, a targeted complement inhibitor, could attenuate NMJ injury in rat MG models. We first demonstrated that CRIg/FH could inhibit complement-dependent cytotoxicity on human rhabdomyosarcoma TE671 cells induced by MG patient-derived IgG in vitro. Furthermore, we investigated the therapeutic effect of CRIg/FH in a passive and an active EAMG rodent model. In both models, administration of CRIg/FH could significantly reduce the complement-mediated end-plate damage and suppress the development of EAMG. In the active EAMG model, we also found that CRIg/FH treatment remarkably reduced the serum concentration of autoantibodies and of the cytokines including IFN-γ, IL-2, IL-6, and IL-17, and upregulated the percentage of Treg cells in the spleen, which was further verified in vitro. Therefore, our findings indicate that CRIg/FH may hold the potential for the treatment of MG via immune modulation.