Allergic conversion of protective mucosal immunity against nasal bacteria in patients with chronic rhinosinusitis with nasal polyposis

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Deleting the BAFF receptor TACI protects against systemic lupus erythematosus without extensive reduction of B cell numbers

B cell-activating factor of the TNF family (BAFF) is an essential B cell survival factor. However, high levels of BAFF promote systemic lupus erythematosus (SLE) in mice and humans. Belimumab (anti-human BAFF) limits B cell survival and is approved for use in patients with SLE. Surprisingly, the efficacy of rituximab (anti-human CD20) in SLE remains controversial, despite depleting B cells more potently than belimumab. This raises the question of whether B cell depletion is really the mechanism of action of belimumab. In BAFF transgenic mice, SLE development is T cell-independent but relies on innate activation of B cells via TLRs, and TLR expression is modulated by the BAFF receptor TACI. Here, we show that loss of TACI on B cells protected against BAFF-mediated autoimmune manifestations while preserving B cells, suggesting that loss of BAFF signaling through TACI rather than loss of B cells may underpin the effect of belimumab in the clinic. Therefore, B cell-sparing blockade of TACI may offer a more specific and safer therapeutic alternative to broad B cell depletion in SLE.     

C-terminal region of activation-induced cytidine deaminase (AID) is required for efficient class switch recombination and gene conversion

Activation-induced cytidine deaminase (AID) introduces single-strand breaks (SSBs) to initiate class switch recombination (CSR), gene conversion (GC), and somatic hypermutation (SHM). CSR is mediated by double-strand breaks (DSBs) at donor and acceptor switch (S) regions, followed by pairing of DSB ends in two S regions and their joining. Because AID mutations at its C-terminal region drastically impair CSR but retain its DNA cleavage and SHM activity, the C-terminal region of AID likely is required for the recombination step after the DNA cleavage. To test this hypothesis, we analyzed the recombination junctions generated by AID C-terminal mutants and found that 0- to 3-bp microhomology junctions are relatively less abundant, possibly reflecting the defects of the classical nonhomologous end joining (C-NHEJ). Consistently, the accumulation of C-NHEJ factors such as Ku80 and XRCC4 was decreased at the cleaved S region. In contrast, an SSB-binding protein, poly (ADP)-ribose polymerase1, was recruited more abundantly, suggesting a defect in conversion from SSB to DSB. In addition, recruitment of critical DNA synapse factors such as 53BP1, DNA PKcs, and UNG at the S region was reduced during CSR. Furthermore, the chromosome conformation capture assay revealed that DNA synapse formation is impaired drastically in the AID C-terminal mutants. Interestingly, these mutants showed relative reduction in GC compared with SHM in chicken DT40 cells. Collectively, our data indicate that the C-terminal region of AID is required for efficient generation of DSB in CSR and GC and thus for the subsequent pairing of cleaved DNA ends during recombination in CSR.Activation-induced cytidine deaminase (AID) is essential for three different genetic events: class switch recombination (CSR), gene conversion (GC), and somatic hypermutation (SHM), which contribute to Ig gene diversification (1–5). Although AID generates single-strand breaks (SSBs) in the Ig genes, subsequent repair steps for CSR and GC are similar to each other but are distinct from SHM in their mechanistic properties, i.e, in (i) generation of the double-strand breaks (DSBs), (ii) recombination, and (iii) the requirement for uracil-DNA-glycosylase (UNG) for the pairing of the DSB ends (6–10). Despite the similarities between GC and CSR, their repair mechanisms have distinct features: CSR recombination requires nonhomologous end joining (NHEJ), and GC depends on homologous recombination (HR). During CSR, DSB ends normally are joined by classical NHEJ (C-NHEJ), which requires specific repair proteins such as Ku80, XRCC4, or DNA ligase IV (11, 12). In the absence of C-NHEJ, a back-up end-joining pathway called “alternative end joining” (A-EJ), which is reported to be slower and also more error prone than C-NHEJ, joins the broken DSBs ends (13). On the other hand, HR, the most common form of homology-directed repair, requires long sequence homology between donor and acceptor DNA to complete the recombination step by recruiting a distinct set of repair proteins such as RAD54, RAD52, and RAD51 to the break sites (14, 15).Various studies on AID mutations in the N-terminal or C-terminal regions (4, 8, 9, 16–19) have shown that N-terminal AID mutants are compromised for CSR and are defective in SHM, indicating that the N-terminal region of AID is required for DNA cleavage (9, 16, 19). On the other hand, the C-terminal region of AID, which contains a nuclear-export signal and is responsible for AID’s shuttling activity between the nucleus and cytoplasm, is required for CSR-specific activity but not for DNA cleavage activity and SHM (8, 16). Among the series of AID C-terminal mutants examined, two mutants show characteristic features: P20, which has an insertion of 34 amino acids at residue 182 and normal nuclear-cytoplasmic shuttling activity, and JP8Bdel, which has a 16-amino acid truncation at residue 183, accumulates in the nucleus, and shows higher DNA break activity at the donor switch (S) region (16, 17). Although several reports suggest that the C-terminal region of AID is involved in protein stability (20, 21), C-terminal mutants of AID stabilized by fusing the hormone-binding domain of estrogen receptor (ER) also show similar CSR-defective phenotypes (8). Taken together, these data suggest that the DNA cleavage activity and CSR-specific activity depend on different regions of AID (8, 19). In addition, the C-terminal region of AID is essential for the interaction of AID with poly (A)⁺ RNA via a specific cofactor (22). Because CSR requires de novo protein synthesis, we proposed that after DNA cleavage the C-terminal region of AID may be involved in the regulation of the recombination step through generation of a new protein (8, 16, 22).DSBs induced by AID during CSR ultimately are joined by the efficient DNA repair pathway that requires C-NHEJ factors such as Ku70/80 (12, 23). However, in the absence of C-NHEJ, the A-EJ pathway that relies on microhomology can join the broken DNA ends, although this pathway is associated with chromosomal translocations (11, 24). Previously, we reported that JP8Bdel enhances aberrant c-myc/IgH translocations and that it fails to carry out the efficient recombination between donor and acceptor S regions in the IgH locus (8). Therefore, it is important to examine whether the AID C-terminal mutants affect the S–S joining in CSR.In the current work we examined whether the C-terminal region of AID is involved in DNA synapse formation and recombination during CSR in CH12F3-2 and spleen B cells. We also examined the effect of AID C-terminal mutations on GC in chicken DT40 cells, which depends on HR between pseudo V genes and the downstream IgVλ region. Using these CSR- and GC-monitoring systems, we demonstrate that efficient CSR and GC require the C-terminal region of AID for the formation of DSB from SSB and subsequent end synapse. Considering these findings together, we conclude that, in addition to DNA cleavage, AID has a unique function in the generation of DSBs, which is required for S–S synapse formation and joining in CSR and recombination in GC.     

归芪活血胶囊对神经根型颈椎病大鼠炎性损伤和微循环血流的影响

目的：探究归芪活血胶囊（GQ）对神经根型颈椎病（CSR）大鼠的治疗效应及机制。方法：观察CSR大鼠自发痛、热痛阈、步态评分、前肢和颈部体表微循环状态、脊髓病理结构及超微结构变化、脊髓p38磷酸化情况以及血清白细胞介素-1β（IL-1β）、IL-6以及肿瘤坏死因子-α（TNF-α）。结果：GQ高、中剂量在干预第14天时可显著升高CSR模型大鼠的热痛阈（P<0.05）,降低其步态评分和自发痛评分（P<0.05,P<0.01）;GQ各剂量均可改善CSR大鼠脊髓炎症水肿变化,显著增加尼氏（Nissl）染色阳性细胞数目（P<0.05）,恢复髓鞘和线粒体正常形态,且GQ中剂量效果较明显;GQ高、中剂量可显著升高CSR大鼠颈部和前肢皮肤血流灌注量（P<0.05）,对前肢远端血流灌注量的改善程度优于芬必得组（P<0.01）;与模型组比较,GQ中剂量可降低CSR大鼠脊髓p38磷酸化比率。结论：GQ可以缓解CSR大鼠热痛觉过敏和步态不稳的程度,改善脊髓炎症病理变化,恢复前肢和颈部体表血流灌注量,且GQ中剂量在改善CSR大鼠炎症损伤方面更有优势。     

Brain natriuretic peptide in patients with congestive heart failure and central sleep apnea

STUDY OBJECTIVE: To assess the possible relationship between Cheyne-Stokes respiration (CSR) associated with central sleep apnea (CSA) syndrome and brain natriuretic peptide (BNP) in an outpatient population presenting with stable congestive heart failure (CHF). MEASUREMENTS AND RESULTS: Ninety patients with CHF due to systolic dysfunction (left ventricular ejection fraction CSR-CSA and determination of the BNP level. The correlation between BNP levels and the apnea-hypopnea index (AHI) and desaturation index (DI) was evaluated, as was the accuracy of BNP in identifying CHF-associated CSR-CSA, as determined by the area under the receiver operating characteristic (ROC) curve. Possible confounding variables were assessed, and a stepwise multiple regression analysis was applied to identify those factors that best predicted the variability in BNP levels. Five of the 90 patients were excluded from the study as they presented with obstructive sleep apnea syndrome. Of the remaining 85 patients, 25 (28%) presented with associated CSR-CSA. The mean (+/-SEM) BNP level was higher in this group (166.44 +/- 29.6 pg/mL) than in the group with isolated CHF (62.01 +/- 13.6 pg/mL; p < 0.001). There was a moderate correlation between BNP levels and AHI. The ROC curve that best identified CSR-CSA was obtained with a BNP cutoff value of 116.25 pg/mL (sensitivity, 62%; specificity, 92%; accuracy, 83%). Differences between the two groups in terms of BNP levels persisted after adjusting for the confounding variables that were analyzed. Only AHI and DI were independently related to the BNP level, and both explain the 30.5% variability. CONCLUSION: Patients with CHF and CSR-CSA have higher BNP levels than those without CSR-CSA. Our results suggest that CSR-CSA and BNP levels are related. However, the possibility that both factors might be independent expressions of the functional status of CHF patients cannot be ruled out.     

基于CSR战略的医院营销实践探讨

目前，组织社会责任（简称CSR）已经成为实现组织经营目标的一种战略。文章通过对国内外组织社会责任发展现状的分析，阐明了组织社会责任战略在医院营销中的作用和意义，并尝试性的探讨了组织社会责任在医院营销中的实践模式。     

定点侧屈旋扳整颈手法对神经根型颈椎病椎间孔的形态学影响

目的 基于三维重建技术分析定点侧屈旋扳整颈手法治疗神经根型颈椎病（cervical spondylotic radiculopathy, CSR）患者椎间孔形态的变化,为手法治疗的有效性提供依据。方法 对40例CSR患者给予定点侧屈旋扳整颈手法治疗,隔日1次,共治疗7次,2周为1个疗程。利用多功能CT、Mimics 21.0、Geomagic、SolidWorks 2017软件对患者治疗前后CT数据进行三维重建分析,分别测量患者治疗前后椎间孔面积、椎间孔前后径、椎间孔上下径以及双侧颈肩部、上肢前侧、上肢后侧红外热成像温差值,并观察患者治疗前以及治疗7、14 d和1月随访时的VAS评分。结果 40例患者治疗后椎间孔面积、前后径、上下径较治疗前均得到改善,治疗前后患者红外热成像温差值均具有统计学意义。患者VAS评分呈逐级递减式下降。结论 定点侧屈旋扳整颈手法可以显著改善CSR患者的椎间孔形态,以此达到解除神经压迫的治疗目的。     

Exposure-driven risk assessment: Applying exposure-based waiving of toxicity tests under REACH

The REACH Regulation 1907/2006/EC aims to improve knowledge of the potential risks to humans and the environment of the large number of chemicals produced and used in the EU. The testing requirements are likely to trigger numerous toxicological studies, potentially involving millions of experimental animals, despite the professed goal of REACH to reduce vertebrate testing. It may be necessary therefore to shift emphasis away from animal studies towards more pragmatic strategies, reserving animal tests for the substances of greatest concern. One approach is to waive certain tests based on levels of exposure to the substance. This review explores application of ‘Exposure-Based Waiving’ (EBW) of toxicity studies, with a particular focus on inhalation where possible, considering the potential qualitative and quantitative supporting arguments that might be made, including the use of thresholds of toxicological concern. Incorporating EBW into intelligent testing strategies for substance registration could advance the goals of REACH and the 3Rs (reduction, replacement and refinement of animals in research) by reducing the usage of animals in toxicity tests, whilst maintaining appropriate protection of human health and the environment. However greater regulatory evaluation, acceptance and guidance are required for EBW to achieve its full impact.     

AID Biology: A pathological and clinical perspective

Activation-induced cytidine deaminase (AID), primarily expressed in activated mature B lymphocytes in germinal centers, is the key factor in adaptive immune response against foreign antigens. AID is responsible for producing high-affinity and high-specificity antibodies against an infectious agent, through the physiological DNA alteration processes of antibody genes by somatic hypermutation (SHM) and class-switch recombination (CSR) and functions by deaminating deoxycytidines (dC) to deoxyuridines (dU), thereby introducing point mutations and double-stranded chromosomal breaks (DSBs). The beneficial physiological role of AID in antibody diversification is outweighed by its detrimental role in the genesis of several chronic immune diseases, under non-physiological conditions. This review offers a comprehensive and better understanding of AID biology and its pathological aspects, as well as addresses the challenges involved in AID-related cancer therapeutics, based on various recent advances and evidence available in the literature till date. In this article, we discuss ways through which our interpretation of AID biology may reflect upon novel clinical insights, which could be successfully translated into designing clinical trials and improving patient prognosis and disease management.