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Transposons are integral genome constituents that can be domesticated for host functions, but they also represent a significant threat to genome stability. Transposon silencing is especially critical in the germline, which is dedicated to transmitting inherited genetic material. The small Piwi-interacting RNAs (piRNAs) have a deeply conserved function in transposon silencing in the germline. piRNA biogenesis and function are particularly well understood in Drosophila melanogaster, but some fundamental mechanisms remain elusive and there is growing evidence that the pathway is regulated in response to genotoxic and environmental stress. Here, we review transposon regulation by piRNAs and the piRNA pathway regulation in response to stress, focusing on the Drosophila female germline. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To examine the accuracy of different periods of continuous glucose monitoring (CGM), hemoglobin A1c (HbA1c), and their combination for estimating mean glycemia over 90 days (AG90). RESEARCH DESIGN AND METHODS: We retrospectively studied 985 CGM periods of 90 days with <10% missing data from 315 adults (86% of whom had type 1 diabetes) with paired HbA1c measurements. The impact of mean red blood cell age as a proxy for nonglycemic effects on HbA1c was estimated using published theoretical models and in comparison with empirical data. Given the lack of a gold standard measurement for AG90, we applied correction methods to generate a reference (eAG90) that we used to assess accuracy for HbA1c and CGM. RESULTS: Using 14 days of CGM at the end of the 90-day period resulted in a mean absolute error (95th percentile) of 14 (34) mg/dL when compared with eAG90. Nonglycemic effects on HbA1c led to a mean absolute error for average glucose calculated from HbA1c of 12 (29) mg/dL. Combining 14 days of CGM with HbA1c reduced the error to 10 (26) mg/dL. Mismatches between CGM and HbA1c >40 mg/dL occurred more than 5% of the time. CONCLUSIONS: The accuracy of estimates of eAG90 from limited periods of CGM can be improved by averaging with an HbA1c-based estimate or extending the monitoring period beyond ∼26 days. Large mismatches between eAG90 estimated from CGM and HbA1c are not unusual and may persist due to stable nonglycemic factors. [ABSTRACT FROM AUTHOR]

The mucosal immunity is crucial for restricting SARS-CoV-2 at its entry site. Intramuscularly applied vaccines against SARS-CoV-2 stimulate high levels of neutralizing Abs in serum, but the impact of these intramuscular vaccinations on features of mucosal immunity is less clear. Here, we analyzed kinetic and functional properties of anti-SARS-CoV-2 Abs in the saliva after vaccination with BNT162b2. We analyzed a total of 24 healthy donors longitudinally for up to 16 months. We found that specific IgG appeared in the saliva after the second vaccination, declined thereafter and reappeared after the third vaccination. Adjusting serum and saliva for the same IgG concentration revealed a strong correlation between the reactivity in these two compartments. Reactivity to VoCs correlated strongly as seen by ELISAs against RBD variants and by live-virus neutralizing assays against replication-competent viruses. For further functional analysis, we purified IgG and IgA from serum and saliva. In vaccinated donors we found neutralizing activity towards authentic virus in the IgG, but not in the IgA fraction of the saliva. In contrast, IgA with neutralizing activity appeared in the saliva only after breakthrough infection. In serum, we found neutralizing activity in both the IgA and IgG fractions. Together, we show that intramuscular mRNA vaccination transiently induces a mucosal immunity that is mediated by IgG and thus differs from the mucosal immunity after infection. Waning of specific mucosal IgG might be linked to susceptibility for breakthrough infection. [ABSTRACT FROM AUTHOR]

Autoantibodies against myelin oligodendrocyte glycoprotein (MOG) have recently been established to define a new disease entity, MOG-antibody-associated disease (MOGAD), which is clinically overlapping with multiple sclerosis. MOG-specific antibodies (Abs) from patients are pathogenic, but the precise effector mechanisms are currently still unknown and no therapy is approved for MOGAD. Here, we determined the contributions of complement and Fc-receptor (FcR)-mediated effects in the pathogenicity of MOG-Abs. Starting from a recombinant anti-MOG (mAb) with human IgG1 Fc, we established MOG-specific mutant mAbs with differential FcR and C1q binding. We then applied selected mutants of this MOG-mAb in two animal models of experimental autoimmune encephalomyelitis. First, we found MOG-mAbinduced demyelination was mediated by both complement and FcRs about equally. Second, we found that MOG-Abs enhanced activation of cognate MOG-specific T cells in the central nervous system (CNS), which was dependent on FcR-, but not C1q-binding. The identification of complement-dependent and -independent pathomechanisms of MOG-Abs has implications for therapeutic strategies in MOGAD. [ABSTRACT FROM AUTHOR]

Background: Limited data exists demonstrating the efficacy of minimally invasive surgery (MIS) compared to transcatheter (TC) closure of atrial septal defects (ASD). This systematic review and meta-analysis aims to compare post-operative outcomes of MIS versus TC repair in ASD closure. Methods: PubMed, Medline and EMBASE were searched from inception until June 2018 for randomised and observational studies comparing post-operative outcomes for MIS and TC repair. The studies were reviewed for bias using the ROBINS-I Score and pooled in a meta-analysis using STATA (version 15). Results: Six observational studies, involving 1524 patients assessing three primary and five secondary outcomes were included. Evidence suggests TC repair yielded shorter hospital stay (MD = 3.32, 95% CI 1.04–5.60) and lower rates of transient atrial fibrillation (AF) (RR = 0.48, 95% CI 0.20–1.15). TC repair patients also had fewer pericardial effusions (RR = 0.27, 95% CI 0.05–1.54, I2 = 0.0%) and pneumothoraxes (RR = 0.18, 95% CI 0.04–0.80, I2 = 0.0%). However, TC repair results in more minor residual shunts (RR = 6.04, 95% CI 1.69–21.63 in favour of MIS, I2 = 39.0%). No differences were found for incidences of strokes (RR = 1.58, 95% CI 0.23–10.91, I2 = 19.3%), unexpected bleeding (RR = 0.44, 95% CI 0.19–1.04, I2 = 0.0%) and blood transfusion (RR = 0.39, 95% CI 0.09–1.59, I2 = 0.0%). Conclusions: MIS closure for ASD has similar outcomes compared to TC repair. However, the lack of randomised literature related to MIS versus TC repair for ASD closure warrants further evidence in the form of RCTs to further support these findings. [ABSTRACT FROM AUTHOR]

Background: Cathelicidin (LL-37) is an antimicrobial peptide known to be associated with various autoimmune diseases. We attempt to determine if cathelicidin can accurately reflect IBD disease activity. We hypothesize that serum cathelicidin correlates with mucosal disease activity, stricture, and clinical prognosis of IBD patients.Methods: Serum samples were collected from two separate cohorts of patients at the University of California, Los Angeles. Cohort 1 consisted of 50 control, 23 UC, and 28 CD patients. Cohort 2 consisted of 20 control, 57 UC, and 67 CD patients. LL-37 levels were determined by ELISA. Data from both cohorts were combined for calculation of accuracies in indicating mucosal disease activity, relative risks of stricture, and odds ratios of predicting disease development.Results: Serum cathelicidin levels were inversely correlated with Partial Mayo Scores of UC patients and Harvey-Bradshaw Indices of CD patients. Among IBD patients with moderate or severe initial disease activity, the patients with high initial LL-37 levels had significantly better recovery than the patients with low initial LL-37 levels after 6-18 months, suggesting that high LL-37 levels correlate with good prognosis. Co-evaluation of LL-37 and CRP levels was more accurate than CRP alone or LL-37 alone in the correlation with Mayo Endoscopic Score of UC patients. Low LL-37 levels indicated a significantly elevated risk of intestinal stricture in CD patients.Conclusion: Co-evaluation of LL-37 and CRP can indicate mucosal disease activity in UC patients. LL-37 can predict future clinical activity in IBD patients and indicate risk of intestinal stricture in CD patients. [ABSTRACT FROM AUTHOR]

Since the late 1990s, the Korean pop-culture wave has had a huge impact, achieving immense popularity and sustaining a global community of consumers and fans. In Singapore, a significant K-pop fan culture has emerged among youths. In this article, we study the emergence of thesasaengfan—a stigmatized fan identity that refers to individuals who are unhealthily interested in the personal lives of K-pop idols. Drawing on data from mass and social media, participant-observation, and interviews, we map the significance of thesasaengfan identity for Singapore K-pop music fans and focus specific attention on how fans negotiate an understanding of their own “authentic” identities vis-à-vis the mediated identity of thesasaengfan. [ABSTRACT FROM AUTHOR]

Background: Cathelicidin (LL-37 in humans and mCRAMP in mice) represents a family of endogenous antimicrobial and anti-inflammatory peptides. Cancer-associated fibroblasts can promote the proliferation of colon cancer cells and growth of colon cancer tumors. Methods: We examined the role of cathelicidin in the development of colon cancer, using subcutaneous human HT-29 colon-cancer-cell-derived tumor model in nude mice and azoxymethane- and dextran sulfate-mediated colon cancer model in C57BL/6 mice. We also determined the indirect antitumoral mechanism of cathelicidin via the inhibition of epithelialmesenchymal transition (EMT) of colon cancer cells and fibroblast-supported colon cancer cell proliferation. Results: Intravenous administration of cathelicidin expressing adeno-associated virus significantly reduced the size of tumors, tumor-derived collagen expression, and tumor-derived fibroblast expression in HT-29-derived subcutaneous tumors in nude mice. Enema administration of the mouse cathelicidin peptide significantly reduced the size and number of colonic tumors in azoxymethane- and dextran sulfate-treated mice without inducing apoptosis in tumors and the adjacent normal colonic tissues. Cathelicidin inhibited the collagen expression and vimentinpositive fibroblast expression in colonic tumors. Cathelicidin did not directly affect HT-29 cell viability, but did significantly reduce tumor growth factor-ß1-induced EMT of colon cancer cells. Media conditioned by the human colonic CCD-18Co fibroblasts promoted human colon cancer HT-29 cell proliferation. Cathelicidin pretreatment inhibited colon cancer cell proliferation mediated by media conditioned by human colonic CCD-18Co fibroblasts. Cathelicidin disrupted tubulin distribution in colonic fibroblasts. Disruption of tubulin in fibroblasts reduced fibroblast-supported colon cancer cell proliferation. Conclusion: Cathelicidin effectively inhibits colon cancer development by interfering with EMT and fibroblast-supported colon cancer cell proliferation. [ABSTRACT FROM AUTHOR]

Great Britain has been subject to an increasing rate of invasion from freshwater species of Ponto-Caspian origin. A recent horizon-scan of potential invaders into Great Britain named the Ponto Caspian quagga mussel, Dreissena rostriformis bugensis (Andrusov, 1897), as the non-native species least wanted. On 29th September 2014 quagga mussels were discovered in the Wraysbury River, Surrey, during a routine kick sample collected by the Environment Agency. Identity was confirmed using genetic markers (Cytochrome Oxidase I - COI) on five individuals encompassing a broad morphological variation. The absence of very large individuals (max. length 16 mm), absence of shells and absence of quagga mussels in samples collected during March 2014 point toward a recent invasion. The quagga mussels were found attached to submerged rocks, vegetation, bridge walls and shells of zebra mussels, Dreissena polymorpha (Pallas, 1771). The collection site is a small (<5m wide), shallow (<50cm deep) stream that is not navigable or regularly fished. This suggests that the species is more widely distributed than the current location, because such a system is unlikely to be the point of introduction. The shallow depth (30cm) in open water at which quagga mussels were abundant is surprising given that zebra mussels have failed to establish in such habitats, despite being present in the catchment for over 100 years. Previously published models predict quagga mussels will establish widely across England, western and southern Wales and central Scotland. The high abundance and inter-connectivity of waterways adjacent to the Wraysbury River suggest further spread is likely. Containment through national biosecurity measures (e.g. 'Check, Clean, Dry' of boats and equipment, as promoted by the UK Environment Agency) is recommended, although ultimately it can be assumed that quagga mussels will cause similar widespread ecological and economic harm in Britain as has been experienced in invaded regions of Western Europe and North America. [ABSTRACT FROM AUTHOR]

NK cells play a crucial role in innate immunity against tumors. In many human tumors, Ras is chronically active, and tumor cells frequently express ligands for the activating NK cell receptor NKG2D. In this study, we report that Ras activation upregulates the expression of Raetl protein family members Rael&agr; and Rael&bgr; in mouse and ULBPl-3 in human cells. In addition, Ras also induced MHC class I chain-related protein expression in some human cell lines. Overexpression of the constitutively active H-RasV12 mutant was sufficient to induce NKG2D ligand expression. H-RasV12-induced NKG2D ligand upregulation depended on Raf, MAPK/MEK, and PI3K, but not ATM or ATR, two PDK-like kinases previously shown to induce NKG2D ligand expression. Analysis of the 5' untranslated regions of Raetl family members suggested the presence of features known to impair translation initiation. Overexpression of the rate-limiting translation initiation factor eIF4E induced Rael and ULBP1 expression in a Ras-and PI3K-dependent manner. Upregulation of NKG2D ligands by H-RasV12 increased sensitivity of cells to NK cell-mediated cytotoxicity. In summary, our data suggest that chronic Ras activation is linked to innate immune responses, which may contribute to immune surveillance of H-Ras transformed cells. [ABSTRACT FROM AUTHOR]

RAS is constitutively active in multiple types of tumor cells. We have recently demonstrated that H-RASV12 enhances the translation of ligands for the activating immune receptor NKG2D, hence rendering cells more susceptible to natural killer (NK) cell-mediated lysis. This effect depends on MAPK and PI3K signaling, but not on the DNA damage response. [ABSTRACT FROM AUTHOR]

The DNA damage response (DDR) upregulates the expression of NKG2D ligands (NKG2DLs).1,2We have recently reported that the DDR also induces the presence of cytosolic DNA in B-cell lymphoma cells, which leads to the activation of STING-dependent cytosolic DNA sensor pathways and the expression of RAE-1 ligands for NKG2D.3 [ABSTRACT FROM PUBLISHER]