고분자필름과 금속막 의료소재에 대한 생체적합성 및 독성 평가를 위한 새로운 세포배양시스템의 개발 및 적용

By presenting antigenic peptides on major histocompatibility complex class (MHC) II determinants to CD4(+) T cells, macrophages help to direct the establishment of adaptive immunity. We found that in these cells, lipopolysaccharide stimulates the expression of MHC II genes via the activation of Erk1/2, which is mediated by Toll-like receptor 4. Erk1/2 then phosphorylates the serine at position 357, which is located in a degron of CIITA isoform 1 that leads to its monoubiquitylation. Thus modified, CIITA isoform 1 binds P-TEFb, which mediates the elongation of RNA polymerase II and co-transcriptional processing of nascent transcripts. This induction leads to the expression of MHC II genes. Subsequent polyubiquitylation results in the degradation of CIITA isoform 1. Thus, the signaling cascade from Toll-like receptor 4 to CIITA isoform 1 represents one connection between innate and adaptive immunity in macrophages.

Upon detecting endoplasmic reticulum (ER) stress, the unfolded protein response (UPR) orchestrates adaptive cellular changes to reestablish homeostasis. If stress resolution fails, the UPR commits the cell to apoptotic death. Here we show that in hematopoietic cells, including multiple myeloma (MM), lymphoma, and leukemia cell lines, ER stress leads to caspase-mediated cleavage of the key UPR sensor IRE1 within its cytoplasmic linker region, generating a stable IRE1 fragment comprising the ER-lumenal domain and transmembrane segment (LDTM). This cleavage uncouples the stress-sensing and signaling domains of IRE1, attenuating its activation upon ER perturbation. Surprisingly, LDTM exerts negative feedback over apoptotic signaling by inhibiting recruitment of the key proapoptotic protein BAX to mitochondria. Furthermore, ectopic LDTM expression enhances xenograft growth of MM tumors in mice. These results uncover an unexpected mechanism of cross-regulation between the apoptotic caspase machinery and the UPR, which has biologically significant consequences for cell survival under ER stress.

Power spectral analysis of fetal heart rate variability has been proposed to provide a non-invasive estimate of autonomic balance. However, there are few systematic data before birth. We therefore examined developmental changes in the frequency power spectrum at very low (0-0.04 Hz), low (0.04-0.15 Hz) and high frequencies (0.15-0.4 Hz), as well as the ratio of low- to high-frequency power (LF/HF), in chronically catheterized, healthy fetal sheep at 0.6 (n = 8), 0.7 (n = 7) and 0.8 gestational age (ga; n = 11). In a second study, 0.8 ga fetuses received either atropine (4.8 mg bolus, then 4.8 mg h(-1) for 30 min, n = 6) or 6-hydroxydopamine (20 mg ml(-1) at 2.5 ml h(-1) for 3 h; n = 9). Data were analysed by sleep state, defined by low-voltage-high-frequency (LV) or high-voltage-low-frequency (HV) EEG. Total spectral power increased with gestational age (P < 0.05), while LF/HF decreased from 0.6 to 0.7 ga. At 0.8 ga, heart rate and LF/HF were significantly higher during HV than LV sleep (P < 0.05). Consistent with this, although total spectral power was not significantly greater during HV sleep, there was a significant interaction between sleep state and frequency band (P = 0.02). Both atropine (P = 0.05) and 6-hydroxydopamine (P < 0.05) were associated with an overall reduction in spectral power but no significant effect on the LF/HF ratio. This study does not support substantial, consistent differences between the frequencies of sympathetic and parasympathetic activity in late-gestation fetal sheep.

Cervical cancers transformed by high risk human papilloma virus (HPV) express the E7 oncoprotein, which accelerates the degradation of the retinoblastoma protein (Rb). Here we show that the E7-mediated degradation of Rb requires the calcium-activated cysteine protease, calpain. E7 bound and activated mu-calpain and promoted cleavage at Rb(810), with mutation of this residue preventing E7-mediated degradation. The calpain cleavage product, Rb(1-810), was unable to mediate cell cycle arrest but retained the ability to repress E6/E7 transcription. E7 also promoted the accelerated proteasomal degradation of Rb(1-810). Calpain inhibitors reduced the viability of HPV-transformed cells and synergized with cisplatin. Calpain, thus, emerges as a central player in E7-mediated degradation of Rb and represents a potential new drug target for the treatment of HPV-associated lesions.

Decreased nitric oxide (NO) bioavailability underlies a number of cardiovascular pathologies, including hypertension. The shear stress exerted by flowing blood is the main determinant of NO release. Rap1 promotes integrin- and cadherin-mediated signaling. Here, we show that Rap1 is a critical regulator of NO production and endothelial function. Rap1 deficiency in murine endothelium attenuates NO production and diminishes NO-dependent vasodilation, leading to endothelial dysfunction and hypertension, without deleterious effects on vessel integrity. Mechanistically, Rap1 is activated by shear stress, promotes the formation of the endothelial mechanosensing complex-comprised of PECAM-1, VE-cadherin and VEGFR2- and downstream signaling to NO production. Our study establishes a novel paradigm for Rap1 as a regulator of mechanotransduction.

IntroductionPatient-reported experience metric (PREM) questionnaires are important tools used to evaluate patient experience but have yet to be widely used for patients undergoing cardiovascular procedures. Validated PREM tools may assist...

Assessment and Analysis of Roundness Error in Drilling GFRP- Armour Steel Sandwich Composites

Chemokine Receptor CCR5 Mediates AlloImmune Responses in Graft-versus-Host Disease

Akt-Mediated Phosphorylation of Argonaute 2 Downregulates Cleavage and Upregulates Translational Repression of MicroRNA Targets

Computational analyses of in-vivo cerebral activity show that gamma oscillations in the olfactory cortex originate from local feedback inhibition following each sniff and serve to segregate competing odor representations through a winner-take-all process, providing an optimal window to decode odor.

Interleukin-10 (IL-10) limits inflammatory responses by inhibiting macrophage activation. In macrophages, IL-10 activates Stat1 and Stat3. We characterized IL-10 responses of the J774 mouse macrophage cell line, and of J774 cells expressing wild-type hIL-10R, mutant hIL-10R lacking two membrane-distal tyrosines involved in recruitment of Stat3 (hIL-10R-TyrFF), a truncated Stat3 (DeltaStat3) which acts as a dominant negative, or an inducibly active Stat3-gyraseB chimera (Stat3-GyrB). A neutralizing anti-mIL-10R monoclonal antibody was generated to block the function of endogenous mIL-10R. IL-10 inhibited proliferation of J774 cells and of normal bone marrow-derived macrophages, but not J774 cells expressing hIL-10RTyrFF. Dimerization of Stat3-GyrB by coumermycin mimicked the effect of IL-10, and expression of DeltaStat3 blocked the anti-proliferative activity of IL-10. For macrophage de-activation responses, hIL10R-TyrFF could not mediate inhibition of lipopolysaccharide-induced TNFalpha, IL-1beta or CD86 expression, while DeltaStat3 did not interfere detectably with these IL-10 responses. Thus signals mediating both anti-proliferative and macrophage de-activation responses to IL-10 require the two membrane-distal tyrosines of IL-10R, but Stat3 appears to function only in the anti-proliferative response.

Introduction: Many contemporary trials have compared different management strategies, involving combinations of reperfusion therapies and early invasive approaches, for treatment of ST-elevation myocardial infarction (STEMI). We used multivariable network meta - analysis to compare these approaches. Methods: We identified 29 trials in which patients with STEMI were randomized to at least two of the following strategies: thrombolytic therapy (n=4255), primary PCI (n=5850), or routine PCI after administration of thrombolytic therapy (n=4738). We categorized the latter approach as facilitated PCI (FPCI) when the median time interval between thrombolytic therapy and PCI was less than 2 hours and as a pharmacoinvasive approach when this interval was 2 hours or more. We excluded trials that did not routinely use stents during PCI. We identified short-term outcomes (up to 42 days) of death, nonfatal reinfarction, stroke, and major bleeding. We performed multivariable random-effects meta-analysis to compare these strategies. In addition, we estimated the probability that each strategy was associated with maximum risk for each outcome under a Bayesian model with flat priors. Results: Among the strategies evaluated, primary PCI was associated with the lowest mortality and nonfatal reinfarction rates, as well as the lowest risk of stroke ( Table- top panel ). Of the remaining strategies, the pharmacoinvasive approach was associated with the lowest risks of mortality, reinfarction, and stroke. The Bayesian model indicated that the probabilities of death, nonfatal reinfarction, stroke, and major bleeding were lowest for primary PCI and highest for thrombolytic therapy ( Table- bottom panel ). Furthermore, the probability of these outcomes was lower for the pharmacoinvasive approach relative to facilitated PCI. Conclusions: Primary PCI is the preferred approach for treatment of STEMI. Our analysis suggests that a pharmacoinvasive approach may be more effective and safer as compared to facilitated PCI and thrombolytic therapy.

Although average temperatures are increasing globally, abrupt cold stress in winter can occur regionally. For example, the winter thermal gradient between the Arctic and middle latitudes is weakening because Arctic temperatures are rising faster. This phenomenon can lead to pronounced cold air outbreaks in Eurasia and North America in winter. In eastern Canada, an unusual cold snap occurred in February 2023. In intertidal habitats from southeastern Nova Scotia, entire mussel stands disappeared and some seaweeds experienced massive bleaching shortly afterwards. Winter extremes related to climate change can therefore be as important for species survival as summer heat waves. Photo 1. Stand of intertidal mussels (Mytilus spp.) from southeastern Nova Scotia, Canada, as seen in October 2021 (top panel) and intertidal substrate as seen in April 2023 after the February 2023 cold snap, showing byssal threads as the only remains of mussels (bottom panel). The PVC frame measures 10 × 10 cm. Photo credit: Ricardo A. Scrosati. Photo 2. Massive bleaching in the intertidal algae Corallina officinalis (top panel), Chondrus crispus (middle panel), and Laminaria digitata (bottom panel; scale bar = 5 cm) from southeastern Nova Scotia as seen in April 2023 after the February 2023 cold snap. Photo credit: Ricardo A. Scrosati. These photographs illustrate the article “Mass disappearance of intertidal mussels after an unusual winter cold snap in eastern Canada”, published by Nicole M. Cameron, and Ricardo A. Scrosati in Ecology. https://doi.org/10.1002/ECY.4179.

Page 38272, Figs. 5 and 6 legends: Proteins were resolved on 13% SDS-polyacrylamide gels, not 10%. Page 38274, Fig. 9 legend: Several words were omitted. The corrected legend should read: “Fig. 9. Amino acids 264–324 are required for Purβ binding to MSY1 and Purα. Microtiter wells coated with full-length His-tagged Purβ (Purβ324) or the indicated C-terminal deletion mutants (5.0 pmol application) were incubated with varying amounts of AKR-2B fibroblast nuclear protein as previously described (13). Wells were aspirated and washed three times, and solid phase MSY1-Purβ (top panel) or Purα-Purβ (bottom panel) complexes were detected by ELISA using either rabbit anti-MSY1 242–267 (top panel) or rabbit anti-PurA 291–313 (bottom panel) as the primary antibody (13).”

CPAP--a gene mutated in primary microcephaly--is required for procentriole formation. Here we show that CPAP degradation and function is controlled by the poly(ADP-ribose) polymerase tankyrase 1. CPAP is PARsylated by tankyrase 1 in vitro and in vivo. Overexpression of tankyrase 1 leads to CPAP proteasomal degradation, preventing centriole duplication, whereas depletion of tankyrase 1 stabilizes CPAP in G1, generating elongated procentrioles and multipolarity. Tankyrase 1 localizes to centrosomes exclusively in G1, coinciding with CPAP degradation. Hence, tankyrase 1-mediated PARsylation regulates CPAP levels during the cell cycle to limit centriole elongation and ensure normal centrosome function.