Transposable elements (TE) are mobile DNA sequences whose excessive proliferation endangers the host. Although animals have evolved robust TE-targeting defenses, including Piwi-interacting (pi)RNAs, ...retrotransposon LINE-1 (L1) still thrives in humans and mice. To gain insights into L1 endurance, we characterized L1 Bodies (LBs) and ORF1p complexes in germ cells of piRNA-deficient Maelstrom null mice. We report that ORF1p interacts with TE RNAs, genic mRNAs, and stress granule proteins, consistent with earlier studies. We also show that ORF1p associates with the CCR4-NOT deadenylation complex and PRKRA, a Protein Kinase R factor. Despite ORF1p interactions with these negative regulators of RNA expression, the stability and translation of LB-localized mRNAs remain unchanged. To scrutinize these findings, we studied the effects of PRKRA on L1 in cultured cells and showed that it elevates ORF1p levels and L1 retrotransposition. These results suggest that ORF1p-driven condensates promote L1 propagation, without affecting the metabolism of endogenous RNAs.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
ABSTRACT
Betelgeuse is one of the brightest red supergiant (RSG) stars because of its proximity to the Solar system. This makes it important when deducing the features and evolutionary phases of RSG ...stars. Betelgeuse has always been a well-observed target but especially during the past year, because of the reduction in its brightness. It has been speculated that the star is in its last evolutionary stage(s), and that it is soon going to explode. However, in recent work, it has been proposed that the episodic mass loss and dust condensation around the star are major reasons for the reduction in its brightness. In this work, we have performed detailed thermodynamical equilibrium and non-equilibrium calculations of the condensation of dust grains around the cooling envelope of Betelgeuse. Based on the deduced chemical composition, we have ventured to determine the nature of dust that could condense in the stellar winds. The dust grains are essentially found to be oxides of Al, Ca and Ti, and silicates of Al, Ca, Mg and Fe-metal. Further, we have determined the normalized masses of the dust grains of various compositions that could be present around the star and could be causing the reduction in its brightness.
Implantation of drug-eluting stents (DES) is the dominant treatment strategy for patients with symptomatic coronary artery disease. However, the first-generation DES had substantial drawbacks, ...including delayed healing, local hypersensitivity reactions and neoatherosclerosis, which all led to a steady increase in major adverse cardiovascular events over time. Subsequently, newer-generation DES were introduced with thinner struts, different scaffold designs (to improve deliverability while maintaining radial strength), different durable and biodegradable polymers - and in some cases no polymer (to improve vascular biocompatibility) - and new antiproliferative drug types and doses. Currently, >30 different DES are commercially available in Europe, with fewer available in the USA but with many new entrants coming onto the US market in the next few years. Never before have cardiologists been faced with so many choices of stent, each with its own unique design. In this Review, we detail preclinical and pathology studies for each stent design, examining thromboresistance, speed of neointimal coverage and completeness of healing, including endothelialization. We conclude by discussing how these design characteristics might affect the potential for shortening the minimum duration of dual antiplatelet therapy needed after coronary intervention.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Modulation of the autonomic nervous system has been used to treat refractory ventricular tachycardia (VT). Renal artery denervation (RDN) is under investigation for the treatment of ...sympathetic-driven cardiovascular diseases.
The purpose of this study was to report the largest case series to date using RDN as adjunctive therapy for refractory VT in patients with underlying cardiomyopathy.
Four patients with cardiomyopathy (2 nonischemic, 2 ischemic) with recurrent VT despite maximized antiarrhythmic therapy and prior endocardial (n = 2) or endocardial/epicardial (n = 2) ablation underwent RDN ± repeat VT ablation. RDN was performed spirally along each main renal artery with either a nonirrigated (6 W at 50°C for 60 seconds) or an open irrigated ablation catheter (10-12 W for 30-60 seconds). Renal arteriography was performed before and after RDN.
RDN was well tolerated acutely and demonstrated no clinically significant complications during follow-up of 8.8 ± 2.6 months (range 5.0-11.0 months). No hemodynamic deterioration or worsening of renal function was observed. The number of VT episodes was decreased from 11.0 ± 4.2 (5.0-14.0) during the month before ablation to 0.3 ± 0.1 (0.2-0.4) per month after ablation. All VT episodes occurred in the first 4 months after ablation (2.6 ± 1.5 months). The responses to RDN were similar for ischemic and nonischemic patients.
This case series provides promising preliminary data on the safety and effectiveness of RDN as an adjunctive therapy in the treatment of patients with cardiomyopathy and VT resistant to standard interventions.
Precise editing of genomic DNA can be achieved upon repair of CRISPR-induced DNA double-stranded breaks (DSBs) by homology-directed repair (HDR). However, the efficiency of this process is limited by ...DSB repair pathways competing with HDR, such as non-homologous end joining (NHEJ). Here we individually express in human cells 204 open reading frames involved in the DNA damage response (DDR) and determine their impact on CRISPR-mediated HDR. From these studies, we identify RAD18 as a stimulator of CRISPR-mediated HDR. By defining the RAD18 domains required to promote HDR, we derive an enhanced RAD18 variant (e18) that stimulates CRISPR-mediated HDR in multiple human cell types, including embryonic stem cells. Mechanistically, e18 induces HDR by suppressing the localization of the NHEJ-promoting factor 53BP1 to DSBs. Altogether, this study identifies e18 as an enhancer of CRISPR-mediated HDR and highlights the promise of engineering DDR factors to augment the efficiency of precision genome editing.
Macrophages are key inflammatory immune cells that display dynamic phenotypes and functions in response to their local microenvironment. Major advances have occurred in understanding the ...transcriptional, epigenetic, and functional differences in various macrophage subsets by in vitro modeling and gene expression and epigenetic profiling for biomarker discovery. However, there is still no standardized protocol for macrophage polarization largely due to the lack of thorough validation of macrophage phenotypes following polarization. In addition, transcriptional regulation is recognized as a major mechanism governing differential macrophage polarization programs and as such, many genes have been identified to be associated with each macrophage subset. However, the functional role of many of these genes in macrophage polarization is still unknown. Moreover, the role of other regulatory mechanisms, such as DNA methylation, in macrophage polarization remains poorly understood. Here, we employed an optimized model of human M1 and M2 macrophage polarization which we used for large-scale transcriptional and DNA methylation profiling. We were unable to demonstrate a role for DNA methylation in macrophage polarization, as no significant changes were identified. However, we observed significant changes in the transcriptomes of M1 and M2 macrophages. Additionally, we identified numerous novel differentially regulated genes involved in macrophage polarization, including CYBB and DHCR7 which we show as important regulators of M1 and M2 macrophage polarization, respectively. Taken together, our improved in vitro human M1 and M2 macrophage model provides new understandings of the regulation of macrophage polarization and candidate macrophage biomarkers.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Up to 30% of patients presenting with ascending aortic disease are deemed inoperable. Ascending aortic endovascular repair provides an alternative option for these patients.
From 2018 to 2019, 13 ...patients who were considered to have prohibitive risk for open ascending aortic repair underwent endovascular repair. Aortic disease included type A dissection (n = 8), pseudoaneurysm (n = 3), penetrating ulcer (n = 3), and chronic aortic aneurysm (n = 1). Ascending aortic stent placement with thoracic endovascular aortic repair was performed in 9 patients, endovascular cuff extension was inserted in 3, and in 1 patient endovascular coil embolization was undertaken. Preoperative and follow-up electrocardiogram-gated computed tomographic analysis was performed to compare the remodeling effect of the stent on the aorta. The median follow-up time was 13 months.
The stent graft was successfully implanted in all patients (100%). Operative mortality and stroke rate were 15% (2 of 13) and 8% (1 of 13), respectively. One patient required transcatheter aortic valve replacement for severe aortic insufficiency 5 months after ascending thoracic endovascular aortic repair. The location of the aortic pathologic process was in zone 0A in 2 patients, zone 0B in 7 patients, and zone 0C in 3 patients. No endoleak was observed after the ascending endovascular repair in 9 patients (70%). Follow-up computed tomographic scan analysis revealed a tendency of favorable aortic remodeling in the mid-ascending and descending aorta.
Ascending aortic stent placement for ascending aortic disease is feasible and is associated with favorable aortic remodeling. Despite persistent perfusion to the false lumen in a subset of patients, there is minimal aortic dilation at short-term follow-up with excellent survival.
This study explores how discussing metaphors for AI can help build awareness of the frames that shape our understanding of AI systems, particularly large language models (LLMs) like ChatGPT. Given ...the pressing need to teach “critical AI literacy”, discussion of metaphor provides an opportunity for inquiry and dialogue with space for nuance, playfulness, and critique. Using a collaborative autoethnographic methodology, we analyzed metaphors from a range of sources, and reflected on them individually according to seven questions, then met and discussed our interpretations. We then analyzed how our reflections contributed to the three kinds of literacies delineated in Selber’s multiliteracies framework: functional, critical and rhetorical. These allowed us to analyze questions of ethics, equity, and accessibility in relation to AI. We explored each metaphor along the dimension of whether or not it was promoting anthropomorphizing, and to what extent such metaphors imply that AI is sentient. Our findings highlight the role of metaphor reflection in fostering a nuanced understanding of AI, suggesting that our collaborative autoethnographic approach as well as the heuristic model of plotting AI metaphors on dimensions of anthropomorphism and multiliteracies, might be useful for educators and researchers in the pursuit of advancing critical AI literacy.
Double-blind randomized controlled pilot study.
The purpose of this study was to compare outcomes of steroids with autologous platelet-rich plasma (PRP) administered by lumbar transforaminal ...injection (LTI) in patients with lumbar radiculopathy.
Degenerative disc disease of the lumbar spine is one of the most common conditions managed by spine surgeons in routine practice. Once conservative management fails, LTI is diagnostic and often therapeutic. Steroids are the gold standard drug used for LTI but have limitations and side effects.
In this single-center double-blind randomized controlled pilot study, 46 patients were recruited and randomized by the lottery method. The Visual Analog Scale (VAS) for leg pain, modified Oswestry Disability Index (mODI), and Short-Form 12 (SF-12) were assessed at 1 week, 3 weeks, 6 weeks, 6 months, and 1 year.
Both groups were comparable in terms of demographics, preprocedure VAS scores, mODI, and SF-12 scores (p=0.52). At the 1-week follow-up, the steroid group had significantly better improvement than the PRP group (p=0.0001). At the 3-week follow-up, both groups showed comparable outcomes; however, the PRP group had better symptom improvement. At 6 weeks and 6 months, the PRP group had better outcomes (VAS, p<0.0001; ODI, p=0.02; SF-12, p=0.002). Moreover, 17 and 16 patients in the steroid and PRP groups underwent repeat LTI with steroids or surgery because of pain recurrence during follow-up. At 1 year, no difference in outcomes was observed.
PRP may be a useful alternative to steroids for LTI in lumbar radiculopathy. Although improvement was delayed and 1-year outcomes were comparable, the 6-week and 6-month outcomes were better with PRP than with LTI. Multiple PRP injections may be beneficial because of its autologous nature. However, further studies with a larger number of participants, longer follow-up, and repeat LTIs are warranted to draw definite conclusions.
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