Fibrosis is a common pathology in cardiovascular disease. In the heart, fibrosis causes mechanical and electrical dysfunction and in the kidney, it predicts the onset of renal failure. Transforming ...growth factor β1 (TGFβ1) is the principal pro-fibrotic factor, but its inhibition is associated with side effects due to its pleiotropic roles. We hypothesized that downstream effectors of TGFβ1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicity. Here we show, using integrated imaging-genomics analyses of primary human fibroblasts, that upregulation of interleukin-11 (IL-11) is the dominant transcriptional response to TGFβ1 exposure and required for its pro-fibrotic effect. IL-11 and its receptor (IL11RA) are expressed specifically in fibroblasts, in which they drive non-canonical, ERK-dependent autocrine signalling that is required for fibrogenic protein synthesis. In mice, fibroblast-specific Il11 transgene expression or Il-11 injection causes heart and kidney fibrosis and organ failure, whereas genetic deletion of Il11ra1 protects against disease. Therefore, inhibition of IL-11 prevents fibroblast activation across organs and species in response to a range of important pro-fibrotic stimuli. These results reveal a central role of IL-11 in fibrosis and we propose that inhibition of IL-11 is a potential therapeutic strategy to treat fibrotic diseases.
Background: Transscleral diode laser cyclophotocoagulation (TSCPC) is an established method of treatment for refractory glaucoma, but is associated with significant complications. This study ...evaluates the efficacy and safety of a new form of TSCPC using micropulse diode laser and trans‐pars plana treatment with a novel contact probe.
Methods: Prospective interventional case series of 40 eyes of 38 consecutive patients with refractory glaucoma treated with micropulse TSCPC with a novel probe. Outcomes measured were success, hypotony and response rates.
Results: The mean age of patients was 63.2 ± 16.0 years. The mean follow‐up period was 16.3 ± 4.5 months. The mean intraocular pressure (IOP) before micropulse TSCPC was 39.3 ± 12.6 mmHg. Mean IOP decreased to 31.1 ± 13.4 mmHg at 1 day, 28.0 ± 12.0 mmHg at 1 week, 27.4 ± 12.7 mmHg at 1 month, 27.1 ± 13.6 mmHg at 3 months, 25.8 ± 14.5 mmHg at 6 months, 26.6 ± 14.7 mmHg at 12 months and 26.2 ± 14.3 mmHg at 18 months (P < 0.001 at all time points). No patient had hypotony or loss of best‐corrected visual acuity. The overall success rate after a mean of 1.3 treatment sessions was 72.7%.
Conclusion: Micropulse TSCPC is a safe and effective method of lowering IOP in cases of refractory glaucoma and is comparable with conventional TSCPC.
The maintenance of appropriate arterial tone is critically important for normal physiological arterial function. However, the cellular and molecular mechanisms remain poorly defined. Here, we have ...shown that in the mouse aorta, resident macrophages prevented arterial stiffness and collagen deposition in the steady state. Using phenotyping, transcriptional profiling, and targeted deletion of Csf1r, we have demonstrated that these macrophages—which are a feature of blood vessels invested with smooth muscle cells (SMCs) in both mouse and human tissues—expressed the hyaluronan (HA) receptor LYVE-l. Furthermore, we have shown they possessed the unique ability to modulate collagen expression in SMCs by matrix metalloproteinase MMP-9-dependent proteolysis through engagement of LYVE-1 with the HA pericellular matrix of SMCs. Our study has unveiled a hitherto unknown homeostatic contribution of arterial LYVE-1+ macrophages through the control of collagen production by SMCs and has identified a function of LYVE-1 in leukocytes.
Display omitted
•LYVE-1+ macrophages coat murine and human blood vessels harboring smooth muscle cells•Deficiency in LYVE-1+ macrophages induces arterial stiffness and collagen deposition•LYVE-1+ macrophages degrade collagen on smooth muscle cells via pericellular MMP-9•LYVE-1 on macrophage engages HA on smooth muscle for collagen degradation
Macrophages are essential to maintain tissue homeostasis. Lim and colleagues demonstrate that perivascular LYVE-1-expressing macrophages prevent arterial stiffness by controlling the expression of collagen in vascular smooth muscle cells, a process dependent on the engagement of LYVE-1 with hyaluronan on smooth muscle cells.
The troposphere constitutes the final frontier of global ecosystem research due to technical challenges arising from its size, low biomass, and gaseous state. Using a vertical testing array ...comprising a meteorological tower and a research aircraft, we conducted synchronized measurements of meteorological parameters and airborne biomass (
= 480) in the vertical air column up to 3,500 m. The taxonomic analysis of metagenomic data revealed differing patterns of airborne microbial community composition with respect to time of day and height above ground. The temporal and spatial resolution of our study demonstrated that the diel cycle of airborne microorganisms is a ground-based phenomenon that is entirely absent at heights >1,000 m. In an integrated analysis combining meteorological and biological data, we demonstrate that atmospheric turbulence, identified by potential temperature and high-frequency three-component wind measurements, is the key driver of bioaerosol dynamics in the lower troposphere. Multivariate regression analysis shows that at least 50% of identified airborne microbial taxa (
= ∼10,000) are associated with either ground or height, allowing for an understanding of dispersal patterns of microbial taxa in the vertical air column. Due to the interconnectedness of atmospheric turbulence and temperature, the dynamics of microbial dispersal are likely to be impacted by rising global temperatures, thereby also affecting ecosystems on the planetary surface.
Abstract Background/objectives This study aims to examine iliofemoral anatomy and predictors of vessel size and tortuosity in Asian patients as transfemoral transcatheter aortic valve implantation ...(TAVI) may be limited by the smaller Asian physique. Methods Characteristics and vessel dimensions of 549 patients undergoing ultrasonography were reviewed. The minimal luminal diameter (MLD) along the iliofemoral vasculature of each side was identified and the larger of the two sides was used to determine suitability for transfemoral TAVI. Results The mean age was 66 ± 11 years (68% males). Mean iliac MLD was 7.6 ± 1.7 mm, females smaller than males (7.2 ± 1.7 vs 7.8 ± 1.7, p < 0.001). Mean iliac MLD decreased with age: 7.9 ± 1.7 mm, 7.4 ± 1.9 mm and 7.3 ± 1.6 mm for ages < 70 years, 70–79 years and ≥ 80 years respectively (p = 0.038). Mean femoral MLD was 7.0 ± 1.7 mm, females smaller than males (6.3 ± 1.5 mm vs 7.3 ± 1.8 mm, p < 0.001). Females were more likely than males to have iliac and femoral MLD < 6 mm (20% vs 12%, p = 0.019 and 34% vs 21%, p = 0.001). Independent predictors of smaller iliofemoral dimensions were female gender, lower body surface area, diabetes mellitus, dyslipidemia and smoking history. Significant iliac tortuosity was present in 11.8%, more frequent in males than females (15% vs 6%, p = 0.005), and in those with logistic EuroSCORE ≥ 15 than < 15 (27% vs 10%, p = 0.001). Conclusions This study establishes the mean iliac and femoral artery diameters in a cohort of relatively young Asian patients. Age and female gender were associated with smaller vessel dimension and several independent predictors of smaller vasculature and tortuosity were identified. These results have implications for TF TAVI in Asia.
Circular RNA (circRNA) is a newly validated class of single-stranded RNA, ubiquitously expressed in mammalian tissues and possessing key functions including acting as microRNA sponges and as ...transcriptional regulators by binding to RNA-binding proteins. While independent studies confirm the expression of circRNA in various tissue types, genome-wide circRNA expression in the heart has yet to be described in detail.
We performed deep RNA-sequencing on ribosomal-depleted RNA isolated from 12 human hearts, 25 mouse hearts and across a 28-day differentiation time-course of human embryonic stem cell-derived cardiomyocytes. Using purpose-designed bioinformatics tools, we uncovered a total of 15 318 and 3017 cardiac circRNA within human and mouse, respectively. Their abundance generally correlates with the abundance of their cognate linear RNA, but selected circRNAs exist at disproportionately higher abundance. Top highly expressed circRNA corresponded to key cardiac genes including Titin (TTN), RYR2, and DMD. The most abundant cardiac-expressed circRNA is a cytoplasmic localized single-exon circSLC8A1-1. The longest human transcript TTN alone generates up to 415 different exonic circRNA isoforms, the majority (83%) of which originates from the I-band domain. Finally, we confirmed the expression of selected cardiac circRNA by RT-PCR, Sanger sequencing and single molecule RNA-fluorescence in situ hybridization.
Our data provide a detailed circRNA expression landscape in hearts. There is a high-abundance of specific cardiac-expressed circRNA. These findings open up a new avenue for future investigation into this emerging class of RNA.
Trithorax-like group complex containing KDM6A acts antagonistically to Polycomb-repressive complex 2 (PRC2) containing EZH2 in maintaining the dynamics of the repression and activation of gene ...expression through H3K27 methylation. In urothelial bladder carcinoma,
(a H3K27 demethylase) is frequently mutated, but its functional consequences and therapeutic targetability remain unknown. About 70% of
mutations resulted in a total loss of expression and a consequent loss of demethylase function in this cancer type. Further transcriptome analysis found multiple deregulated pathways, especially PRC2/EZH2, in
-mutated urothelial bladder carcinoma. Chromatin immunoprecipitation sequencing analysis revealed enrichment of H3K27me3 at specific loci in
-null cells, including PRC2/EZH2 and their downstream targets. Consequently, we targeted EZH2 (an H3K27 methylase) and demonstrated that
-null urothelial bladder carcinoma cell lines were sensitive to EZH2 inhibition. Loss- and gain-of-function assays confirmed that cells with loss of KDM6A are vulnerable to EZH2. IGFBP3, a direct KDM6A/EZH2/H3K27me3 target, was up-regulated by EZH2 inhibition and contributed to the observed EZH2-dependent growth suppression in
-null cell lines. EZH2 inhibition delayed tumor onset in
-null cells and caused regression of
-null bladder tumors in both patient-derived and cell line xenograft models. In summary, our study demonstrates that inactivating mutations of
, which are common in urothelial bladder carcinoma, are potentially targetable by inhibiting EZH2.
The battery management system (BMS) is the main safeguard of a battery system for electric propulsion and machine electrification. It is tasked to ensure reliable and safe operation of battery cells ...connected to provide high currents at high voltage levels. In addition to effectively monitoring all the electrical parameters of a battery pack system, such as the voltage, current, and temperature, the BMS is also used to improve the battery performance with proper safety measures within the system. With growing acceptance of lithium-ion batteries, major industry sectors such as the automotive, renewable energy, manufacturing, construction, and even some in the mining industry have brought forward the mass transition from fossil fuel dependency to electric powered machinery and redefined the world of energy storage. Hence, the functional safety considerations, which are those relating to automatic protection, in battery management for battery pack technologies are particularly important to ensure that the overall electrical system, regardless of whether it is for electric transportation or stationary energy storage, is in accordance with high standards of safety, reliability, and quality. If the system or product fails to meet functional and other safety requirements on account of faulty design or a sequence of failure events, then the environment, people, and property could be endangered. This paper analyzed the details of BMS for electric transportation and large-scale energy storage systems, particularly in areas concerned with hazardous environment. The analysis covers the aspect of functional safety that applies to BMS and is in accordance with the relevant industrial standards. A comprehensive evaluation of the components, architecture, risk reduction techniques, and failure mode analysis applicable to BMS operation was also presented. The article further provided recommendations on safety design and performance optimization in relation to the overall BMS integration.
Dendritic cells (DC) are professional antigen-presenting cells that orchestrate immune responses. The human DC population comprises two main functionally specialized lineages, whose origins and ...differentiation pathways remain incompletely defined. Here, we combine two high-dimensional technologies-single-cell messenger RNA sequencing (scmRNAseq) and cytometry by time-of-flight (CyTOF)-to identify human blood CD123
CD33
CD45RA
DC precursors (pre-DC). Pre-DC share surface markers with plasmacytoid DC (pDC) but have distinct functional properties that were previously attributed to pDC. Tracing the differentiation of DC from the bone marrow to the peripheral blood revealed that the pre-DC compartment contains distinct lineage-committed subpopulations, including one early uncommitted CD123
pre-DC subset and two CD45RA
CD123
lineage-committed subsets exhibiting functional differences. The discovery of multiple committed pre-DC populations opens promising new avenues for the therapeutic exploitation of DC subset-specific targeting.
PDF
