bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased oxidative stress alters coronary microvascular tone in exercising swine with multiple comorbidities
Authors: Sorop O , Van Drie RWA , Van De Wouw J , Duncker DJ , Merkus D
Published: June 2022

Funding Acknowledgements

Type of funding sources: Foundation. Main funding source(s): Netherlands CardioVascular Research Initiative: an initiative with support of the Dutch Heart Foundation

Introduction

Diabetes mellitus (DM), chronic kidney disease (CKD) and hypercholesterolemia either alone or in combination, induce sustained systemic inflammation, increased oxidative stress and coronary endothelial dysfunction. The resulting alterations in microvascular tone may contribute to impaired myocardial perfusion in patients chronically affected by these comorbidities.

Purpose

We tested, in exercising swine, the hypothesis that increased production of reactive oxygen species (ROS) due to DM, CKD and high fat diet (HFD) results in loss of NO bioavailability in the coronary microvasculature leading to altered myocardial perfusion.

Methods

In 12 female swine, DM (streptozotocin 3x50mg/kg iv), CKD (renal embolization), and hypercholesterolemia (via high fat diet, HFD) were induced for 6 months (DM+HFD+CKD). 10 female healthy swine on normal pig chow served as controls (Normal). The role of ROS in the regulation of coronary flow was studied at rest and during graded treadmill exercise with or without ROS scavengers (MPG+Tempol).

Results 6 months after the induction of comorbidities, DM+HFD+CKD animals had sustained  hyperglycemia (19.5±1.1 vs 8.7±0.5mmol/L), renal dysfunction (plasma creatinine: 163±7 vs 120±3 µmol/l), hypercholesterolemia (12.7±2.1 vs 1.7±0.1mmol/l) and sustained systemic inflammation (TNF 52±5 vs 25±6 pg/ml, all P<0.05). Myocardial superoxide production was increased in DM+HFD+CKD animals due to NADPH oxidase activation and eNOS uncoupling, (Sorop et al, CVR 2018) and total antioxidant capacity was reduced (Fig. A), which was associated with a lower myocardial NO production, (P<0.05). In vivo experiments showed that myocardial oxygen delivery was impaired in DM+HFD+CKD swine at rest and during exercise, requiring an increased myocardial oxygen extraction (MO2ex) compared to Healthy (compare control runs in panels C and D, P<0.05), that is due to a loss of NO vasodilator influence (van de Wouw et al. BRIC 2021). Interestingly, scavenging of ROS had no effect in Healthy but resulted in increased MO2ex in DM+HFD+CKD (Fig. C, D), indicating that increased oxidative stress resulted in increased production of vasodilator ROS, most likely H2O2. The latter was also supported by an increase in ceramide production (138±34 vs 45±4 nmol/ml, P<0.05) and increased activity of catalase in the myocardium (Fig. B, P<0.05).

Conclusion

In swine, 6 months exposure to multiple comorbidities resulted in increased oxidative stress associated with impaired myocardial oxygen delivery, due to a loss of NO that was partially compensated for by increased H2O2-mediated coronary vasodilation.
Changes in endothelial characteristics as a new strategy to identify intracranial aneurysm at risk of rupture
Authors: Cayron A , Morel S , Bijlenga P , Allemann E , Kwak B
Published: June 2022

Funding Acknowledgements

Type of funding sources: None.

Background

Intracranial aneurysm (IA) is an arterial disease resulting in abnormal enlargement of the vessel lumen. Most IAs are asymptomatic but their rupture induces subarachnoid hemorrhage with 24% resulting in death and 11% in severe disability. Occlusion of an unruptured IA by microsurgical or endovascular treatment results in a procedural morbidity and mortality of between 4 to 7%. Decision making between "intervention" or "continuing observation" for an individual patient is currently based on clinical scores and further supported by radiologic imaging of IA characteristics including the observation of vessel wall enhancement (VWE) on magnetic resonance imaging (MRI). VWE reflects a local accumulation of colloid contrast agent, which has been associated with IA wall instability. The pathophysiology of VWE is unknown but enhanced permeability of arterial endothelium, excessive macrophage infiltration, or presence of vasa vasorum have been proposed as potential mechanisms.

Purpose

The goal of our study is to investigate the expression of tight junction (TJ) proteins in the arterial endothelium of human IA domes in the context of IA wall instability. To this end, we have compared ruptured and unruptured IA domes from a human IA biobank.

Methods

Human aneurysms from the middle cerebral artery were obtained during microsurgery by resection of the IA dome after clipping of the neck, embedded in paraffin, and then sectioned and stained for the endothelial cell marker CD31 and the TJ proteins Claudin-5 and Zonula occludens-1 (ZO-1). The expression of these proteins was compared between ruptured and unruptured IAs. Results are expressed as a median (interquartile range).

Results

Histological analyses for CD31 revealed that endothelial cell coverage in ruptured (N=16) IAs tended to be decreased compared to unruptured (N=30) domes (27% (10-49) versus 38% (23-77) respectively, P=0.06). Interestingly, in ruptured aneurysms the expression of the TJ proteins Claudin-5 (1.70um (1.52-2.04)) and ZO-1 (2.29um (1.96-2.75) was lower in comparison with unruptured samples (Claudin-5: 2.15um (1.90-2.76), P<0.05; ZO-1: 2.66um (2.40-3.66), P<0.05).

Conclusion

Our study revealed reduced expression of Claudin-5 and ZO-1 in ruptured IAs in comparison with unruptured IA domes. Reduction in TJ proteins may lead to increased endothelial permeability thus favoring the accumulation of MRI contrast agent in the IA wall and the observation of VWE. Focusing on changes in endothelial characteristics and permeability may represent a new strategy to identify IAs at risk of rupture.
Saraf implication in the vascular remodeling
Authors: Martin Bornez M , Rosado JA , Ordonez A , Smani T
Published: June 2022

Funding Acknowledgements

Type of funding sources: Public Institution(s). Main funding source(s): Agencia Estatal de Investigación

Background

Orai1 and STIM1, molecular components of Store-Operated Calcium Entry (SOCE), have been associated with vascular smooth muscle cells (VSMCs) proliferation in vascular remodeling. Nevertheless, the role of SARAF (SOCE Associated Regulatory Factor), a regulatory protein involved in STIM1 inhibition, has not been firmly established in the vascular remodeling.

Objetive

The aim of this study was to examine the role of SARAF and Orai1 in VSMCs proliferation and neointima formation after balloon injury of rat carotid arteries.

Methods and Results

Experiments were conducted in an animal model of rat carotid angioplasty to characterize neointima formation. VSMC isolated from rat coronary artery was also used to examine cell proliferation. The formation of neointima after balloon injury of rat carotid arteries was confirmed by haematoxylin and eosin staining of tissue sections up to 3 weeks after surgery. Injured arteries showed significant higher expression of SARAF, STIM1 and Orai1 compared to control tissues, corroborating the presence of these regulatory proteins in the neointima layer. Proximity ligation and co-immunoprecipitation assays revealed that SARAF interacts with Orai1 in the neointima. Furthermore, selective silencing of SARAF and Orai1 by small interfering RNA (siRNA) inhibited VSMC proliferation.

Conclusions

Our data suggest that SARAF is involved in VSMC proliferation and neointima formation after vascular injury.
Multiplexed apolipoprotein profiling advances the assessment of residual lipid-related cardiovascular risk
Authors: Schmidt L , Clarke R , Von Ende A , Yin X , Theofilatos K , Hopewell J , Mayr M
Published: June 2022

Funding Acknowledgements

Type of funding sources: Foundation. Main funding source(s): British Heart Foundation

Background and Purpose

Low-density lipoprotein cholesterol (LDL-C) is among the conventional lipid parameters used to predict risk of cardiovascular disease (CVD). Statins lower blood levels of pro-atherogenic LDL-C, but a residual cardiovascular risk remains in some individuals with therapeutically optimised LDL-C levels. Although the metabolism of LDL-C and other lipoprotein particles is governed by a range of different apolipoproteins, only apolipoproteins A-I and B are measured in clinical assays. Using a more comprehensive apolipoprotein panel in a large epidemiological cohort, this study aimed to determine the association of individual apolipoprotein levels with risk of coronary heart disease (CHD).

Methods

Bottom-up multiple reaction monitoring–mass spectrometry (MRM–MS) was used in conjunction with stable isotope-labelled peptide standards to quantify plasma levels of 13 apolipoproteins in participants of the Precocious Coronary Artery Disease (PROCARDIS) study (N = 1916; 941 cases of CHD, 975 controls). The relationship between apolipoprotein levels and CHD was assessed after adjusting for established risk factors for CVD and correcting for statin use.

Results

The strongest positive associations with CHD in the PROCARDIS study were seen for triglyceride-related apolipoproteins C-I (odds ratio [OR] 2.38, 95% confidence interval [CI] 1.63–3.46), C-III (OR 2.95, 95% CI 1.85–4.71) and E (OR 2.35, 95% CI 1.54–3.58), as well as for apolipoprotein (a) (kringle IV type 2 repeat, OR 2.84, 95% CI 2.04–3.95). Comparing these with associations of apolipoproteins with CVD in the Bruneck study (N = 688) revealed consistency across the two cohorts. Robust inverse associations with CHD were observed for apolipoproteins A-IV (OR 0.45, 95% CI 0.31–0.65) and M (OR 0.29, 95% CI 0.19–0.44).

Conclusion

Analysing two large epidemiological cohorts, Bruneck and PROCARDIS, demonstrated that multiplexed apolipoprotein profiling improves the understanding of cardiovascular risk independent of conventional lipid parameters. Most prominently, triglyceride-related apolipoproteins were shown to positively associate with residual cardiovascular risk. The findings of this study support the need for development and implementation of standardised, MRM–MS-based apolipoprotein profiling assays to guide novel lipid-modifying therapies beyond statins.
Micromanaging atherosclerosis: myeloid cell-specific microRNA-26b attenuates atherosclerosis development
Authors: Peters L , Bidzhekov K , Jansen Y , Bayasgalan S , Gencer S , Sundararaman SS , Bonnin-Marquez A , Yan Y , Jans AM , Bartneck M , Doering Y , Weber C , Van Der Vorst E
Published: June 2022

Funding Acknowledgements

Type of funding sources: None.

Increasing evidence has shown that microRNAs (miRs) are fundamental players in atherosclerosis, but the exact role of various miRs remains elusive. Preliminary data showed that, with a 5-fold increase, miR-26b was the most highly expressed miR in human atherosclerotic plaques compared to healthy vessels. Therefore, we aimed to determine its cell-specific effects on atherosclerosis development.

We examined the role of miR-26b in atherosclerosis by using full-body knockout (KO) mice on a 4 weeks and 12 weeks Western type diet (WTD) and myeloid cell-specific miR-26b KO (LysM-Cre) mice on 12 weeks WTD on an apolipoprotein E-deficient background. Atherosclerotic plaque size and phenotype were analyzed via immunohistochemical and immunofluorescent stainings. The phenotype and function of bone marrow-derived macrophages (BMDMs) from full body KO mice were analyzed via PCR, ELISA and gelatinase assays. Lipid nanoparticles (LNPs) served as vehicles for miR-26b mimics to restore miR-26b levels in knockout BMDMs.

A full-body miR-26b-KO on a 12 weeks WTD resulted in a striking 3.5-fold increase in atherosclerotic lesion size, compared to control. Consistent with a more advanced plaque phenotype, collagen content, smooth muscle cell percentage and relative necrotic core area were all significantly increased in plaques from miR-26b KO mice whilst the relative macrophage content was significantly reduced. Interestingly, the full-body KO mice on a 4 weeks WTD showed a remarkable 10-fold increase in plaque size and the respective plaques also had a reduced macrophage percentage, showing that miR-26b has very strong effects on both atherogenesis as well as atherosclerosis progression. Intriguingly, relative plaque size in the arches of miR-26b LysM-Cre mice were increased by 3-fold and collagen content was also increased significantly, suggesting a role for myeloid-specific miR-26b in atherosclerosis development. Further highlighting its myeloid-specific effects, miR-26b KO BMDMs showed an increase in IL-6 and TNFα secretion, which could be rescued by LNPs containing miR-26b mimics. Additionally, these miR-26b KO BMDMs showed a reduction in collagen breakdown.

Overall, our results clearly demonstrate an atheroprotective role of myeloid cell-specific miR-26b by attenuating lesion initiation as well as progression, mainly by suppressing inflammation and stimulating collagen breakdown. Our study leads to exciting new insights into the role of miR-26b in atherosclerosis development, providing an important back-bone for future research and potential new treatment options.
MiR-6821-5p and coronary calcification in familial hypercholesterolemia patients with subclinical atherosclerosis
Authors: Padro T , Escate R , Suades R , Mata P , Badimon L
Published: June 2022

Funding Acknowledgements

Type of funding sources: Public Institution(s). Main funding source(s): Agencia Estatal de Investigaciópn (AEI)” - Spanish Ministry of Economy Competitiveness of Science Agencia Estatal de Investigaciópn (AEI)” - Spanish Institute of Health Carlos III, ISCIII

Background

Familial hypercholesterolemia (FH) is associated with premature atherosclerosis but FH patients have a highly variable risk of clinical atherosclerotic cardiovascular disease (ACVD) presentation. Preclinical atherosclerosis has been identified by imaging of coronary artery calcium (CAC); however, little is known of the molecular pathways involved in vascular calcification in FH. Circulating microRNAs are proven as a powerful epigenetic regulators of atherosclerosis development.

Purpose

We have investigated the circulating microRNA signature of FH patients with CAC and asymptomatic atherosclerosis.

Methods

Differential plasma miRNA profiling was performed by Affymetrix microarray technology (discovery studies) and RT-PCR using TaqMan technology (validation studies) in plasma of FH subjects (N=86) included in a multicentric nationwide cohort. FH-patients with and without coronary calcification (determined by Agatston score) by computed tomographic angiography imaging were investigated. Proof-of-concept validation studies were performed in cell culture of human coronary-derived vascular smooth muscle cells (hcVSMC) calcification analysis.

Results

Using a non-targeted approach, a differential signature of 15 miRNA (all upregulated) was identified in FH-patients presenting subclinical atherosclerosis with calcified plaques (FH-CCS+, N=49, Agatston score >100) compared with FH-subjects without coronary calcification (FH-CCS-, N=37, Agatston score 0). After RT-PCR validation, 3 miRNAs (miR-193a-5p, miR-30e-5p and miR-6821-5p) were significantly upregulated in FH-CCS+ patients. ROC-analysis confirmed miR-6821-5p as the best miRNA for discriminating FH-patients with coronary calcification (AUC 0.70±0.06, P=0.003). High miR-6821-5p levels associated to older age (P=0.003) and high LDL burden (P=0.014), two established risk factors for calcification. In vitro studies showed miR-6821-5p up-regulation (P=0.018) in hcVSMC cultured under calcification conditions (high-phosphate medium) and expressing increased levels of calcification-related genes such as SPP1 (Secreted Phosphoprotein 1, osteopontin) and BMP2 (Bone Morphogenetic Protein 2) when compared with non-calcified hcVSMC.

Conclusion

Up-regulated levels of miR-6821-5p are found in FH patient with CAC+ atherosclerotic plaques, as well as in calcified isolated human coronary smooth muscle cells that express the pro-calcification genes as osteopontin and BMP2. miR-6821-5p is involved in the development of calcification in the coronary arteries and in the development of atherosclerotic plaques.
Beneficial impact of pork dry-cured ham consumption on blood pressure and cardiometabolic markers in individuals with high cardiovascular risk
Authors: Montoro-Garcia S , Velasco-Soria A , Abellan-Aleman J
Published: June 2022

Funding Acknowledgements

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Fundación Séneca de la Región de Murcia through the project “Jovenes Líderes en Investigación" RETOS-COLABORACIÓN (Ministerio de Ciencia y Tecnología.

Background

Evidence suggests that bioactive-peptides reduce hypertension and affect certain metabolic pathways.

Methods

Fifty-four volunteers with stage 1-hypertension and/or hypercholesterolemia and/or basal glucose >100 mg/dL were recruited and randomized to particular pork dry-cured ham (treatment) and cooked-ham (placebo) products for 2.5 months. Bioactive-peptides composition and enzyme inhibitory activities of both particular meat products were characterized. Treatment comparisons for the main effects were made using a 2 (treatment) × 2 (times) repeated measures minus the effect of cooked-ham.

Results

24h mean systolic and diastolic pressures decreased up to 2.4 mmHg in the dry-cured ham period (p=0.0382 y p=0.0233, respectively) as well as the number of systolic pressure measures > 135 mmHg (p=0.0070). Total cholesterol levels also decreased significantly after dry-cured ham intake (p=0.049). No significant differences were observed between the two treatments for basal glucose, HOMA-IR index and insulin levels (p>0.05). However, significant rise of ghrelin level was observed, while leptin plasma values slightly decreased (treatment effect, p=0.0350 and p=0.0528, respectively).

Conclusions

This study suggested the beneficial effects of regular bioactive-peptides consumption on the improvement of systolic/diastolic blood pressures and emphasized the potentially regulation of ghrelin/leptin levels which provides new therapeutic opportunities for metabolic disorders in the cardiovascular primary prevention.
Does targeted temperature management increase the risk of stent thrombosis in survivors of out-of-hospital cardiac arrest? A single centre experience
Authors: Kanji R , Gue YX , Saw AM , Shahid MQ , Gorog DA
Published: June 2022

Funding Acknowledgements

Type of funding sources: None.

Introduction

Acute Myocardial Infarction (AMI) complicated by out-of-hospital cardiac arrest (OCHA) carries a poor prognosis. Emergent angiography and primary percutaneous coronary intervention (PPCI) has been shown to improve survival, however some patients are left with significant neurological sequelae. Targeted Temperature Management (TTM) in randomised controlled trials has improved neurological status in survivors, however concerns have arisen from case series demonstrating a higher incidence of stent thrombosis. Reduced absorption of orally-administered P2Y12 inhibitor medication has been demonstrated in this cohort on the intensive care unit (ICU) and has been proposed to account for an observed increase in stent thrombosis.

Purpose

Our aim was to assess the relationship between stent thrombosis and TTM in patients with OHCA due to AMI and undergoing primary percutaneous coronary intervention (PPCI).

Methods

We conducted a single centre, retrospective analysis of consecutive patients admitted to the East and North Hertfordshire NHS Trust with an OHCA secondary to ST-elevation myocardial infarction and treated with PPCI.  All patients received aspirin loading and either enteral P2Y12 inhibitor loading (ticagrelor or clopidogrel) or intravenous (cangrelor) prior to or immediately after PPCI, according to clinician preference. Glycoprotein IIb/IIIa administration was determined by physician choice and documented. All patients were transferred to the ICU straight after PPCI, where some received TTM. Notes were reviewed to allow recording of demographic and procedural data, including post resuscitation care up to hospital discharge.

Results

A total of 92 patients were identified, 80% male and aged 62 +/-12.5 years. In addition to aspirin, patients were treated with P2Y12 inhibitors with 72.5% loaded with ticagrelor, 2.5% with clopidogrel and the remaining 25% with intravenous cangrelor. In addition, 49% of patients received periprocedural glycoprotein IIb/IIIa inhibitor.

TTM was initiated in 38 patients (41%) using surface pads. The average duration of TTM was 24 hours. No cases of stent thrombosis occurred. In-hospital all-cause mortality was 24%. The death rate was higher amongst those patients who were cooled, but this difference was not statistically significant (35% vs 17%, p = 0.08). Cangrelor use was significantly higher in the cooled cohort (43% vs. 8%, p < 0.001), but glycoprotein IIb/IIIa inhibitor use was similar between those receiving and not receiving TTM (38% vs. 57%, p = 0.088).

Conclusion

No definite stent thromboses were recorded in the 92 patients reviewed, suggesting that TTM does not increase the risk of stent thrombosis. Our conclusion is limited by the small sample size, and the heterogeneity in P2Y12 inhibitor use, particularly the higher use of cangrelor in the cooled cohort.
Ursolic acid reduces inflammation and fibrosis in the kidney of diabetic mice
Authors: Manea SA , Lazar AG , Vlad ML , Manea A
Published: June 2022

Funding Acknowledgements

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): UEFISCDI

Background

Diabetic kidney disease (DKD) is arguably the major disabling and life-threatening microvascular-related disorder associated with both type I and type II diabetes. Inflammation of glomerular capillary system and progressive accumulation of glomerular extracellular proteins are important culprit mechanisms leading to glomerulosclerosis and ultimately renal failure in end-stage DKD. Conventional anti-diabetic therapies can only delay the progression of DKD. The naturally-occurring triterpenic acids emerged as important candidate pharmacological compounds for the treatment of cardiometabolic disorders.

Purpose

We aimed at investigating the potential regulatory effects of ursolic acid, a pentacyclic triterpenoid, on the expression of key pro-inflammatory and pro-fibrotic mediators in diabetic kidney.

Methods

Non-diabetic and streptozotocin-induced diabetic C57BL/6J male mice were randomized to receive via intraperitoneal injection 1 mg/kg ursolic acid (UA), or its vehicle (5% DMSO + 95% PBS, pH 7.4), for 4 weeks. Human endothelial cells (EC) were exposed to normal (5 mM) or high (25mM) concentration of glucose in the absence/presence of 1-10 μM UA. Real-time PCR, Western blot, and immunofluorescence microscopy techniques were employed to investigate the expression of selected DKD-relevant pro-inflammatory and pro-fibrotic molecules. Morphological aspects of the kidney and glomeruli were assessed by histochemistry.

Results

The mRNA/protein levels of pro-inflammatory (MCP-1, TNFα, NOS2, ICAM-1, VCAM-1, E-selectin) and pro-fibrotic (collagen IV, fibronectin, laminin, TGFβ) mediators were found significantly elevated in the kidney of diabetic mice as compared to non-diabetic counterparts. Treatment of diabetic mice with UA significantly reduced the up-regulated expression of pro-inflammatory mediators, extracellular matrix proteins, and pro-fibrotic factor TGFβ. Moreover, glomerular hypertrophy and the up-regulation of glomerular collagen IV, fibronectin, and laminin protein levels were significantly reduced in UA-treated diabetic mice. In cultured human EC, UA suppressed the high glucose-induced up-regulation of ICAM-1, VCAM-1, E-selectin and NF-kB signaling.

Conclusion

In experimental diabetes, ursolic acid down-regulates the expression of DKD-relevant pro-inflammatory and pro-fibrotic molecules in the kidney of diabetic mice by potentially targeting NF-kB signaling pathway. The data of this study suggest that triterpenic acids and their chemical derivates could become important pharmacological tools to reduce inflammation and fibrosis associated with DKD.
B cell depletion skews cd4+ t cell towards a pro-inflammatory phenotype in aged atherosclerotic mice
Authors: De Mol J , Postel R , Smit V , Bernabe Kleijn MNA , Bot I , Kuiper J , Foks AC
Published: June 2022

Funding Acknowledgements

Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation

ERA CVD

Aims

Aging is associated with changes in the composition and function of the immune system, such as decreased B cell numbers and reduced antibody responses (1). In addition, aging is related to an increased incidence of inflammatory diseases, such as the lipid-driven chronic inflammatory disease atherosclerosis, the main underlying cause of cardiovascular disease (2). B cells play a major role in atherosclerosis progression by antibody secretion, antigen presentation and T cell regulation. Different B cell subsets, with either proatherogenic or antiatherogenic properties, have been identified in atherosclerosis, but the impact of aging on B cells during atherosclerosis remains to be elucidated. In contrast to young atherosclerotic mice where few B cells are found within the plaque, single cell RNA sequencing and flow cytometry data from our group revealed that B cells are one of the most dominant leukocytes present in atherosclerotic aortas from naturally aged LDLr-/- mice. In this study, we aimed to gain further insights into the role of these aged B cells on T cell immunity in atherosclerosis by depleting B cells in aged atherosclerotic mice.

Methods and Results

Aged (85-95 weeks) atherosclerotic male LDLr-/- mice were kept on a chow diet for six weeks, during which the mice received 250 µg B cell-depleting anti-CD20 antibody (Genentech) (n=12) or 250 µg rat IgG2a isotype control (n=12) once a week intraperitoneally. Mice that received the anti-CD20 antibody showed effective B cell depletion in the blood and lymphoid organs, such as the spleen and lymph nodes, but also locally in the atherosclerotic plaque. In addition, B cell depleted mice showed a significant increase in the percentage of T-bet expressing CD4+ T cells in aortic plaques compared to control mice (αCD20: 25.05±2.88% vs. ctrl: 15.94±2.14%, p<0.05). Furthermore, the percentage of RORyt+ and IL-17+ CD4+ T cells in the spleen and heart draining lymph nodes was increased after B cell depletion, indicating a shift towards Th17 differentiation.

Conclusions

Collectively, we show that CD20+ B cell depletion in aged LDLr-/- mice skews CD4+ T cells towards a Th1 phenotype in the atherosclerotic plaque and towards a Th17 phenotype in lymphoid organs, suggesting a protective role for aged B cells in atherosclerosis. However, B cells are a heterogeneous population and further research should elucidate whether aged B cells exert a pro- or anti-atherogenic role. In conclusion, our results indicate that aged B cells have an important function in CD4+ T cell differentiation and could be attractive targets to combat age-related cardiovascular disease.
Induction of CD73 prevents death after emergency open aortic surgery
Authors: Spicer AJS , Venermo MV , Hakovirta HH , Jalkanen JMJ
Published: June 2022

Funding Acknowledgements

Type of funding sources: Other. Main funding source(s): Faron Pharmaceuticals Ltd

Background

Cluster of differentiation (CD73) has been a focus of drug development in immuno-oncology for numerous years now. This however disregards the major role of CD73 in inflammatory conditions by the conversion of the majorly conserved and pro-inflammatory, adenosine triphosphate (ATP) to the equally conserved and anti-inflammatory, adenosine. Therefore the induction of CD73 for conditions of major inflammation would occur such as during times of ischemia post major surgery would be therapeutically beneficial. The therapeutic induction of CD73 has previously been shown in other inflammatory condtions by utilising intravenous interferon beta.

A ruptured abdominal aortic aneurysm (RAAA) is a medical emergency. Whilst rarely scene now due to improvements to screening, the only lifesaving treatment remains to be is immediate aortic surgery. Half of RAAA patients die before reaching the hospital and despite successful surgery another 30-40% of these patients die post-surgery in intensive care due to multi-organ failure (MOF).

The cause of MOF is systemic inflammatory response is brought forth by inflammatory mediators such as ATP, that are released from stressed and dying cells which perpetuate the cycle of inflammation.

Purpose

Can intravenous interferon beta-1a induce CD73 production and improve survival after emergency open surgery for a ruptured abdominal aortic aneurysm?

Methods

A multi-center phase II double-blind, randomised, parallel group comparison of the efficacy and safety of intravenous interferon beta-1a vs. placebo for the induction of CD73 to prevent death after open surgery for an infra-renal ruptured abdominal aortic aneurysm

Results

The initial aim of the trial, better RAAA survival after emergency surgery with INF beta-1a treatment could not be demonstrated due to the under powering of the trial. Nevertheless, the anticipated target mechanism, up-regulation of CD73 was associated with 100% survival. In tandem, both neutralising antibodies and systemic glucocorticoid blocked the up-regulation of CD73.

Conclusion

Contrary to the initial hypothesis IV IFN beta-1a did not prevent post operative RAAA mortality. Further studies are required to draw definitive conclusions as the clinical trial had to be stopped and did not reach the expected number of participants. Future trials should take into account the potential interaction with glucocorticoids and interferon beta-1a neutralising antibodies. Nonetheless, the anticipated target mechanism of up-regulation of CD73 was associated with survival and is a highly potential molecule to target to improve post-operative RAAA Survival
Observational medical treatment or surgery for giant paraesophageal hiatal hernia in elderly patients
Authors: Braghetto Italo , Molina Juan Carlos , Korn Owen , Lanzarini Enrique , Musleh Maher , Figueroa Manuel , Rojas Jorge
Published: June 2022

Giant paraesophageal hernias (GPHH) occur frequently in the elderly and account for about 5–10% of all hiatal hernias. Up to now controversy persists between expected medical treatment and surgical treatment. To assess if an indication for surgical repair of GPHH is possible in elderly patients. A prospective study that includes patients over 70 years of age hospitalized from January 2015 to December 2019 with GPHH. Patients were separated into Group A and Group B. Group A consisted of a cohort of 23 patients in whom observation and medical treatment were performed. Group B consisted of 44 patients submitted to elective laparoscopic hiatal hernia repair. Symptomatic patients were observed in both groups (20/23 in Group A and 38/44 in Group B). Charlson’s score >6 and ASA II or III were more frequent in Group A. Patients in Group A presented symptoms many years before their hospitalization in comparison to Group B (21.8+7.8 vs. 6.2+3.5 years, respectively) (P=0.0001). Emergency hospitalization was observed exclusively in Group A. Acute complications were frequently observed and hospital stays were significantly longer in Group A, 14 patients were subjected to medical management and 6 to emergency surgery. In-hospital mortality occurred in 13/20 patients (65%) versus 1/38 patients (2.6%) in Group B (P=0.0001). Laparoscopic paraesophageal hiatal hernia repair can be done safely, effectively, and in a timely manner in elderly patients at specialized surgical teams. Advanced age alone should not be a limiting factor for the repair of paraesophageal hernias.
Changes in resonance frequency of rock columns due to thermoelastic effects on a daily scale: observations, modelling and insights to improve monitoring systems
Authors: Guillemot Antoine , Baillet Laurent , Larose Eric , Bottelin Pierre
Published: June 2022

Slope instabilities, including prone-to-fall rock columns, are known to exhibit clear vibrational modes. The resonance frequencies of these modes can be tracked by seismic instrumentation, allowing the rock column's mechanical and structural properties to be monitored, as well as providing precursors of imminent irreversible failures. In previous studies, superficial thermoelastic effects were assumed to drive daily fluctuations in resonance frequencies, but no qualitative or quantitative evidence was provided. The results presented here corroborate this hypothesis and quantify the physical processes involved. We interpreted daily variations of resonance frequencies in the Les Arches study site (Vercors, French Prealps) using a thermo-mechanical finite-element model. Modelled fluctuations of the resonance frequencies over a day closely matched experimental observations, reproducing the daytime frequency increase of around 2 per cent. In addition, our model provides explanation of the various behaviours observed across study sites: the frequency response strongly depends on solar exposure, as well as the timing and intensity of both radiative and convective heat fluxes. We highlight acousto-elastic constants as key parameters of our semi-quantitative model, although they remain poorly constrained here. For future instrumentation, we therefore recommend the deployment of pyranometers on rocky sites to accurately invert these parameters over time, thus allowing rock fracturing to be quantitatively tracked by acousto-elastic monitoring.
Impacts of an early childhood obesity prevention program in Mexico
Authors: Flores-Peña Y , He M , Sosa E T , Avila-Alpirez H , Trejo-Ortiz P M , Gutiérrez-Sánchez G
Published: June 2022

The Healthy Change Program aimed to improve the accuracy of maternal perceptions of children’s weight (MPCW), maternal feeding style (MFS) and feeding practices. Using a randomized control trial design, the intervention group received 4-weekly group sessions focusing on MPCW, MFS and healthy behaviors. The control group received the same dose of attention-control sessions on food hygiene. Data were collected at the baseline and at the end of the program via self-administered questionnaires and anthropometric measurements. Participants included 294 mother–child dyads with 149 in the intervention group and 145 in the control group. The accuracy of MPCW significantly increased at the study end point in the intervention group (57.0–67.1%, P < 0.05) but not in the control group (67.6–69.7%, P > 0.05), with no between-group difference in pre- and post-change (P > 0.05). At the study end point, more mothers of overweight and obese children in the intervention group had accurate MPCW than their control counterparts (31.4% versus 11.1%, P < 0.01). The intervention group had a shift toward an authoritative style at the study end point (17.4% versus 26.2%, P < 0.001) and favorable changes in feeding practices. The Healthy Change Program contributed to improving the accuracy of MPCW and shifts toward favorable MFS and feeding practices.
Multi-Joint Analysis of Pose Viability Supports the Possibility of Salamander-Like Hindlimb Configurations in the Permian TetrapodEryops megacephalus
Authors: Herbst Eva C , Manafzadeh Armita R , Hutchinson John R
Published: June 2022

Synopsis

Salamanders are often used as analogs for early tetrapods in paleontological reconstructions of locomotion. However, concerns have been raised about whether this comparison is justifiable, necessitating comparisons of a broader range of early tetrapods with salamanders. Here, we test whether the osteological morphology of the hindlimb in the early tetrapod (temnospondyl amphibian) Eryops megacephalus could have facilitated the sequence of limb configurations used by salamanders during terrestrial locomotion. To do so, we present a new method that enables the examination of full limb configurations rather than isolated joint poses. Based on this analysis, we conclude that E. megacephalus may indeed have been capable of salamander-like hindlimb kinematics. Our method facilitates the holistic visual comparison of limb configurations between taxa without reliance on the homology of coordinate system definitions, and can thus be applied to facilitate various comparisons between extinct and extant taxa, spanning the diversity of locomotion both past and present.
Septic shock due to candida and disseminated herpes simplex virus-1 (HSV1) after elective spinal surgery in an immunocompromised patient with chronic HSV1 infection
Authors: Trivedi Aakash A , Yang James Y , Johnston Jackie , Sori Alan
Published: June 2022

Herpes simplex virus is an infection that can result in a variety of symptoms ranging from blistering or ulcers to severe, systemic manifestations. We report a case of patient who underwent elective spinal surgery and developed invasive herpes as well as candidiasis postoperatively without any direct evidence of immunosuppression.
Discovery of three new near-pristine absorption clouds at z = 2.6–4.4
Authors: Robert P Frédéric , Murphy Michael T , O’Meara John M , Crighton Neil H M , Fumagalli Michele
Published: June 2022

We report the discovery of three new ‘near-pristine’ Lyman limit systems (LLSs), with metallicities ≈1/1000 solar, at redshifts 2.6, 3.8, and 4.0, with a targeted survey at the Keck Observatory. High-resolution echelle spectra of eight candidates yielded precise column densities of hydrogen and weak, but clearly detected, metal lines in seven LLSs; we previously reported the one remaining, apparently metal-free LLS, to have metallicity <1/10 000 solar. Robust photoionization modelling provides metallicities [Si/H] = −3.05 to −2.94, with 0.26 dex uncertainties (95 per cent confidence) for three LLSs, and $\textrm {[Si/H]} \gtrsim -2.5$ for the remaining four. Previous simulations suggest that near-pristine LLSs could be the remnants of PopIII supernovae, so comparing their detailed metal abundances with nucleosynthetic yields from supernovae models is an important goal. Unfortunately, at most two different metals were detected in each new system, despite their neutral hydrogen column densities ($10^{19.2}\textrm {--}10^{19.4}\, \textrm {cm}^{-2}$) being two orders of magnitude larger than the two previous, serendipitously discovered near-pristine LLSs. Nevertheless, the success of this first targeted survey for near-pristine systems demonstrates the prospect that a much larger, future survey could identify clear observational signatures of PopIII stars. With a well-understood selection function, such a survey would also yield the number density of near-pristine absorbers that, via comparison to future simulations, could reveal the origin(s) of these rare systems.
How many extragalactic stellar mass binary black holes will be detected by space gravitational-wave interferometers?
Authors: Seto Naoki , Kyutoku Koutarou
Published: June 2022

On the basis of GWTC-3, we discuss the detection prospect of extragalactic binary black holes (BBHs) by space gravitational-wave interferometers, mainly targeting BBHs in the range of chirp masses with abundant detections. In particular, we directly incorporate the chirp mass distribution of the 62 BBHs detected so far at high significance. We find that, due to the reduction of both the comoving merger rate and a weighted average of chirp masses, the expected detection numbers are generally much smaller than the results obtained by the same authors immediately after the report of GW150914. For LISA, the total BBH detections in the chirp mass range are estimated to be Ntot ∼ 2(T/4yr)3/2(ρthr/10)−3, dominated by nearly monochromatic BBHs (ρthr: the detection threshold, T: the observational period). TianQin will have a total detection number Ntot similar to LISA. Meanwhile, TianQin has potential to find Nmer ∼ 0.6(T/4yr)7/4(ρthr/10)−3 BBHs that merge in the observational period. This number for merging BBHs is 4–5 times larger than that of LISA because of the difference of the optimal bands. We also investigate prospects for joint operations of multiple detectors, finding that concurrent observations will be more advantageous than sequential ones.
Magnetic activities on two single-lined RS Canum Venaticorum binaries IM Pegasi and σ Geminorum
Authors: Cao Dongtao , Gu Shenghong , Grundahl F , Pallé P L
Published: June 2022

We present the study on continuous high-resolution spectroscopic observations of two long-period single-lined RS Canum Venaticorum (RS CVn) binary stars IM Pegasi (IM Peg) and σ Geminorum (σ Gem), obtained with the Hertzsprung SONG telescope during the 2015–2016 season. Chromospheric activity indicators Hα, $\rm{Na\,\,{\small I}}$ D1, D2 doublet, $\rm{He\,\,{\small I}}$ D3, and Hβ lines have been analysed by using the spectral subtraction technique. The expected chromospheric emission features in the Hα, $\rm{Na\,\,{\small I}}$ D1, D2 doublet, and Hβ lines confirm that both of two stars are very active systems. In the spectra, the $\rm{He\,\,{\small I}}$ D3 line had been always detected in absorption feature. Although the behaviour of chromospheric activity indicators is very similar for both stars, the activity level of IM Peg is much stronger than that of σ Gem. Moreover, the equivalent width variations of the Hα, $\rm{He\,\,{\small I}}$ D3, and Hβ line subtractions correlate well and show different behaviour among different orbital cycles, which indicates the presence and evolution of activity longitudes over the surface of two stars. Furthermore, the subtracted Hα line profile is usually asymmetric. The red-shifted excess absorption features could be interpreted as a strong down-flow of cool absorbing material, while the blue-shifted emission component is probably caused by up-flow of hot materials through microflare events.
Comprehensive analysis of PNA-based antisense antibiotics targeting various essential genes in uropathogenicEscherichia coli
Authors: Popella Linda , Jung Jakob , Do Phuong Thao , Hayward Regan J , Barquist Lars , Vogel Jörg
Published: June 2022

Antisense peptide nucleic acids (PNAs) that target mRNAs of essential bacterial genes exhibit specific bactericidal effects in several microbial species, but our mechanistic understanding of PNA activity and their target gene spectrum is limited. Here, we present a systematic analysis of PNAs targeting 11 essential genes with varying expression levels in uropathogenic Escherichia coli (UPEC). We demonstrate that UPEC is susceptible to killing by peptide-conjugated PNAs, especially when targeting the widely-used essential gene acpP. Our evaluation yields three additional promising target mRNAs for effective growth inhibition, i.e.dnaB, ftsZ and rpsH. The analysis also shows that transcript abundance does not predict target vulnerability and that PNA-mediated growth inhibition is not universally associated with target mRNA depletion. Global transcriptomic analyses further reveal PNA sequence-dependent but also -independent responses, including the induction of envelope stress response pathways. Importantly, we show that 9mer PNAs are generally as effective in inhibiting bacterial growth as their 10mer counterparts. Overall, our systematic comparison of a range of PNAs targeting mRNAs of different essential genes in UPEC suggests important features for PNA design, reveals a general bacterial response to PNA conjugates and establishes the feasibility of using PNA antibacterials to combat UPEC.
40S hnRNP particles are a novel class of nuclear biomolecular condensates
Authors: Domanski Michal , Dedic Emil , Pérez Maria Escura , Cléry Antoine , Campagne Sébastien , Uldry Anne-Christine , Braga Sophie , Heller Manfred , Rabl Julius , Afanasyev Pavel , Boehringer Daniel , Nováček Jiří , Allain Frédéric T , Mühlemann Oliver
Published: June 2022

Heterogenous nuclear ribonucleoproteins (hnRNPs) are abundant proteins implicated in various steps of RNA processing that assemble on nuclear RNA into larger complexes termed 40S hnRNP particles. Despite their initial discovery 55 years ago, our understanding of these intriguing macromolecular assemblies remains limited. Here, we report the biochemical purification of native 40S hnRNP particles and the determination of their complete protein composition by label-free quantitative mass spectrometry, identifying A-group and C-group hnRNPs as the major protein constituents. Isolated 40S hnRNP particles dissociate upon RNA digestion and can be reconstituted in vitro on defined RNAs in the presence of the individual protein components, demonstrating a scaffolding role for RNA in nucleating particle formation. Finally, we revealed their nanometer scale, condensate-like nature, promoted by intrinsically disordered regions of A-group hnRNPs. Collectively, we identify nuclear 40S hnRNP particles as novel dynamic biomolecular condensates.
The dsRBP Staufen2 governs RNP assembly of neuronal Argonaute proteins
Authors: Ehses Janina , Schlegel Melina , Schröger Luise , Schieweck Rico , Derdak Sophia , Bilban Martin , Bauer Karl , Harner Max , Kiebler Michael A
Published: June 2022

Mature microRNAs are bound by a member of the Argonaute (Ago1-4) protein family, forming the core of the RNA-induced silencing complex (RISC). Association of RISC with target mRNAs results in ribonucleoprotein (RNP) assembly involved in translational silencing or RNA degradation. Yet, the dynamics of RNP assembly and its underlying functional implications are unknown. Here, we have characterized the role of the RNA-binding protein Staufen2, a candidate Ago interactor, in RNP assembly. Staufen2 depletion resulted in the upregulation of Ago1/2 and the RISC effector proteins Ddx6 and Dcp1a. This upregulation was accompanied by the displacement of Ago1/2 from processing bodies, large RNPs implicated in RNA storage, and subsequent association of Ago2 with polysomes. In parallel, Staufen2 deficiency decreased global translation and increased dendritic branching. As the observed phenotypes can be rescued by Ago1/2 knockdown, we propose a working model in which both Staufen2 and Ago proteins depend on each other and contribute to neuronal homeostasis.
HSFs drive transcription of distinct genes and enhancers during oxidative stress and heat shock
Authors: Himanen Samu V , Puustinen Mikael C , Da Silva Alejandro J , Vihervaara Anniina , Sistonen Lea
Published: June 2022

Reprogramming of transcription is critical for the survival under cellular stress. Heat shock has provided an excellent model to investigate nascent transcription in stressed cells, but the molecular mechanisms orchestrating RNA synthesis during other types of stress are unknown. We utilized PRO-seq and ChIP-seq to study how Heat Shock Factors, HSF1 and HSF2, coordinate transcription at genes and enhancers upon oxidative stress and heat shock. We show that pause-release of RNA polymerase II (Pol II) is a universal mechanism regulating gene transcription in stressed cells, while enhancers are activated at the level of Pol II recruitment. Moreover, besides functioning as conventional promoter-binding transcription factors, HSF1 and HSF2 bind to stress-induced enhancers to trigger Pol II pause-release from poised gene promoters. Importantly, HSFs act at distinct genes and enhancers in a stress type-specific manner. HSF1 binds to many chaperone genes upon oxidative and heat stress but activates them only in heat-shocked cells. Under oxidative stress, HSF1 localizes to a unique set of promoters and enhancers to trans-activate oxidative stress-specific genes. Taken together, we show that HSFs function as multi-stress-responsive factors that activate distinct genes and enhancers when encountering changes in temperature and redox state.