bluuebunny/crossref_metadata_2025_split huggingface dataset:
Apelin improves angiogenesis and blood flow reperfusion following lower limb ischemia in diabetic mice
Authors: Robillard Stéphanie , Trân Kien , Brazeau Tristan , Boisvert Elizabeth , Lizotte Farah , Auger-Messier Mannix , Boudreault Pierre-Luc , Marsault Éric , Geraldes Pedro 
Published: February 2023

AbstractBACKGROUNDPeripheral artery disease (PAD) is a major risk factor for lower-extremity amputation in diabetic patients caused by an insufficient angiogenic response. Unfortunately, therapeutic angiogenesis using growth factors, such as the vascular endothelial growth factor (VEGF), are ineffective in diabetic conditions due to diabetes-induced growth factor resistance. The apelinergic system (APJ receptor/apelin) is highly upregulated under hypoxic condition and acts as an activator of angiogenesis. Apelin treatment has been shown to improve revascularization in nondiabetic models of ischemia, however, its role on angiogenesis in diabetic conditions remains poorly investigated. Thus, this study explored the impact of Pyr-apelin-13 in endothelial cell function and diabetic mouse model of hindlimb ischemia.METHODSNondiabetic and diabetic mice underwent femoral artery ligation to induce lower limb ischemia. A group of diabetic mice was implanted subcutaneously with osmotic pumps delivering Pyr-apelin-13 for 28 days. Blood flow reperfusion was measured for 4 weeks post-surgery and exercise willingness was assessed in individual cages with voluntary wheels.In vitro, BAECs were exposed to normal (NG) or high glucose (HG) levels and hypoxia. Cell migration, proliferation and tube formation assays were performed following either VEGF or Pyr-apelin-13 stimulation.RESULTSFollowing limb ischemia, blood flow reperfusion, functional recovery of the limb and vascular density were improved in diabetic mice receiving Pyr-apelin-13 compared to untreated diabetic mice. In cultured BAECs, exposure to HG concentrations and hypoxia reduced VEGF proangiogenic actions, whereas apelin proangiogenic effects remained unaltered. Pyr-apelin-13 induced its proangiogenic actions through Akt/AMPK/eNOS and RhoA/ROCK signaling pathways under both NG or HG concentrations and hypoxia exposure.CONCLUSIONSPyr-apelin-13 promoted endothelial cell function and angiogenesis in the ischemic limb despite diabetes and HG level exposure. Therefore, our results identified the apelinergic system as a potential therapeutic target for angiogenic therapy in diabetic patients with PAD.HighlightsSustained delivery of Pyr-apelin-13 improves blood flow reperfusion, functional recovery of the hindlimb and capillary density in diabetic mice following ischemia.Unlike VEGF, signaling pathways and proangiogenic actions induced by apelin/APJ stimulation are not impaired by high glucose exposure.Despite the presence of tissue ischemia, diabetes reduces the expression of apelin and APJ in the ischemic adductor muscle, an effect overcome by apelin administration.
Female gene networks are expressed in myofibroblast-like smooth muscle cells in vulnerable atherosclerotic plaques
Authors: Benavente Ernest Diez , Karnewar Santosh , Buono Michele , Mili Eloi , Hartman Robin J. G. , Kapteijn Daniek , Slenders Lotte , Daniels Mark , Aherrahrou Redouane , Reinberger Tobias , Mol Barend M. , de Borst Gert J. , de Kleijn Dominique P. V. , Prange Koen H. M. , Depuydt Marie A. C. , de Winther Menno P. J. , Kuiper Johan , Björkegren Johan L. M. , Erdmann Jeanette , Civelek Mete , Mokry Michal , Owens Gary K , Pasterkamp Gerard , den Ruijter Hester M. 
Published: February 2023

AbstractWomen presenting with coronary artery disease (CAD) more often present with fibrous atherosclerotic plaques, which are currently understudied. Phenotypically modulated smooth muscle cells (SMCs) contribute to atherosclerosis in women. How these phenotypically modulated SMCs shape female versus male plaques is unknown. Here, we show sex-stratified gene regulatory networks (GRNs) from human carotid atherosclerotic tissue. Prioritization of these networks identified two main SMC GRNs in late-stage atherosclerosis. Single-cell RNA-sequencing mapped these GRNs to two SMC phenotypes: a phenotypically modulated myofibroblast-like SMC network and a contractile SMC network. The myofibroblast-like GRN was mostly expressed in plaques that were vulnerable in females. Finally, mice orthologs of the female myofibroblast-like genes showed retained expression in advanced plaques from female mice but were downregulated in male mice during atherosclerosis progression. Female atherosclerosis is driven by GRNs that promote a fibrous vulnerable plaque rich in myofibroblast-like SMCs.
Functional comparisons of the virus sensor RIG-I from humans, the microbatMyotis daubentonii, and the megabatRousettus aegyptiacus, and their response to SARS-CoV-2 infection
Authors: Schoen Andreas , Hölzer Martin , Müller Marcel A. , Drosten Christian , Marz Manja , Lamp Benjamin , Weber Friedemann 
Published: February 2023

ABSTRACTBats (orderChiroptera) are a major reservoir for emerging and re-emerging zoonotic viruses. Their tolerance towards highly pathogenic human viruses led to the hypothesis that bats may possess an especially active antiviral interferon (IFN) system. Here, we cloned and functionally characterized the virus RNA sensor, Retinoic Acid-Inducible Gene-I (RIG-I), from the “microbat”Myotis daubentonii(suborderYangochiroptera) and the “megabat”Rousettus aegyptiacus(suborder Yinpterochiroptera), and compared them to the human ortholog. Our data show that the overall sequence and domain organization is highly conserved and that all three RIG-I orthologs can mediate a similar IFN induction in response to viral RNA at 37° and 39°C, but not at 30°C. Like human RIG-I, bat RIG-Is were optimally activated by double stranded RNA containing a 5’-triphosphate end and required Mitochondrial Antiviral-Signalling Protein (MAVS) for antiviral signalling. Moreover, the RIG-I orthologs of humans and ofR. aegyptiacus, but not ofM. daubentonii, enable innate immune sensing of SARS-CoV-2 infection. Our results thus show that microbats and megabats express a RIG-I that is not substantially different from the human counterpart with respect to function, temperature dependency, antiviral signaling, and RNA ligand properties, and that human and megabat RIG-I are able to sense SARS-CoV-2 infection.IMPORTANCEA common hypothesis holds that bats (orderChiroptera) are outstanding reservoirs for zoonotic viruses because of a special antiviral interferon (IFN) system. However, functional studies about key components of the bat IFN system are rare. RIG-I is a cellular sensor for viral RNA signatures that activates the antiviral signalling chain to induce IFN. We cloned and functionally characterized RIG-I genes from representatives of the subordersYangochiropteraandYinpterochiroptera. The bat RIG-Is were conserved in their sequence and domain organization, and similar to human RIG-I in (i) mediating virus- and IFN-activated gene expression, (ii) antiviral signalling, (iii) temperature dependence, and (iv) recognition of RNA ligands. Moreover, RIG-I ofRousettus aegyptiacus(suborderYinpterochiroptera) and of humans were found to recognize SARS-CoV-2 infection. Thus, members of both bat suborders encode RIG-Is that are comparable to their human counterpart. The ability of bats to harbour zoonotic viruses therefore seems due to other features.
Effects of supervised exercises on pain and disability in patients with hip or knee osteoarthritis: A systematic review and meta-analysis
Authors: Mapinduzi Jean , Ndacayisaba Gérard , Mitchaϊ Penielle Mahutchegnon , Bonnechère Bruno , Oyéné Kossi 
Published: February 2023

AbstractBackgroundHip and knee osteoarthritis are among the most prevalent and disabling conditions affecting mainly older adults, with a risk of undergoing a total hip or knee replacement for the end stage. Increasing recommendations of conservative treatments have been reported as the first-line strategy for the initial management of this condition.ObjectiveThis review sought to investigate the effects of supervised exercises versus non-pharmacological conservative therapies to reduce pain and disability levels on patients with hip or knee osteoarthritis.MethodsThree databases (PubMed, Cochrane Library, and ScienceDirect) were systematically searched for randomized-controlled trials published between 01-01-2001 and 31-10-2022. PEDro scale was used to assess the methodological quality of the included studies. The PRISMA guidelines were applied for this review.ResultsTwelve randomized-controlled trials of moderate-to-high quality were included in this review. The studies involved 1,049 participants with a mean age (SD) of 64 (6) years old. The duration of the intervention and follow-up varied from 2 weeks to 16 months. Supervised exercises for hip or knee osteoarthritis were significantly less effective in terms of pain reduction (SMD=-0.40 [95%CI 0.16, 0.65], p=0.001) compared to home-based exercises (active musculoskeletal therapies), but not in terms of disability reduction (SMD=-0.04[95%CI −0.43, 0.36], p=0.86). There was a non-significant difference of supervised exercises compared to passive musculoskeletal therapies in terms of disability (SMD=0.21[95%CI −0.09, 0.50], p=0.17), or pain reduction (SMD=-0.19; [95%CI −0.57, 0.19], p=0.33).ConclusionSupervised exercises were found to be less effective in reducing pain, but not in disability reduction when compared to home-based exercises.Systematic review registrationProspero CRD42021271912
Caloric restriction prevents inflammation and insulin dysfunction in middle-aged ovariectomized mice
Authors: Sapatini Leticia Roberta Leme , Calsa Bruno , Marim Lais Jorge , Helaehil Júlia Venturini , Chiarotto Gabriela Bortolança , Corezola do Amaral Maria Esméria 
Published: February 2023

AbstractLoss of ovarian function is associated with increased visceral fat. In this study, we aimed to study the effects of caloric restriction (CR) on metabolism in ovariectomized mice. Female, 8–12-month-old mice were divided into three groups: OVX (ovariectomized mice), OVXR (40% CR) and Sham. CR increased insulin sensitivity and glucose tolerance. AMPK phosphorylation was observed in the liver of OVXR mice. CR also increased hepatic cholesterol and triglyceride levels. The reductions in the level of TBARS in the serum and liver and of H2O2 in the liver of OVXR mice suggested alterations in the redox state of the liver. Although expression of catalase protein was reduced by CR, expression of superoxide dismutase was not altered by CR. Although interleukin IL-6 and IL-10 levels in OVXR mice were similar to those in Sham mice, macrophage infiltration was reduced in OVXR mice. OVXR mice had increased sirtuin1 levels and decreased sirtuin3 levels in the liver. In conclusion, CR improved the condition of ovariectomized mice by reducing adiposity and increasing insulin sensitivity and glucose tolerance through a mechanism that may involve AMPK.
Racial Differences in FMD
Authors: Martinez Andrea , Okoh Alexis , Ko Yi-An , Wells Bryan 
Published: February 2023

AbstractBackgroundFibromuscular dysplasia (FMD) is a non-atherosclerotic arteriopathy associated with stenosis, aneurysm, and dissection. We aimed to characterize racial differences in clinical presentation and diagnosis among patients with FMD at our institution.MethodsWe utilized an ambulatory FMD database to review demographics, clinical presentation, and diagnostic assessments of patients diagnosed with FMD within a university-affiliated healthcare system. Patients were classified as White or Non-White based on self-identified race. We evaluated race-specific differences in diagnosis and disease manifestations.ResultsA total of 208 patients (White: n=160 (77%); Non-White; n=48 (23%)) were included in the analysis. The time from initial FMD symptom to diagnosis was longer in Non-Whites than Whites (5.5 vs. 1.5 yrs; p<0.001), yet time from diagnosis to Emory specialist center visit was longer in Whites (3.2 vs. 1.2 yrs; p=0.035). Whites were more likely to undergo ≥ 5 multi-imaging diagnostic assessments than Non-Whites (89% vs. 73%; p=0.002). History of hypertension, stroke, & chronic kidney disease were more common in Non-Whites. FMD involvement of the internal carotid artery and upper extremity vessels were more common in Non-Whites, while Whites had more renal artery involvement.ConclusionWe found racial differences in the diagnosis of FMD. The time from symptom onset to diagnosis was longer in Non-White than White FMD patients. Multimodality diagnostic imaging was more often utilized in Whites than Non-Whites. Research is needed to investigate these racial differences.
Major depression, suicidal behaviors and neuroticism are pro-atherogenic states driven by lowered reverse cholesterol transport
Authors: Jirakran Ketsupar , Vasupanrajit Asara , Tunvirachaisakul Chavit , Kubera Marta , Maes Michael 
Published: February 2023

AbstractBackgroundThere are strong associations between major depressive disorder (MDD), metabolic syndrome (MetS) and cardiovascular disorder, which may be explained by increased atherogenicity and the microimmuneoxysome (Maes et al., 1994; 2011). The present study was conducted to determine if MDD, the severity of depression, suicidal behaviors, and neuroticism are associated with increased pro-atherogenic versus anti-atherogenic indices (PRO/ANTI-AI) and a reverse cholesterol transport (RCT) index.MethodsThis study included 34 healthy controls, 33 participants with MetS, and MDD patients with (n=31) and without (n=35) MetS, and measured total (TC) and free (FC) cholesterol, high (HDLc) and low (LDLc) density lipoprotein cholesterol, triglycerides (TG), apolipoprotein (ApoA), ApoB, cholesterol esterification rate (CER) and a composite (based on HDLc, ApoA and CER), reflecting RCT.ResultsIn the combined MDD + MetS study group, no associations between MDD and lipids were detected. After the exclusion of all MetS participants, MDD is strongly associated with (a) increased FC, TG, ApoB, Castelli risk index 1, ApoB/ApoA, and (b) decreased HDLc, ApoA and the RCT index. In participants without MetS, there are significant associations between severity of depression, suicidal behaviors, and neuroticism and ApoB/ApoA, Castelli risk, and RCT indices.ConclusionsStudies linking lipids to depressive subtypes can only be interpreted after MetS patients are excluded. The depression phenome, suicidal behaviors, and neuroticism are associated with a lowered RCT and increased atherogenicity, which are likely involved in the microimmuneoxidative pathophysiology of MDD. The RCT is a new drug target to treat and prevent MDD, neuroticism, and suicidal behaviors.
Epistatic Features and Machine Learning Improve Alzheimer’s Risk Prediction Over Polygenic Risk Scores
Authors: Hermes Stephen , Cady Janet , Armentrout Steven , O’Connor James , Carlson Sarah , Cruchaga Carlos , Wingo Thomas , Greytak Ellen McRae ,   The Alzheimer’s Disease Neuroimaging Initiative
Published: February 2023

AbstractBackgroundPolygenic risk scores (PRS) are linear combinations of genetic markers weighted by effect size that are commonly used to predict disease risk. For complex heritable diseases such as late onset Alzheimer’s disease (LOAD), PRS models fail to capture much of the heritability. Additionally, PRS models are highly dependent on the population structure of data on which effect sizes are assessed, and have poor generalizability to new data.ObjectiveThe goal of this study is to construct a paragenic risk score that, in addition to single genetic marker data used in PRS, incorporates epistatic interaction features and machine learning methods to predict lifetime risk for LOAD.MethodsWe construct a new state-of-the-art genetic model for lifetime risk of Alzheimer’s disease. Our approach innovates over PRS models in two ways: First, by directly incorporating epistatic interactions between SNP loci using an evolutionary algorithm guided by shared pathway information; and second, by estimating risk via an ensemble of machine learning models (gradient boosting machines and deep learning) instead of simple logistic regression. We compare the paragenic model to a PRS model from the literature trained on the same dataset.ResultsThe paragenic model is significantly more accurate than the PRS model under 10-fold cross-validation, obtaining an AUC of 83% and near-clinically significant matched sensitivity/specificity of 75%, and remains significantly more accurate when evaluated on an independent holdout dataset. Additionally, the paragenic model maintains accuracy within APOE genotypes.ConclusionParagenic models show potential for improving lifetime disease risk prediction for complex heritable diseases such as LOAD over PRS models.
Recruitment of apolipoprotein E facilitates Herpes simplex virus 1 attachment, entry, and release
Authors: Liu Lifeng , Thorsteinsson Konrad , Bano Fouzia , Jayaweera Sanduni Wasana , Avinens Damien , Conca Dario , Pace Hudson , Lövheim Hugo , Olofsson Anders , Bally Marta 
Published: February 2023

AbstractOver two decades, epidemiological studies have revealed that interactions between human polymorphic apolipoprotein 4 (ApoE, isoform 4) and herpes simplex virus type 1 (HSV1) associate with higher risk of Alzheimer’s disease, a serious and increasing issue among elder populations worldwide. Nevertheless, little is known about the mechanisms behind ApoE-HSV1 interactions at molecular levels. Here, we investigate the effects of ApoE on the HSV1 infectious life cycle inin vitrocell experiments. Analysis of HSV1 growth curves shows that HSV1 production is promoted in presence of any of the three ApoE isoforms, with ApoE 3 or 4 demonstrating more proviral effects than ApoE 2. Quantification by qPCR reveals that the presence of ApoE 2, 3, or 4 leads to an increase of HSV1 extracellular release but unchanged levels of viral genome copies within cells or on the cell surface, indicating that virus replication, assembly, or transport to cell membrane are not affected. Further test of virus release directly demonstrates that HSV1 detachment from the cell surface is promoted by ApoE. Subsequent results reveal that ApoE is both present in purified HSV1 particles produced in ApoE-expressing cells after ultra-centrifugation and able to incorporate into HSV1 particles after purification, suggesting that harbouring ApoE may play a key role in the pro-viral effect of ApoE. Along these lines, we tested the infectious behaviour of ApoE-coated viruses and observed faster attachment kinetics and higher entry efficiencies of ApoE decorated HSV1. Our hypothesis that the association with ApoE leads to modified interactions of the virus with the cell membrane during entry and egress, was further validated in biophysical experiments. In such experiments, HSV1-membrane interaction kinetics and apparent affinity between HSV1 and native supported lipid bilayers (a plasma membrane mimic) were quantified using total internal reflection microscopy. HSV1 particles decorated with ApoE demonstrate both higher association (kon) and dissociation rate constants (koff), as well as less irreversible binding to the membrane, which is in line with the biological experiments. Overall, our results provide new insights into the roles of ApoE during HSV1 infections, which is worth to be considered when studying their involvement during Alzheimer’s disease development.
Rhizosphere bacterial colonization of beet occurs in discrete phases regardless of bioinoculation with the wild sea beet root community
Authors: Gołębiewski Marcin , Sikora Marcin , Mazur Justyna , Szymańska Sonia , Tyburski Jarosław , Hrynkiewicz Katarzyna , Ulrich Werner 
Published: February 2023

AbstractBioinoculation can increase crop yields under environmental stress. Plant colonization by microbes is an example of succession, with its distinct phases differing in community structure and diversity. This process needs to be studied to determine the optimal timing for bioinoculation and its effects. Haere, we show that, regardless of bio-inoculation, soil type and plant genotype, bacteria colonize the rhizosphere of axenic beets and tissues in two phases, differing in bacterial load, nestedness, community structure, diversity and assembly mechanism, and associated with taproot development. Communities remained stable after five weeks of growth in soil. The alpha diversity was greater and the bacterial load was lower in the late samples than in the early ones. Time, soil type and genotype determined community structure but not alpha diversity, bacterial load, nestedness or assembly mechanisms both in the rhizosphere and in the endosphere. Inoculation changed the community structure and members of Pseudomonadota and Bacillota of low abundance in the inoculant were recruited by beets.Axenic beet colonization occurs through phases similar to other instances of microbial succession, and bacteria are recruited mostly randomly. The transition from the early to late phase involves a decrease in the bacterial load in plant tissues, which may be linked to plant growth and the arrest of bacterial cell division. Therefore, early inoculation seems to be favourable. Five weeks of growth in soil enabled formation of stable bacterial communities in both the rhizosphere and the endosphere. The influence of inoculation seems to be indirect, probably due to microbe-microbe interactions.
Retrospective identification of intrinsic factors that mark pluripotency potential in rare somatic cells
Authors: Jain Naveen , Goyal Yogesh , Dunagin Margaret C. , Cote Christopher J. , Mellis Ian A. , Emert Benjamin , Jiang Connie L. , Dardani Ian P. , Reffsin Sam , Raj Arjun 
Published: February 2023

AbstractPluripotency can be induced in somatic cells by the expression of the four “Yamanaka” factors OCT4, KLF4, SOX2, and MYC. However, even in homogeneous conditions, usually only a rare subset of cells admit reprogramming, and the molecular characteristics of this subset remain unknown. Here, we apply retrospective clone tracing to identify and characterize the individual human fibroblast cells that are primed for reprogramming. These fibroblasts showed markers of increased cell cycle speed and decreased fibroblast activation. Knockdown of a fibroblast activation factor identified by our analysis led to increased reprogramming efficiency, identifying it as a barrier to reprogramming. Changing the frequency of reprogramming by inhibiting the activity of LSD1 led to an enlarging of the pool of cells that were primed for reprogramming. Our results show that even homogeneous cell populations can exhibit heritable molecular variability that can dictate whether individual rare cells will reprogram or not.