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Abstract The consumption of unrefined vegetable oil poses acute and chronic health issues, yet improper disposal of waste plantain peels is not environmentally sustainable. This research investigates the feasibility, mechanism and thermodynamics of waste plantain peels, and commercial bentonite clay for soybean oil refining. Experiment was carried out using masses (1–4 g) of commercial bentonite clay, and unripe plantain peel ash (UPPA) to degummed and neutralized free fatty acid (FFA) contents in crude soybean oil at varying temperatures (50–120 °C), and time (15–35 min) for treatment of soybean oil. FTIR spectroscopy, SEM, and XRF techniques were applied to characterize the sample. The results established that at optimum 4.0 g dosage, the UPPA (97.73%) was more effective in the removal of FFA from oil at 50 °C and 20 min, while the clay (90%) was more effective in the removal of colour pigment from the vegetable oil 100 °C, and 25 min. The optimum efficiency of Clay-Ash-composite (70:30) in adsorbing pigment from soybean oil corresponds to 80%. The impact of changing viscosities, densities, and acid values on the performance of UPPA, clay, and clay-UPPA composite was investigated. Mechanistic studies confirmed the pseudo-second-order kinetics at 5 × 10–2 g/mg min−1 and 1.87 × 10–1 g/mg min−1, with corresponding adsorption capacity of 30.40 mg/g and 4.91 mg/g, at R2 ≤ 0.9982. The UPPA-driven sorption of FFA occurred as a physisorption and exothermic process (− 620.60 kJ/mol), while colour pigment removal occurred by chemisorption and endothermic process (22.40 kJ/mol). The finding recommends UPPA and composite as economically feasible for refining soybean oil.

Abstract Inflammatory cytokine mediated responses are important in the development of many diseases that are associated with angiogenesis. Targeting angiogenesis as a prominent strategy has shown limited effects in many contexts such as cardiovascular diseases and cancer. One potential reason for the unsuccessful outcome is the mutual dependent role between inflammation and angiogenesis. Inflammation-based therapies primarily target inflammatory cytokines such as interleukin-6 (IL-6) in T cells, macrophages, cancer cells, and muscle cells, and there is a limited understanding of how these cytokines act on endothelial cells. Thus, we focus on one of the major inflammatory cytokines, IL-6, mediated intracellular signaling in endothelial cells by developing a detailed computational model. Our model quantitatively characterized the effects of IL-6 classic and trans-signaling in activating the signal transducer and activator of transcription 3 (STAT3), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), and mitogen-activated protein kinase (MAPK) signaling to phosphorylate STAT3, extracellular regulated kinase (ERK) and Akt, respectively. We applied the trained and validated experiment-based computational model to characterize the dynamics of phosphorylated STAT3 (pSTAT3), Akt (pAkt), and ERK (pERK) in response to IL-6 classic and/or trans-signaling. The model predicts that IL-6 classic and trans-signaling induced responses are IL-6 and soluble IL-6 receptor (sIL-6R) dose-dependent. Also, IL-6 classic and trans-signaling showed similar potency in inducing downstream signaling; however, trans-signaling induces stronger downstream responses and plays a dominant role in the overall effects from IL-6 due to the in vitro experimental setting of abundant sIL-6R. In addition, both IL-6 and sIL-6R levels regulate signaling strength. Moreover, our model identifies the influential species and kinetic parameters that specifically modulate the downstream inflammatory and/or angiogenic signals, pSTAT3, pAkt, and pERK responses. Overall, the model predicts the effects of IL-6 classic and/or trans-signaling stimulation quantitatively and provides a framework for analyzing and integrating experimental data. More broadly, this model can be utilized to identify potential targets that influence IL-6 mediated signaling in endothelial cells and to study their effects quantitatively in modulating STAT3, Akt, and ERK activation.

Abstract We reassessed several orbital topographic data sets for the Perseverance rover landing site at Jezero Crater, Mars to better understand its floor units. Tens‐of‐meters deep topographic anomalies occur in the volcanic floor of Jezero crater and are not a result of impact cratering. Eight km‐scale steep escarpment‐bounded depressions may be locations of paleotopographic highs that were embayed by the volcanic floor lava flows, forming inverted topography from either contemporaneous upward inflation of embaying lavas or later deep scour due to differential erosion over 107−9 years. Five multi km‐scale shallow‐sloped depressions linked by channel‐like forms may record locations of buried paleolakes and channels that predate the volcanic floor units or a drained magma system. These results indicate Jezero experienced multiple closed‐basin or dry phases, allowing erosion of the crater floor and creation of topography, which provides new geologic context for the samples gathered by Perseverance.

Introduction: Several signaling pathways are activated during hypoxia to promote angiogenesis, leading to endothelial cell patterning, interaction, and downstream signaling. Understanding the mechanistic signaling differences between endothelial cells under normoxia and hypoxia and their response to different stimuli can guide therapies to modulate angiogenesis. We present a novel mechanistic model of interacting endothelial cells, including the main pathways involved in angiogenesis.Methods: We calibrate and fit the model parameters based on well-established modeling techniques that include structural and practical parameter identifiability, uncertainty quantification, and global sensitivity.Results: Our results indicate that the main pathways involved in patterning tip and stalk endothelial cells under hypoxia differ, and the time under hypoxia interferes with how different stimuli affect patterning. Additionally, our simulations indicate that Notch signaling might regulate vascular permeability and establish different Nitric Oxide release patterns for tip/stalk cells. Following simulations with various stimuli, our model suggests that factors such as time under hypoxia and oxygen availability must be considered for EC pattern control.Discussion: This project provides insights into the signaling and patterning of endothelial cells under various oxygen levels and stimulation by VEGFA and is our first integrative approach toward achieving EC control as a method for improving angiogenesis. Overall, our model provides a computational framework that can be built on to test angiogenesis-related therapies by modulation of different pathways, such as the Notch pathway.

The vascular endothelial growth factor (VEGF) family of cytokines are key drivers of blood vessel growth and remodeling. These ligands act via multiple VEGF receptors (VEGFR) and co-receptors such as Neuropilin (NRP) expressed on endothelial cells. These membrane-associated receptors are not solely expressed on the cell surface, they move between the surface and intracellular locations, where they can function differently. The location of the receptor alters its ability to 'see' (access and bind to) its ligands, which regulates receptor activation; location also alters receptor exposure to subcellularly localized phosphatases, which regulates its deactivation. Thus, receptors in different subcellular locations initiate different signaling, both in terms of quantity and quality. Similarly, the local levels of co-expression of other receptors alters competition for ligands. Subcellular localization is controlled by intracellular trafficking processes, which thus control VEGFR activity; therefore, to understand VEGFR activity, we must understand receptor trafficking. Here, for the first time, we simultaneously quantify the trafficking of VEGFR1, VEGFR2, and NRP1 on the same cells-specifically human umbilical vein endothelial cells (HUVECs). We build a computational model describing the expression, interaction, and trafficking of these receptors, and use it to simulate cell culture experiments. We use new quantitative experimental data to parameterize the model, which then provides mechanistic insight into the trafficking and localization of this receptor network. We show that VEGFR2 and NRP1 trafficking is not the same on HUVECs as on non-human ECs; and we show that VEGFR1 trafficking is not the same as VEGFR2 trafficking, but rather is faster in both internalization and recycling. As a consequence, the VEGF receptors are not evenly distributed between the cell surface and intracellular locations, with a very low percentage of VEGFR1 being on the cell surface, and high levels of NRP1 on the cell surface. Our findings have implications both for the sensing of extracellular ligands and for the composition of signaling complexes at the cell surface versus inside the cell.

IntroductionAlthough both COVID-19 and non-COVID-19 ARDS can be accompanied by significantly increased levels of circulating cytokines, the former significantly differs from the latter by its higher vasculopathy, characterized by increased oxidative stress and coagulopathy in lung capillaries. This points towards the existence of SARS-CoV2-specific factors and mechanisms that can sensitize the endothelium towards becoming dysfunctional. Although the virus is rarely detected within endothelial cells or in the circulation, the S1 subunit of its spike protein, which contains the receptor binding domain (RBD) for human ACE2 (hACE2), can be detected in plasma from COVID-19 patients and its levels correlate with disease severity. It remains obscure how the SARS-CoV2 RBD exerts its deleterious actions in lung endothelium and whether there are mechanisms to mitigate this.MethodsIn this study, we use a combination of in vitro studies in RBD-treated human lung microvascular endothelial cells (HL-MVEC), including electrophysiology, barrier function, oxidative stress and human ACE2 (hACE2) surface protein expression measurements with in vivo studies in transgenic mice globally expressing human ACE2 and injected with RBD.ResultsWe show that SARS-CoV2 RBD impairs endothelial ENaC activity, reduces surface hACE2 expression and increases reactive oxygen species (ROS) and tissue factor (TF) generation in monolayers of HL-MVEC, as such promoting barrier dysfunction and coagulopathy. The TNF-derived TIP peptide (a.k.a. solnatide, AP301) -which directly activates ENaC upon binding to its a subunit- can override RBD-induced impairment of ENaC function and hACE2 expression, mitigates ROS and TF generation and restores barrier function in HL-MVEC monolayers. In correlation with the increased mortality observed in COVID-19 patients co-infected with S. pneumoniae, compared to subjects solely infected with SARS-CoV2, we observe that prior intraperitoneal RBD treatment in transgenic mice globally expressing hACE2 significantly increases fibrin deposition and capillary leak upon intratracheal instillation of S. pneumoniae and that this is mitigated by TIP peptide treatment.

Background In endothelial cells (ECs), glycolysis, regulated by PFKFB3 (6‐phosphofructo‐2‐kinase/fructose‐2,6‐biphosphatase, isoform‐3), is the major metabolic pathway for ATP generation. In preclinical peripheral artery disease models, VEGF165a (vascular endothelial growth factor165a) and microRNA‐93 both promote angiogenesis. Methods and Results Mice following hind‐limb ischemia (HLI) and ECs with, and without, hypoxia and serum starvation were examined with, and without, microRNA‐93 and VEGF165a. Post‐HLI perfusion recovery was monitored. EC metabolism was studied using seahorse assay, and the expression and activity of major metabolism genes were assessed. Reactive oxygen species levels and EC permeability were evaluated. C57Bl/6J mice generated a robust angiogenic response to HLI, with ECs from ischemic versus nonischemic muscle demonstrating no increase in glycolysis. Balb/CJ mice generated a poor angiogenic response post‐HLI; ischemic versus nonischemic ECs demonstrated significant increase in glycolysis. MicroRNA‐93‐treated Balb/CJ mice post‐HLI showed better perfusion recovery, with ischemic versus nonischemic ECs showing no increase in glycolysis. VEGF165a‐treated Balb/CJ mice post‐HLI showed no improvement in perfusion recovery with ischemic versus nonischemic ECs showing significant increase in glycolysis. ECs under hypoxia and serum starvation upregulated PFKFB3. In ECs under hypoxia and serum starvation, VEGF165a versus control significantly upregulated PFKFB3 and glycolysis, whereas miR‐93 versus control demonstrated no increase in PFKFB3 or glycolysis. MicroRNA‐93 versus VEGF165a upregulated glucose‐6‐phosphate dehydrogenase expression and activity, activating the pentose phosphate pathway. MicroRNA‐93 versus control increased reduced nicotinamide adenine dinucleotide phosphate and virtually eliminated the increase in reactive oxygen species. In ECs under hypoxia and serum starvation, VEGF165a significantly increased and miR‐93 decreased EC permeability. Conclusions In peripheral artery disease, activation of the pentose phosphate pathway to promote angiogenesis may offer potential therapeutic advantages.

IntroductionPatients with systemic lupus erythematosus (SLE) are at elevated risk for Q10 cardiovascular disease (CVD) due to accelerated atherosclerosis. Compared to heathy control subjects, lupus patients have higher volumes and densities of thoracic aortic perivascular adipose tissue (PVAT), which independently associates with vascular calcification, a marker of subclinical atherosclerosis. However, the biological and functional role of PVAT in SLE has not been directly investigated.MethodsUsing mouse models of lupus, we studied the phenotype and function of PVAT, and the mechanisms linking PVAT and vascular dysfunction in lupus disease. Results and discussionLupus mice were hypermetabolic and exhibited partial lipodystrophy, with sparing of thoracic aortic PVAT. Using wire myography, we found that mice with active lupus exhibited impaired endothelium-dependent relaxation of thoracic aorta, which was further exacerbated in the presence of thoracic aortic PVAT. Interestingly, PVAT from lupus mice exhibited phenotypic switching, as evidenced by “whitening” and hypertrophy of perivascular adipocytes along with immune cell infiltration, in association with adventitial hyperplasia. In addition, expression of UCP1, a brown/beige adipose marker, was dramatically decreased, while CD45-positive leukocyte infiltration was increased, in PVAT from lupus mice. Furthermore, PVAT from lupus mice exhibited a marked decrease in adipogenic gene expression, concomitant with increased pro-inflammatory adipocytokine and leukocyte marker expression. Taken together, these results suggest that dysfunctional, inflamed PVAT may contribute to vascular disease in lupus.

Abstract The Mars 2020 Mastcam‐Z stereo camera investigation enables the generation of three dimension (3D) data products needed to visualize and analyze rocks, outcrops, and other geological and aeolian features. The Planetary Robotics Vision Processing framework “PRoViP” as well as the Instrument Data System on a tactical—sol‐by‐sol—timeframe generate 3D vision products, such as panoramas, distance maps, and textured meshes. Structure‐from‐motion used by the Advanced Science Targeting Toolkit for Robotic Operations (ASTTRO) “Landform” tool and long baseline stereo pipelines add to the 3D vision products' suite on various scales. Data fusion with textured meshes from satellite imagery and 3D data analysis and interpretation of the resulting large 3D data sets is realized by visualization assets like the Planetary Robotics Vision 3D Viewer PRo3D, the 3D Geographical Information System GIS CAMP (Campaign Analysis Mapping and Planning tool), the ASTTRO 3D data presentation and targeting tool, and the Mastcam‐Z planning tool Viewpoint. The pipelines' workflows and the user‐oriented features of the visualization assets, shared across the Mars 2020 mission, are reported. The individual role and interplay, complements and synergies of the individual frameworks are explained. Emphasis is laid on publicly available 3D vision data products and tools. A representative set of scientific use cases from planetary geology, aeolian activity, soil analysis and impact science illustrates the scientific workflow, and public data deployment modes are briefly outlined, demonstrating that 3D vision processing and visualization is an essential mission‐wide asset to solve important planetary science questions such as prevailing wind direction, soil composition, or geologic origin.

Background Peripheral artery disease (PAD) affects >10 million people in the United States. PAD is associated with poor outcomes, including premature death. Machine learning (ML) has been increasingly used on big data to predict clinical outcomes. This study aims to develop ML models to predict in‐hospital mortality in patients hospitalized for PAD based on a national database. Methods and Results Inpatient hospitalization data were obtained from the 2016 to 2019 National Inpatient Sample. A total of 150 921 inpatients were identified with a primary diagnosis of PAD and PAD‐related procedures using codes of the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD‐10‐CM) and International Classification of Diseases, Tenth Revision, Procedure Coding System (ICD‐10‐PCS). Four ML models, including logistic regression, random forest, light gradient boosting, and extreme gradient boosting models, were trained to predict the risk of in‐hospital death based on a selection of variables, including patient characteristics, comorbidities, procedures, and hospital‐related factors. In‐hospital mortality occurred in 1.8% of patients. The performance of the 4 models was comparable, with the area under the receiver operating characteristic curve ranging from 0.83 to 0.85, sensitivity of 77% to 82%, and specificity of 72% to 75%. These results suggest adequate predictability for clinical decision‐making. In all 4 models, the total number of diagnoses and procedures, age, endovascular revascularization procedure, congestive heart failure, diabetes, and diabetes with complications were critical predictors of in‐hospital mortality. Conclusions This study demonstrates the feasibility of ML in predicting in‐hospital mortality in patients with a primary PAD diagnosis. Findings highlight the potential of ML models in identifying high‐risk patients for poor outcomes and guiding personalized intervention.

Abstract The Ang–Tie signaling pathway is an important vascular signaling pathway regulating vascular growth and stability. Dysregulation in the pathway is associated with vascular dysfunction and numerous diseases that involve abnormal vascular permeability and endothelial cell inflammation. The understanding of the molecular mechanisms of the Ang–Tie pathway has been limited due to the complex reaction network formed by the ligands, receptors, and molecular regulatory mechanisms. In this study, we developed a mechanistic computational model of the Ang–Tie signaling pathway validated against experimental data. The model captures and reproduces the experimentally observed junctional localization and downstream signaling of the Ang–Tie signaling axis, as well as the time-dependent role of receptor Tie1. The model predicts that Tie1 modulates Tie2’s response to the context-dependent agonist Ang2 by junctional interactions. Furthermore, modulation of Tie1’s junctional localization, inhibition of Tie2 extracellular domain cleavage, and inhibition of VE-PTP are identified as potential molecular strategies for potentiating Ang2’s agonistic activity and rescuing Tie2 signaling in inflammatory endothelial cells.

Crater counting is a widely applied methodology for dating large areas of planetary surfaces, but is difficult to apply the method to constrain the durations of stratigraphic unconformities. Unconformities with exhumed craters are thought to indicate long hiatuses that can only be indirectly dated through stratigraphic relationships with other surfaces with uniform exposure ages. On Mars, sedimentary deposits with prominent unconformities with exhumed craters are found in layered deposits in the Arabia Terra region as well as Gale crater within Mount Sharp. In this work, we present a Linear Crater Counting methodology and apply it to constrain these unconformities observed in Arabia Terra and in Mount Sharp. The method applies a linear sampling domain correction to conventional two‐dimensional crater size frequency distributions and Bayesian Poisson process statistics in order to constrain the likely durations of these unconformities. We found that unconformities in Arabia Terra were on the order of 0.1–1 Gyr in length and that the unconformity preserved at Mount Sharp is at least 0.2 Gyr in length given estimates of the ages of the host craters. Hiatuses of these lengths constrain the age of the overlying deposits to be Late Hesperian or Amazonian in age. Two utility plots are also provided, along with the derivation, for researchers to apply this method to dating arbitrary geologic contacts on Mars and to adapt it to other bodies. Plain Language Summary: The crater counting method is a widely used method to date planetary surfaces. Crater counting works by comparing the number of craters in an area to the expected number of craters that should be observed for that area using a model of how many craters form and their expected size through time. On Mars, geologic contacts of sedimentary deposits with exhumed craters are seen in Arabia Terra and in Gale crater in Mount Sharp. Craters exhumed in these geologic contacts are thought to indicate long gaps in time between the formation dates of the upper and lower rock layers. However, dating these time gaps directly is not possible with conventional crater counting. To solve this problem, we developed a new linear crater counting method which describes the likely number of craters for a given age that could be found along a line on the surface of Mars. We apply this method to the geologic contacts seen in Arabia Terra and in Gale crater, and find that the time gaps are hundreds of millions of years in length to over a billion years in length. Our results confirm predictions that these deposits are geologically younger than previously thought. Key Points: We describe a novel linear crater counting method to date stratigraphic unconformities using partially exhumed craters along unit boundariesWe found that layered deposits in Arabia Terra and the Upper mound unit in Gale crater could be Amazonian in Age from applying our methodOur methodology can be applied broadly to better understand chronostratigraphy across the solar system [ABSTRACT FROM AUTHOR]

Cassini and many investigators reported whistler chorus near Saturn equatorial plane moving outwards. Whistler can propagate when going to high latitude and can alter its characteristics while interacting resonantly with available energetic electrons. Here investigating wave for a relativistic beam of the electron. It is observed and reported by Cassini Magnetospheric Imaging Instrument (MIMI) that inward radial injection of highly energetic particles is most dominant in Saturn intrinsic magnetosphere. Within this paradigm, an empirical energy dispersion relation for propagated whistler-mode oscillations in quasi Saturn magnetospheric plasma from such a non-monotonous ringed distribution function has been established. The kinetic approach and method of characteristics methodologies were used in the computations, which have been shown to be the best for building perturbed plasma states. The perturbed distribution function was estimated using the unperturbed particle routes. The ring distribution function was used to construct an unexpected growth rate expression for relativistic plasma in the inner magnetosphere. The results from the Saturn magnetosphere have been calculated and interpreted using a range of parameters. Temperature heterogeneity was shown to be a significant source of free energy that aided the propagation of a whistler-mode wave. By raising the peak value, the bulk injection of energetic hot electron injection impacts the growth rate. Growth was also demonstrated to be accelerated when the propagation angle increased. The research contributes to a better understanding of the relationship between wave and particle emissions and VLF emissions on a large scale.

ABSTRACT The vascular endothelial injury occurs in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, but the mechanisms are poorly understood. We sought to determine the frequency and type of cytokine elevations and their relationship to endothelial injury induced by plasma from patients with SARS-CoV-2 versus controls. Plasma from eight consecutively enrolled patients hospitalized with acute SARS-CoV-2 infection was compared to controls. Endothelial cell (EC) barrier integrity was evaluated using ECIS (electric cell-substrate impedance sensing) on human lung microvascular EC. Plasma from all SARS-CoV-2 but none from controls decreased transendothelial resistance to a greater degree than that produced by tumor necrosis factor-alpha (TNF-α), the positive control for the assay. Thrombin, angiopoietin 2 (Ang2), and vascular endothelial growth factor (VEGF), complement factor C3a and C5a, and spike protein increased endothelial permeability, but to a lesser extent and a shorter duration when compared to SARS-CoV-2 plasma. Analysis of Ang2, VEGF, and 15 cytokines measured in plasma revealed striking patient-to-patient variability within the SARS-CoV-2 patients. Pretreatment with thrombin inhibitors, single, or combinations of neutralizing antibodies against cytokines, Ca3 and C5a receptor antagonists, or with ACE2 antibody failed to lessen the SARS-CoV-2 plasma-induced EC permeability. The EC barrier destructive effects of plasma from patients with SARS-CoV-2 were susceptible to heat inactivation. Plasma from patients hospitalized with acute SARS-CoV-2 infection uniformly disrupts lung microvascular integrity. No predicted single, or set of, cytokine(s) accounted for the enhanced vascular permeability, although the factor(s) were heat-labile. A still unidentified but potent circulating factor(s) appears to cause the EC disruption in SARS-CoV-2 infected patients. IMPORTANCE Lung vascular endothelial injury in SARS-CoV-2 patients is one of the most important causes of morbidity and mortality and has been linked to more severe complications including acute respiratory distress syndrome (ARDS) and subsequent death due to multiorgan failure. We have demonstrated that in eight consecutive patients with SARS-CoV-2, who were not selected for evidence of endothelial injury, the diluted plasma-induced intense lung microvascular damage, in vitro. Known endothelial barrier-disruptive agents and proposed mediators of increased endothelial permeability in SARS-CoV-2, induced changes in permeability that were smaller in magnitude and shorter in duration than plasma from patients with SARS-CoV-2. The effect on endothelial cell permeability of plasma from patients with SARS-CoV-2 was heat-labile. The main plasma factor that causes the increased endothelial permeability remains to be identified. Our study provides a possible approach for future studies to understand the underlying mechanisms leading to vascular injury in SARS-CoV-2 infections.

Using relative reflectance measurements from the Mastcam‐Z and SuperCam instruments on the Mars 2020 Perseverance rover, we assess the variability of Fe mineralogy in Noachian/Hesperian‐aged rocks at Jezero crater. The results reveal diverse Fe3+ and Fe2+ minerals. The igneous crater floor, where small amounts of Fe3+‐phyllosilicates and poorly crystalline Fe3+‐oxyhydroxides have been reported, is spectrally similar to most oxidized basalts observed at Gusev crater. At the base of the western Jezero sedimentary fan, new spectral type points to an Fe‐bearing mineral assemblage likely dominated by Fe2+. By contrast, most strata exposed at the fan front show signatures of Fe3+‐oxides (mostly fine‐grained crystalline hematite), Fe3+‐sulfates (potentially copiapites), strong signatures of hydration, and among the strongest signatures of red hematite observed in situ, consistent with materials having experienced vigorous water‐rock interactions and/or higher degrees of diagenesis under oxidizing conditions. The fan top strata show hydration but little to no signs of Fe oxidation likely implying that some periods of fan construction occurred either during a reduced atmosphere era or during short‐lived aqueous activity of liquid water in contact with an oxidized atmosphere. We also report the discovery of alternating cm‐scale bands of red and gray layers correlated with hydration and oxide variability, which has not yet been observed elsewhere on Mars. This could result from syn‐depositional fluid chemistry variations, possibly as seasonal processes, or diagenetic overprint of oxidized fluids percolating through strata having variable permeability. Plain Language Summary: The oxidation states of the atmosphere and waters (whether rich or poor in oxidants such as oxygen) of Mars and their evolution are poorly constrained but can be recorded in the iron (Fe) mineralogy of rocks. Using data from the Perseverance rover, we analyzed the Fe mineralogy of ∼4–3 Ga old rocks from an ancient lake at Jezero crater. Oxidized Fe is found in igneous rocks and lowermost portions of sedimentary rocks, carried by clays and poorly crystalline oxides in the former and by sulfates and crystalline oxides in the latter, pointing to past action of oxidizing fluids, affecting more intensely the sedimentary rocks. Fe shows poor to no signs of oxidation in the uppermost strata, which might be evidence for a reducing atmosphere during sediment deposition or that the aqueous environment was too cold or too short‐lived to oxidize minerals. We also report Fe mineralogy variability at the cm‐scale in alternating colored layers, which has not been observed previously on Mars and could possibly mean that seasonal processes are recorded at Jezero crater. Key Points: In situ reflectance data measured with Mars 2020 show variable Fe mineralogy in sedimentary rocks at Jezero craterStrata exposed at the fan front experienced stronger oxidative water‐rock interactions compared to the upper fan and igneous crater floorWe identify cm‐scale color banding correlated with Fe‐oxide variability that likely indicates time variation in redox [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is the critical regulator of VEGFR2-induced angiogenesis. Neither VEGF-A over-expression nor L-Arginine (NO-precursor) supplementation has been effective in helping patients with Peripheral Artery Disease (PAD) in clinical trials. One incompletely studied reason may be due to the presence of the less characterized anti-angiogenic VEGF-A (VEGF165b) isoform. We have recently shown that VEGF165b inhibits ischemic angiogenesis by blocking VEGFR1, not VEGFR2 activation. Here we wanted to determine whether VEGF165b inhibition using a monoclonal isoform-specific antibody against VEGF165b vs. control, improved perfusion recovery in preclinical PAD models that have impaired VEGFR2-NO signaling, including (1) type-2 diabetic model, (2) endothelial Nitric oxide synthase-knock out mice, and (3) Myoglobin transgenic mice that have impaired NO bioavailability. In all PAD models, VEGF165b inhibition vs. control enhanced perfusion recovery, increased microvascular density in the ischemic limb, and activated VEGFR1-STAT3 signaling. In vitro, VEGF165b inhibition vs. control enhanced a VEGFR1-dependent endothelial survival/proliferation and angiogenic capacity. These data demonstrate that VEGF165b inhibition induces VEGFR1-STAT3 activation, which does not require increased NO to induce therapeutic angiogenesis in PAD. These results may have implications for advancing therapies for patients with PAD where the VEGFR2-eNOS-NO pathway is impaired.

Perivascular cells are essential to the formation and stabilization of new blood vessels during angiogenesis. Here, Hess and Kelly-Goss et al. show that the stem cell pluripotency factor Oct4 promotes perivascular cell survival and migration required for angiogenesis in contexts of tissue injury and hypoxia.

Abstract Background The health-related quality of life (HRQoL) is an important treatment goal that could serve as low-cost prognostication tool in resource poor settings. We sought to validate the Kansas City Cardiomyopathy Questionnaire (KCCQ) and evaluate its use as a predictor of 3 months all-cause mortality among heart failure participants in rural Uganda. Methods The Mbarara Heart Failure Registry Cohort study observes heart failure patients during hospital stay and in the community in rural Uganda. Participants completed health failure evaluations and HRQoL questionnaires at enrollment, 1 and 3 months of follow-up. We used Cronbach’s alpha coefficients to define internal consistency, intraclass correlation coefficients as a reliability coefficient, and Cox proportional hazard models to predict the risk of 3 months all-cause mortality. Results Among the 195 participants who completed HRQoL questionnaires, the mean age was 52 (standard deviation (SD) 21.4) years, 68% were women and 29% reported history of hypertension. The KCCQ had excellent internal consistency (87% Cronbach alpha) but poor reliability. Independent predictors of all-cause mortality within 3 months included: worse overall KCCQ score (Adjusted Hazard ratio (AHR) 2.9, 95% confidence interval (CI) 1.1, 8.1), highest asset ownership (AHR 3.6, 95% CI 1.2, 10.8), alcoholic drinks per sitting (AHR per 1 drink 1.4, 95% CI 1.0, 1.9), New York Heart Association (NYHA) functional class IV heart failure (AHR 2.6, 95% CI 1.3, 5.4), estimated glomerular filtration rate (eGFR) 30 to 59 ml/min/1.73 m2 (AHR 3.4, 95% CI 1.1, 10.8), and eGFR less than 15 ml/min/1.73 m2 (AHR 2.7, 95% CI 1.0, 7.1), each 1 pg/mL increase in Brain Natriuretic Peptide (BNP) (AHR, 1.0, 95% CI 1.0, 1.0), and each 1 ng/mL increase in Creatine-Kinase MB isomer (CKMB) (AHR 1.0, 95% CI 1.0, 1.1). Conclusion The KCCQ showed excellent internal consistency. Worse overall KCCQ score, highest asset ownership, increasing alcoholic drink per sitting, NYHA class IV, decreased estimated glomerular filtration rate, BNP, and CKMB predicted all-cause mortality at 3 months. The KCCQ could be an additional low-cost tool to aid in the prognostication of acute heart failure patients.

Macrophages respond to signals in the microenvironment by changing their functional phenotypes, a process known as polarization. Depending on the context, they acquire different patterns of transcriptional activation, cytokine expression and cellular metabolism which collectively constitute a continuous spectrum of phenotypes, of which the two extremes are denoted as classical (M1) and alternative (M2) activation. To quantitatively decode the underlying principles governing macrophage phenotypic polarization and thereby harness its therapeutic potential in human diseases, a systems-level approach is needed given the multitude of signaling pathways and intracellular regulation involved. Here we develop the first mechanism-based, multi-pathway computational model that describes the integrated signal transduction and macrophage programming under M1 (IFN-γ), M2 (IL-4) and cell stress (hypoxia) stimulation. Our model was calibrated extensively against experimental data, and we mechanistically elucidated several signature feedbacks behind the M1-M2 antagonism and investigated the dynamical shaping of macrophage phenotypes within the M1-M2 spectrum. Model sensitivity analysis also revealed key molecular nodes and interactions as targets with potential therapeutic values for the pathophysiology of peripheral arterial disease and cancer. Through simulations that dynamically capture the signal integration and phenotypic marker expression in the differential macrophage polarization responses, our model provides an important computational basis toward a more quantitative and network-centric understanding of the complex physiology and versatile functions of macrophages in human diseases.

We reassessed several orbital topographic data sets for the Perseverance rover landing site at Jezero Crater, Mars to better understand its floor units. Tens‐of‐meters deep topographic anomalies occur in the volcanic floor of Jezero crater and are not a result of impact cratering. Eight km‐scale steep escarpment‐bounded depressions may be locations of paleotopographic highs that were embayed by the volcanic floor lava flows, forming inverted topography from either contemporaneous upward inflation of embaying lavas or later deep scour due to differential erosion over 107−9 years. Five multi km‐scale shallow‐sloped depressions linked by channel‐like forms may record locations of buried paleolakes and channels that predate the volcanic floor units or a drained magma system. These results indicate Jezero experienced multiple closed‐basin or dry phases, allowing erosion of the crater floor and creation of topography, which provides new geologic context for the samples gathered by Perseverance. Plain Language Summary: The Perseverance rover has been on Mars in Jezero Crater for over 2 years collecting rock samples. We reexamined elevation data to better understand the volcanic lava unit on the floor of the crater. We found that the floor is slightly tilted south‐southeast, possibly due to sediment, sourced from the north, beneath the volcanic floor. In the floor we found eight depressions bounded by cliffs, possibly formed by past lava flows around hills of weaker rocks that are now eroded away or by the lavas rising upward around the hills of rock. We also found five large, shallow depressions connected by channels. These might indicate old locations of lakes and rivers before the more recent volcanic activity or a drained magma system. This suggests Jezero Crater experienced alternating phases of being dry and being filled with water, providing key information to help interpret the collected samples. Key Points: Tens‐of‐meters deep topographic anomalies occur in the volcanic floor of Jezero CraterSeveral multi‐km2 scale shallow‐sloped depressions and channels may record lower lake levels or a drained magma systemEight escarpment‐bounded depressions formed by lava embayment of preexisting topography followed by lava inflation or differential erosion [ABSTRACT FROM AUTHOR]

Introduction: Several signaling pathways are activated during hypoxia to promote angiogenesis, leading to endothelial cell patterning, interaction, and downstream signaling. Understanding the mechanistic signaling differences between endothelial cells under normoxia and hypoxia and their response to different stimuli can guide therapies to modulate angiogenesis. We present a novel mechanistic model of interacting endothelial cells, including the main pathways involved in angiogenesis. Methods: We calibrate and fit the model parameters based on well-established modeling techniques that include structural and practical parameter identifiability, uncertainty quantification, and global sensitivity. Results: Our results indicate that the main pathways involved in patterning tip and stalk endothelial cells under hypoxia differ, and the time under hypoxia interferes with how different stimuli affect patterning. Additionally, our simulations indicate that Notch signaling might regulate vascular permeability and establish different Nitric Oxide release patterns for tip/stalk cells. Following simulations with various stimuli, our model suggests that factors such as time under hypoxia and oxygen availability must be considered for EC pattern control. Discussion: This project provides insights into the signaling and patterning of endothelial cells under various oxygen levels and stimulation by VEGFA and is our first integrative approach toward achieving EC control as a method for improving angiogenesis. Overall, our model provides a computational framework that can be built on to test angiogenesis-related therapies by modulation of different pathways, such as the Notch pathway. [ABSTRACT FROM AUTHOR]

Purpose: Retrospective audit of recurrent glioma patients treated by different fractionation schedules and to validate the modified Combs prognostic score in Indian patient cohort. Materials and Methods: Between Jan 2009 and June 2022, 66 recurrent gliomas patients treated with standard adjuvant treatment--radiation (RT) ± temozolomide (chemotherapy)--and re-treated with RT (± chemotherapy) were categorized as per modified Combs prognostic criteria and outcomes were compared. Results: Sixty-six patients with recurrent gliomas who received reirradiation (re-RT) were audited--53% males; 61% Karnofsky performance status (KPS) =80 at time of re-RT; median age 41.5 years (range, 6 to 70 years); 67% <50 years; primary histology low-grade glioma in 33%; grade III 27%, grade IV 40%; initial median dose of 60 Gy equivalent dose in 2 Gy fractions (EQD2); maximum safe resection at recurrence 41%; mean and median follow-up 78 ± 51 months and 66 months. Mean time interval between RT was 46.4 ± 39 months. Mean planning target volume (PTV) volume in conventional RT (Conv-RT), hypofractionated RT (Hypo-RT), and ultra-hypofractionated RT (UF-RT) was 226.1 ± 140.7 mL, 162.8 ± 123.3 mL, and 143.3 ± 145.8 mL. Mean dose for Conv-RT, Hypo-RT, and UF-RT was 50 Gy (range, 40 to 60), 31 Gy (range, 20 to 40), and 20 Gy (range, 10 to 30). Mean overall survival (OS) in Conv-RT, Hypo-RT, and UF-RT cohort was 18.8 months (range, 2.4 to 76.8); 6.6 months (range, 2 to 17.4), and 13.9 months (range, 3 to 131.9). Median OS as per Combs criteria were 16.6 months (Group a), 24.6 months (Group b), 4.6 months (Group c), and 3 months (Group d). Significant survival benefit was with good KPS score (KPS >80 vs. <80; 20.46 vs. 5.25 months; p < 0.001), patients receiving salvage chemotherapy (20.46 vs. 6.96 months; p = 0.001), and patients received re-RT biological equivalent dose (BED3) >80 Gy (16.62 vs. 5.48 months; p = 0.03). Median overall survival (OS) in our patient cohort and Combs cohort in Group a was 16.6 and 19.5 months; Group b was 24.6 and 11.3 months; Group c was 4.7 and 8.1 months, and Group d was 2 and 5.5 months, respectively. Six months survival in our patient cohort and Combs cohort in Groups a, b, c, d were 100%, 92%, 34%, 17% and 94%, 79%, 70%, 41%, respectively. Twelve months survival in our patient cohort and Combs cohort in Groups a, b, c, d were 88%, 74%, 22%, 0% and 88%, 47%, 22%, 7%, respectively. Conclusion: Modified Combs prognostic factors predicts OS and is applicable in Indian subcontinent patient population. [ABSTRACT FROM AUTHOR]

The vascular endothelial growth factor (VEGF) family of cytokines are key drivers of blood vessel growth and remodeling. These ligands act via multiple VEGF receptors (VEGFR) and co-receptors such as Neuropilin (NRP) expressed on endothelial cells. These membrane-associated receptors are not solely expressed on the cell surface, they move between the surface and intracellular locations, where they can function differently. The location of the receptor alters its ability to 'see' (access and bind to) its ligands, which regulates receptor activation; location also alters receptor exposure to subcellularly localized phosphatases, which regulates its deactivation. Thus, receptors in different subcellular locations initiate different signaling, both in terms of quantity and quality. Similarly, the local levels of co-expression of other receptors alters competition for ligands. Subcellular localization is controlled by intracellular trafficking processes, which thus control VEGFR activity; therefore, to understand VEGFR activity, we must understand receptor trafficking. Here, for the first time, we simultaneously quantify the trafficking of VEGFR1, VEGFR2, and NRP1 on the same cells—specifically human umbilical vein endothelial cells (HUVECs). We build a computational model describing the expression, interaction, and trafficking of these receptors, and use it to simulate cell culture experiments. We use new quantitative experimental data to parameterize the model, which then provides mechanistic insight into the trafficking and localization of this receptor network. We show that VEGFR2 and NRP1 trafficking is not the same on HUVECs as on non-human ECs; and we show that VEGFR1 trafficking is not the same as VEGFR2 trafficking, but rather is faster in both internalization and recycling. As a consequence, the VEGF receptors are not evenly distributed between the cell surface and intracellular locations, with a very low percentage of VEGFR1 being on the cell surface, and high levels of NRP1 on the cell surface. Our findings have implications both for the sensing of extracellular ligands and for the composition of signaling complexes at the cell surface versus inside the cell. Author summary: Receptors and their ligands are at the heart of cell-to-cell signaling, but can only interact if they are in the same place at the same time. This is controlled in part by expression–only if a cell expresses a receptor can the cell perceive and respond to that ligand. But it is also controlled in part by where in the cell that receptor is. If the receptor is on the cell surface, it may be able to bind extracellular ligands. If inside the cell, e.g. on endosomal vesicles, it may not. Similarly, the intracellular portions of receptors at the cell surface and inside the cell are exposed to different local environments and can initiate different signaling pathways. Therefore, understanding receptor localization and trafficking (how the receptors move within the cell) is an important starting point for understanding receptor function. Here, we use mechanistic computational modeling and quantitative experimental data to define the localization and trafficking of the VEGF receptors, which are key drivers of blood vessel growth and remodeling. We show that these receptors each has different trafficking and patterns of localization, which has significant implications for the differential responses of these receptors to extracellular ligands. [ABSTRACT FROM AUTHOR]

Sedimentary fans are key targets of exploration on Mars because they record the history of surface aqueous activity and habitability. The sedimentary fan extending from the Neretva Vallis breach of Jezero crater's western rim is one of the Mars 2020 Perseverance rover's main exploration targets. Perseverance spent ∼250 sols exploring and collecting seven rock cores from the lower ∼25 m of sedimentary rock exposed within the fan's eastern scarp, a sequence informally named the "Shenandoah" formation. This study describes the sedimentology and stratigraphy of the Shenandoah formation at two areas, "Cape Nukshak" and "Hawksbill Gap," including a characterization, interpretation, and depositional framework for the facies that comprise it. The five main facies of the Shenandoah formation include: laminated mudstone, laminated sandstone, low‐angle cross stratified sandstone, thin‐bedded granule sandstone, and thick‐bedded granule‐pebble sandstone and conglomerate. These facies are organized into three facies associations (FA): FA1, comprised of laminated and soft sediment‐deformed sandstone interbedded with broad, unconfined coarser‐grained granule and pebbly sandstone intervals; FA2, comprised predominantly of laterally extensive, soft‐sediment deformed laminated, sulfate‐bearing mudstone with lenses of low‐angle cross‐stratified and scoured sandstone; and FA3, comprised of dipping planar, thin‐bedded sand‐gravel couplets. The depositional model favored for the Shenandoah formation involves the transition from a sand‐dominated distal alluvial fan setting (FA1) to a stable, widespread saline lake (FA2), followed by the progradation of a river delta system (FA3) into the lake basin. This sequence records the initiation of a relatively long‐lived, habitable lacustrine and deltaic environment within Jezero crater. Plain Language Summary: Fan‐shaped deposits are important exploration targets on Mars because they record the activity of water and conditions suitable for life on the surface. The Mars 2020 Perseverance rover has been exploring an ancient impact crater, named Jezero, since landing on Mars in February 2021. One of the rover's main exploration targets is a fan‐shaped deposit of sedimentary rock extending into the crater from the western rim. One Earth year into the rover's mission, Perseverance arrived at the eroded edge of this fan, exploring several outcrops of sedimentary rock, and collecting seven rock samples. This study uses images and data from Perseverance to describe these rocks, called the "Shenandoah" formation, and to determine how they formed. The oldest rocks of the Shenandoah formation contain sand and pebbles that were likely laid down at the edge of an alluvial fan. Next, very fine‐grained rocks were deposited in a lake setting. Dipping layers of alternating sand and pebbles represent a change in the local setting and the growth of a delta into a relatively long‐lived lake. The rover's observations of the Shenandoah formation show that past conditions in Jezero crater were capable of hosting and preserving signs of ancient life. Key Points: The Shenandoah formation is a sand‐dominated, clastic, sedimentary sequence comprising the lower 25 m of Jezero's western fanThis sequence records the transition from an alluvial fan setting to a lacustrine setting, followed by progradation of a river deltaThis sequence records evidence for a warm, wet, habitable depositional setting with the potential to preserve biosignatures [ABSTRACT FROM AUTHOR]

The matricellular protein thrombospondin-1 (TSP1) is a potent inhibitor of angiogenesis. Specifically, TSP1 has been experimentally shown to inhibit signaling downstream of vascular endothelial growth factor (VEGF). The molecular mechanism of this inhibition is not entirely clear. We developed a detailed computational model of VEGF signaling to Akt–endothelial nitric oxide synthase (eNOS) to investigate the quantitative molecular mechanism of TSP1 inhibition. The model demonstrated that TSP1 acceleration of VEGFR2 degradation is sufficient to explain the inhibition of VEGFR2 and eNOS phosphorylation. However, Akt inhibition requires TSP1-induced phosphatase recruitment to VEGFR2. The model was then utilized to test various strategies for the rescue of VEGF signaling to Akt and eNOS. Inhibiting TSP1 was predicted to be not as effective as CD47 depletion in rescuing signaling to Akt. The model further predicts that combination strategy involving depletion of CD47 and inhibition of TSP1 binding to CD47 is necessary for effective recovery of signaling to eNOS. In all, computational modeling offers insight to molecular mechanisms involving TSP1 interaction with VEGF signaling and provides strategies for rescuing angiogenesis by targeting TSP1–CD47 axis.