The challenges and opportunities of battery-powered flight.

Aircraft, and the aviation ecosystem in which they operate, are shaped by complex trades among technical requirements, economics and environmental concerns, all built on a foundation of safety. This Perspective explores the requirements of battery-powered aircraft and the chemistries that hold promise to enable them. The difference between flight and terrestrial needs and chemistries are highlighted. Safe, usable specific energy rather than cost is the major constraint for aviation. We conclude that battery packs suitable for flight with specific energy approaching 600 kilowatt hours per kilogram may be achievable in the next decade given sufficient investment targeted at aeronautical applications.

Endothelial Cell TGF-ß (Transforming Growth Factor-Beta) Signaling Regulates Venous Adaptive Remodeling to Improve Arteriovenous Fistula Patency.

BACKGROUND: Arteriovenous fistulae (AVF) are the gold standard for vascular access for hemodialysis. Although the vein must thicken and dilate for successful hemodialysis, excessive wall thickness leads to stenosis causing AVF failure. Since TGF-ß (transforming growth factor-beta) regulates ECM (extracellular matrix) deposition and smooth muscle cell (SMC) proliferation-critical components of wall thickness-we hypothesized that disruption of TGF-ß signaling prevents excessive wall thickening during venous remodeling. METHODS: A mouse aortocaval fistula model was used. SB431542-an inhibitor of TGF-ß receptor I-was encapsulated in nanoparticles and applied to the AVF adventitia in C57BL/6J mice. Alternatively, AVFs were created in mice with conditional disruption of TGF-ß receptors in either SMCs or endothelial cells. Doppler ultrasound was performed serially to confirm patency and to measure vessel diameters. AVFs were harvested at predetermined time points for histological and immunofluorescence analyses. RESULTS: Inhibition of TGF-ß signaling with SB431542-containing nanoparticles significantly reduced p-Smad2-positive cells in the AVF wall during the early maturation phase (days 7-21) and was associated with decreased AVF wall thickness that showed both decreased collagen density and decreased SMC proliferation. SMC-specific TGF-ß signaling disruption decreased collagen density but not SMC proliferation or wall thickness. Endothelial cell-specific TGF-ß signaling disruption decreased both collagen density and SMC proliferation in the AVF wall and was associated with reduced wall thickness, increased outward remodeling, and improved AVF patency. CONCLUSIONS: Endothelial cell-targeted TGF-ß inhibition may be a translational strategy to improve AVF patency.

PD-L1 (Programmed Death Ligand 1) Regulates T-Cell Differentiation to Control Adaptive Venous Remodeling.

OBJECTIVE: Patients with end-stage renal disease depend on hemodialysis for survival. Although arteriovenous fistulae (AVF) are the preferred vascular access for hemodialysis, the primary success rate of AVF is only 30% to 50% within 6 months, showing an urgent need for improvement. PD-L1 (programmed death ligand 1) is a ligand that regulates T-cell activity. Since T cells have an important role during AVF maturation, we hypothesized that PD-L1 regulates T cells to control venous remodeling that occurs during AVF maturation. Approach and results: In the mouse aortocaval fistula model, anti-PD-L1 antibody (200 mg, 3×/wk intraperitoneal) was given to inhibit PD-L1 activity during AVF maturation. Inhibition of PD-L1 increased T-helper type 1 cells and T-helper type 2 cells but reduced regulatory T cells to increase M1-type macrophages and reduce M2-type macrophages; these changes were associated with reduced vascular wall thickening and reduced AVF patency. Inhibition of PD-L1 also inhibited smooth muscle cell proliferation and increased endothelial dysfunction. The effects of anti-PD-L1 antibody on adaptive venous remodeling were diminished in nude mice; however, they were restored after T-cell transfer into nude mice, indicating the effects of anti-PD-L1 antibody on venous remodeling were dependent on T cells. CONCLUSIONS: Regulation of PD-L1 activity may be a potential therapeutic target for clinical translation to improve AVF maturation.

Inhibition of T-Cells by Cyclosporine A Reduces Macrophage Accumulation to Regulate Venous Adaptive Remodeling and Increase Arteriovenous Fistula Maturation.

OBJECTIVE: Arteriovenous fistulae (AVF) are the preferred vascular access for hemodialysis, but the primary success rate of AVF remains poor. Successful AVF maturation requires vascular wall thickening and outward remodeling. A key factor determining successful AVF maturation is inflammation that is characterized by accumulation of both T-cells and macrophages. We have previously shown that anti-inflammatory (M2) macrophages are critically important for vascular wall thickening during venous remodeling; therefore, regulation of macrophage accumulation may be an important mechanism promoting AVF maturation. Since CD4+ T-cells such as T-helper type 1 cells, T-helper type 2 cells, and regulatory T-cells can induce macrophage migration, proliferation, and polarization, we hypothesized that CD4+ T-cells regulate macrophage accumulation to promote AVF maturation. Approach and Results: In a mouse aortocaval fistula model, T-cells temporally precede macrophages in the remodeling AVF wall. CsA (cyclosporine A; 5 mg/kg, sq, daily) or vehicle (5% dimethyl sulfoxide) was administered to inhibit T-cell function during venous remodeling. CsA reduced the numbers of T-helper type 1 cells, T-helper type 2, and regulatory T-cells, as well as M1- and M2-macrophage accumulation in the wall of the remodeling fistula; these effects were associated with reduced vascular wall thickening and increased outward remodeling in wild-type mice. However, these effects were eliminated in nude mice, showing that the effects of CsA on macrophage accumulation and adaptive venous remodeling are T-cell-dependent. CONCLUSIONS: T-cells regulate macrophage accumulation in the maturing venous wall to control adaptive remodeling. Regulation of T-cells during AVF maturation may be a strategy that can improve AVF maturation. Graphic Abstract: A graphic abstract is available for this article.

A central arteriovenous fistula reduces systemic hypertension in a mouse model.

Objective: A central arteriovenous fistula (AVF) has been proposed as a potential novel solution to treat patients with refractory hypertension. We hypothesized that venous remodeling after AVF creation in the hypertensive environment reduces systemic blood pressure but results in increased AVF wall thickness compared with remodeling in the normotensive environment. Methods: A central AVF was performed in C57BL6/J mice previously made hypertensive with angiotensin II (Ang II); mice were sacrificed on postoperative day 7 or 21. Results: In mice treated with Ang II alone, the mean systolic blood pressure increased from 90 ± 5 mmHg to 160 ± 5 mmHg at day 21; however, in mice treated with both Ang II and an AVF, the blood pressure decreased with creation of an AVF. There were significantly more PCNA-positive cells, SM22α/PCNA-positive cells, collagen I deposition, and increased Krüppel-like Factor 2 immunoreactivity in hypertensive mice with an AVF compared with normotensive mice with an AVF. Conclusions: These data show that a central AVF decreases systemic hypertension as well as induces local alterations in venous remodeling.

Transplant Fellowship and Presenting at a Transplant-Specific Conference.

INTRODUCTION: The ASTS implemented a task force in 2018 to increase residents' interest in careers in organ transplantation. National meetings offer important experiences that can increase interest. The present study examines an association that exists between presenting at a major transplant surgery meeting and a trainee's likelihood of pursuing a career in transplant surgery. METHODS: All abstracts from the ASTS State of the Art Winter Symposium from 2010 to 2019 were evaluated. Using a combination of internet-based resources, it was determined if the presenter was a resident, what year of residency they were in, and if that individual went into a transplant fellowship. RESULTS: 1544 abstracts were reviewed and 133 were presented by residents. Out of residents that presented, 68.4% (54/79) were senior residents and 31.6% (25/79) were junior residents. Of senior residents, 66.7% (36/54) went into transplant fellowships, while only 20.0% (5/25) of junior residents went into transplant fellowships. Being a senior resident when presenting was statistically significant for pursuing a transplant fellowship (P = .000113). DISCUSSION: Senior residents who present at ASTS SAWS are likely to pursue a transplant surgery fellowship. Junior residents who present are less likely to pursue transplantation, and this represents an opportunity to improve the engagement of young surgeons in the specialty.

EphB4 monomer inhibits chronic graft vasculopathy in an aortic transplant model.

T cells and macrophages play an important role in the formation of allograft vasculopathy, which is the predominant form of chronic rejection in cardiac transplants. Arteries express Ephrin-B2 as a marker of arterial identity, whereas circulating monocytes express the cognate receptor EphB4, which facilitates monocyte adhesion to the endothelial surface. Adherent monocytes transmigrate and differentiate into macrophages that activate T cells and are a main source of tissue damage during rejection. We hypothesized that inhibition of Ephrin-B2-EphB4 binding would decrease immune cell accumulation within a transplanted graft and prevent allograft vasculopathy. We used EphB4 monomer to inhibit Ephrin-B2-EphB4 binding in a rat infrarenal aortic transplant model. Rats treated with EphB4 monomer had fewer macrophages and T cells in the aortic allografts at 28 days, as well as significantly less neointima formation. These data show that the Ephin-B2-EphB4 axis may be an important target for prevention or treatment of allograft vasculopathy.

Revisiting the Principles of Preservation in an Era of Pandemic Obesity.

The current obesity epidemic has caused a significant decline in the health of our donor population. Organs from obese deceased donors are more prone to ischemia reperfusion injury resulting from organ preservation. As a consequence, these donors are more likely to be discarded under the assumption that nothing can be done to make them viable for transplant. Our current methods of organ preservation-which remain relatively unchanged over the last ~40 years-were originally adopted in the context of a much healthier donor population. But methods that are suitable for healthier deceased donors are likely not optimal for organs from obese donors. Naturally occurring models of acute obesity and fasting in hibernating mammals demonstrate that obesity and resilience to cold preservation-like conditions are not mutually exclusive. Moreover, recent advances in our understanding of the metabolic dysfunction that underlies obesity suggest that it may be possible to improve the resilience of organs from obese deceased donors. In this mini-review, we explore how we might adapt our current practice of organ preservation to better suit the current reality of our deceased donor population.

Sex Differences in Inflammation During Venous Remodeling of Arteriovenous Fistulae.

Vascular disorders frequently have differing clinical presentations among women and men. Sex differences exist in vascular access for hemodialysis; women have reduced rates of arteriovenous fistula (AVF) maturation as well as fistula utilization compared with men. Inflammation is increasingly implicated in both clinical studies and animal models as a potent mechanism driving AVF maturation, especially in vessel dilation and wall thickening, that allows venous remodeling to the fistula environment to support hemodialysis. Sex differences have long been recognized in arterial remodeling and diseases, with men having increased cardiovascular events compared with pre-menopausal women. Many of these arterial diseases are driven by inflammation that is similar to the inflammation during AVF maturation. Improved understanding of sex differences in inflammation during vascular remodeling may suggest sex-specific vascular therapies to improve AVF success.

Arteriovenous Fistula-induced Cardiac Remodeling Shows Cardioprotective Features in Mice.

OBJECTIVE---: Arteriovenous fistulae (AVF) placed for hemodialysis have high flow rates that can stimulate left ventricular (LV) hypertrophy. LV hypertrophy generally portends poor cardiac outcomes, yet clinical studies point to superior cardiac-specific outcomes for patients with AVF when compared to other dialysis modalities. We hypothesize that AVF induce physiologic cardiac hypertrophy with cardioprotective features. METHODS---: 9-11 week C57Bl/6 male and female mice were treated with sham laparotomy or an aortocaval fistula via a 25Ga needle. Cardiac chamber size and function were assessed with serial echocardiography, and cardiac CTA. Hearts were harvested at 5 weeks post-operatively, and collagen content assessed with Masson's trichrome. Bulk mRNA sequencing was performed from LV of sham and AVF mice at 10 days. Differentially expressed genes were analyzed using Ingenuity Pathway Analysis (Qiagen) to identify affected pathways and predict downstream biological effects. RESULTS---: Mice with AVF had similar body weight and wet lung mass, but increased cardiac mass compared to sham-operated mice. AVF increased cardiac output while preserving LV systolic and diastolic function, as well as indices of right heart function; all 4 cardiac chambers were enlarged, with slight decrement in relative LV wall thickness. Histology showed preserved collagen density within each of the 4 chambers without areas of fibrosis. RNA sequencing captured 19,384 genes, of which 857 were significantly differentially expressed, including transcripts from extracellular matrix-related genes, ion channels, metabolism, and cardiac fetal genes. Top upstream regulatory molecules predicted include activation of angiogenic (Vegf, Akt1), pro-cardiomyocyte survival (Hgf, Foxm1, Erbb2, Lin9, Areg), and inflammation-related (CSF2, Tgfb1, TNF, Ifng, Ccr2, IL6) genes, as well as the inactivation of cardiomyocyte antiproliferative factors (Cdkn1a, FoxO3, α-catenin). Predicted downstream effects include reduction to heart damage, and increased arrhythmia, angiogenesis, and cardiogenesis. There were no significant sex-dependent differences in the AVF-stimulated cardiac adaptation. CONCLUSIONS---: AVF stimulate adaptive cardiac hypertrophy in wild-type mice without heart failure or pathological fibrosis. Transcriptional correlates suggest AVF-induced cardiac remodeling has some cardioprotective, although also arrhythmogenic features.

Human-Induced Pluripotent Stem-Cell-Derived Smooth Muscle Cells Increase Angiogenesis to Treat Hindlimb Ischemia.

Induced pluripotent stem cells (iPSC) represent an innovative, somatic cell-derived, easily obtained and renewable stem cell source without considerable ethical issues. iPSC and their derived cells may have enhanced therapeutic and translational potential compared with other stem cells. We previously showed that human iPSC-derived smooth muscle cells (hiPSC-SMC) promote angiogenesis and wound healing. Accordingly, we hypothesized that hiPSC-SMC may be a novel treatment for human patients with chronic limb-threatening ischemia who have no standard options for therapy. We determined the angiogenic potential of hiPSC-SMC in a murine hindlimb ischemia model. hiPSC-SMC were injected intramuscularly into nude mice after creation of hindlimb ischemia. Functional outcomes and perfusion were measured using standardized scores, laser Doppler imaging, microCT, histology and immunofluorescence. Functional outcomes and blood flow were improved in hiPSC-SMC-treated mice compared with controls (Tarlov score, p < 0.05; Faber score, p < 0.05; flow, p = 0.054). hiPSC-SMC-treated mice showed fewer gastrocnemius fibers (p < 0.0001), increased fiber area (p < 0.0001), and enhanced capillary density (p < 0.01); microCT showed more arterioles (<96 µm). hiPSC-SMC treatment was associated with fewer numbers of macrophages, decreased numbers of M1-type (p < 0.05) and increased numbers of M2-type macrophages (p < 0.0001). Vascular endothelial growth factor (VEGF) expression in ischemic limbs was significantly elevated with hiPSC-SMC treatment (p < 0.05), and inhibition of VEGFR-2 with SU5416 was associated with fewer capillaries in hiPSC-SMC-treated limbs (p < 0.0001). hiPSC-SMC promote VEGF-mediated angiogenesis, leading to improved hindlimb ischemia. Stem cell therapy using iPSC-derived cells may represent a novel and potentially translatable therapy for limb-threatening ischemia.

Distinct subsets of T cells and macrophages impact venous remodeling during arteriovenous fistula maturation.

Patients with end-stage renal failure depend on hemodialysis indefinitely without renal transplantation, requiring a long-term patent vascular access. While the arteriovenous fistula (AVF) remains the preferred vascular access for hemodialysis because of its longer patency and fewer complications compared with other vascular accesses, the primary patency of AVF is only 50-60%, presenting a clinical need for improvement. AVF mature by developing a thickened vascular wall and increased diameter to adapt to arterial blood pressure and flow volume. Inflammation plays a critical role during vascular remodeling and fistula maturation; increased shear stress triggers infiltration of T-cells and macrophages that initiate inflammation, with involvement of several different subsets of T-cells and macrophages. We review the literature describing distinct roles of the various subsets of T-cells and macrophages during vascular remodeling. Immunosuppression with sirolimus or prednisolone reduces neointimal hyperplasia during AVF maturation, suggesting novel approaches to enhance vascular remodeling. However, M2 macrophages and CD4+ T-cells play essential roles during AVF maturation, suggesting that total immunosuppression may suppress adaptive vascular remodeling. Therefore it is likely that regulation of inflammation during fistula maturation will require a balanced approach to coordinate the various inflammatory cell subsets. Advances in immunosuppressive drug development and delivery systems may allow for more targeted regulation of inflammation to improve vascular remodeling and enhance AVF maturation.

Molecular Targets for Improving Arteriovenous Fistula Maturation and Patency.

The increasing prevalence of chronic and end-stage renal disease creates an increased need for reliable vascular access, and although arteriovenous fistulae (AVF) are the preferred mode of hemodialysis access, 60% fail to mature and only 50% remain patent at one year. Fistulae mature by diameter expansion and wall thickening; this outward remodeling of the venous wall in the fistula environment relies on a delicate balance of extracellular matrix (ECM) remodeling, inflammation, growth factor secretion, and cell adhesion molecule upregulation in the venous wall. AVF failure occurs via two distinct mechanisms with early failure secondary to lack of outward remodeling, that is insufficient diameter expansion or wall thickening, whereas late failure occurs with excessive wall thickening due to neointimal hyperplasia (NIH) and insufficient diameter expansion in a previously functional fistula. In recent years, the molecular basis of AVF maturation and failure are becoming understood in order to develop potential therapeutic targets to aide maturation and prevent access loss. Erythropoietin-producing hepatocellular carcinoma (Eph) receptors, along with their ligands, ephrins, determine vascular identity and are critical for vascular remodeling in the embryo. Manipulation of Eph receptor signaling in adults, as well as downstream pathways, is a potential treatment strategy to improve the rates of AVF maturation and patency. This review examines our current understanding of molecular changes occurring following fistula creation, factors predictive of fistula success, and potential areas of intervention to decrease AVF failure.

Chromatography of proteins on charge-variant ion exchangers and implications for optimizing protein uptake rates.

Intraparticle transport of proteins usually represents the principal resistance controlling their uptake in preparative separations. In ion-exchange chromatography two limiting models are commonly used to describe such uptake: pore diffusion, in which only free protein in the pore lumen contributes to transport, and homogeneous diffusion, in which the transport flux is determined by the gradient in the total protein concentration, free or adsorbed. Several studies have noted a transition from pore to homogeneous diffusion with increasing ionic strength in some systems, and here we investigate the mechanistic basis for this transition. The studies were performed on a set of custom-synthesized methacrylate-based strong cation exchangers differing in ligand density into which uptake of two proteins was examined using confocal microscopy and frontal loading experiments. We find that the transition in uptake mechanism occurs in all cases studied, and generally coincides with an optimum in the dynamic binding capacity at moderately high flow rates. The transition appears to occur when protein-surface attraction is weakened sufficiently, and this is correlated with the isocratic retention factor k' for the system of interest: the transition occurs in the vicinity of k' approximately 3000. This result, which may indicate that adsorption is sufficiently weak to allow the protein to diffuse along or near the surface, provides a predictive basis for optimizing preparative separations using only isocratic retention data.

Recellularization via the bile duct supports functional allogenic and xenogenic cell growth on a decellularized rat liver scaffold.

Recent years have seen a proliferation of methods leading to successful organ decellularization. In this experiment we examine the feasibility of a decellularized liver construct to support growth of functional multilineage cells. Bio-chamber systems were used to perfuse adult rat livers with 0.1% SDS for 24 hours yielding decellularized liver scaffolds. Initially, we recellularized liver scaffolds using a human tumor cell line (HepG2, introduced via the bile duct). Subsequent studies were performed using either human tumor cells co-cultured with human umbilical vein endothelial cells (HUVECs, introduced via the portal vein) or rat neonatal cell slurry (introduced via the bile duct). Bio-chambers were used to circulate oxygenated growth medium via the portal vein at 37C for 5-7 days. Human HepG2 cells grew readily on the scaffold (n = 20). HepG2 cells co-cultured with HUVECs demonstrated viable human endothelial lining with concurrent hepatocyte growth (n = 10). In the series of neonatal cell slurry infusion (n = 10), distinct foci of neonatal hepatocytes were observed to repopulate the parenchyma of the scaffold. The presence of cholangiocytes was verified by CK-7 positivity. Quantitative albumin measurement from the grafts showed increasing albumin levels after seven days of perfusion. Graft albumin production was higher than that observed in traditional cell culture. This data shows that rat liver scaffolds support human cell ingrowth. The scaffold likewise supported the engraftment and survival of neonatal rat liver cell slurry. Recellularization of liver scaffolds thus presents a promising model for functional liver engineering.

Community water fluoridation and health outcomes in England: a cross-sectional study.

BACKGROUND: Six million people in England live in areas where the level of fluoride in water is adjusted to reduce the significant public health burden of dental caries. The dental effects of fluoride are well established, but evidence for suggested adverse health effects is limited, with a lack of rigorous small area population studies that control for confounding. This study aims to test the association between water fluoridation schemes and selected health outcomes using the best available routine data sources. METHODS: Ecological level exposure to fluoridated water was estimated for standard small areas and administrative districts in England using Geographical Information Systems and digitized boundaries based on known patterns of water supply. The association between fluoridation and dental and nondental health indicators was tested using multivariable regression models including ecological level confounding variables. Health indicator data were obtained from routine sources. RESULTS: There was strong evidence of lower prevalence of dental caries (P < 0.001) among children living in fluoridated areas, they also had fewer teeth affected on average (P < 0.001), and lower admission rates for tooth extraction (55% lower; 95% CI-73%, -27%; P = 0.001). There was no strong evidence of an association between fluoridation and hip fracture, Down syndrome, all-cancer, all-cause mortality or osteosarcoma. Fluoridation was negatively associated with the incidence of renal stones (7.9% lower; 95% CI-9.6%,-6.2%; P < 0.001) and bladder cancer (8.0% lower; 95% CI-9.9%,-6.0%; P < 0.001). CONCLUSION: This study uses the comprehensive data sets available in England to provide reassurance that fluoridation is a safe and highly effective public health measure to reduce dental decay. Although lower rates of certain nondental outcomes were found in fluoridated areas, the ecological, observational design prohibits any conclusions being drawn regarding a protective role of fluoridation.

Bilateral decreased vision and cotton-wool spots in a 42-year-old man.

A 42-year-old man presented with bilateral decreased vision, transient visual loss, and anterior segment inflammation. The diagnosis of ocular ischemic syndrome was established by arteriography.