This paper argues that liberal philosophy underestimates the importance of political ethics, which I define as the question of how individual citizens should comport themselves politically under ...largely normal conditions. Using three case studies from popular dystopian science fiction as 'intuition pumps', I contend that the behaviour of such individuals, both discretely and collectively speaking, has significant causal potency when it comes to contemporary politics. Upon this basis, I diagnose as pathological the faith that liberal philosophers place in the power of institutional arrangements to curtail human behaviour. I conclude that liberal philosophy should embrace an 'ethical turn', in pursuit of which I make some indicative recommendations as to what such a development might comprise.
Brown (BAT) and white (WAT) adipose tissues play distinct roles in maintaining whole-body energy homeostasis, and their dysfunction can contribute to non-alcoholic fatty liver disease (NAFLD) and ...type 2 diabetes. The AMP-activated protein kinase (AMPK) is a cellular energy sensor, but its role in regulating BAT and WAT metabolism is unclear. We generated an inducible model for deletion of the two AMPK β subunits in adipocytes (iβ1β2AKO) and found that iβ1β2AKO mice were cold intolerant and resistant to β-adrenergic activation of BAT and beiging of WAT. BAT from iβ1β2AKO mice had impairments in mitochondrial structure, function, and markers of mitophagy. In response to a high-fat diet, iβ1β2AKO mice more rapidly developed liver steatosis as well as glucose and insulin intolerance. Thus, AMPK in adipocytes is vital for maintaining mitochondrial integrity, responding to pharmacological agents and thermal stress, and protecting against nutrient-overload-induced NAFLD and insulin resistance.
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•Adipocyte AMPK is required for cold and β-adrenergic-stimulated thermogenesis•AMPK is required for the browning of white adipose tissue (beige/brite fat)•AMPK is critical for mitophagy and maintaining BAT mitochondrial quality•Adipocyte AMPK is required to prevent NAFLD and insulin resistance
Mottillo et al. find mice lacking AMPK specifically in adipocytes are intolerant to cold and resistant to β-adrenergic stimulation of brown and beige adipose tissues. These defects, independent of lipolysis, are caused by impaired mitophagy, which results in defective BAT mitochondria, non-alcoholic fatty liver disease, and insulin resistance.
The AMP-activated protein kinase (AMPK) activates autophagy, but its role in aging and fasting-induced muscle function has not been defined. Here we report that fasting mice lacking skeletal muscle ...AMPK (AMPK-MKO) results in hypoglycemia and hyperketosis. This is not due to defective fatty acid oxidation, but instead is related to a block in muscle proteolysis that leads to reduced circulating levels of alanine, an essential amino acid required for gluconeogenesis. Markers of muscle autophagy including phosphorylation of Ulk1 Ser555 and Ser757 and aggregation of RFP-LC3 puncta are impaired. Consistent with impaired autophagy, aged AMPK-MKO mice possess a significant myopathy characterized by reduced muscle function, mitochondrial disease, and accumulation of the autophagy/mitophagy proteins p62 and Parkin. These findings establish an essential requirement for skeletal muscle AMPK-mediated autophagy in preserving blood glucose levels during prolonged fasting as well as maintaining muscle integrity and mitochondrial function during aging.
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•Muscle AMPK is required for the induction of autophagy during fasting•AMPK is required for proteolysis to maintain blood glucose during fasting•A loss of AMPK accelerates aging-induced myopathy and mitochondrial dysfunction
Bujak et al. highlight a critical role for the energy sensor AMPK in maintaining glycemia and muscle homeostasis. During fasting, muscle AMPK induces autophagy and muscle protein breakdown to prevent hypoglycemia. With old age, AMPK delays the onset of muscle myopathy and mitochondrial dysfunction.
We report a comparison of charge transport and recombination dynamics in dye-sensitized solar cells (DSSCs) employing nanocrystalline TiO2 and SnO2 films and address the impact of these dynamics upon ...photovoltaic device efficiency. Transient photovoltage studies of electron transport in the metal oxide film are correlated with transient absorption studies of electron recombination with both oxidized sensitizer dyes and the redox couple. For all three processes, the dynamics are observed to be 2−3 orders of magnitude faster for the SnO2 electrode. The origins of these faster dynamics are addressed by studies correlating the electron recombination dynamics to dye cations with chronoamperometric studies of film electron density. These studies indicate that the faster recombination dynamics for the SnO2 electrodes result both from a 100-fold higher electron diffusion constant at matched electron densities, consistent with a lower trap density for this metal oxide relative to TiO2, and from a 300 mV positive shift of the SnO2 conduction band/trap states density of states relative to TiO2. The faster recombination to the redox couple results in an increased dark current for DSSCs employing SnO2 films, limiting the device open-circuit voltage. The faster recombination dynamics to the dye cation result in a significant reduction in the efficiency of regeneration of the dye ground state by the redox couple, as confirmed by transient absorption studies of this reaction, and in a loss of device short-circuit current and fill factor. The importance of this loss pathway was confirmed by nonideal diode equation analyses of device current−voltage data. The addition of MgO blocking layers is shown to be effective at reducing recombination losses to the redox electrolyte but is found to be unable to retard recombination dynamics to the dye cation sufficiently to allow efficient dye regeneration without resulting in concomitant losses of electron injection efficiency. We conclude that such a large acceleration of electron dynamics within the metal oxide films of DSSCs may in general be detrimental to device efficiency due to the limited rate of dye regeneration by the redox couple and discuss the implications of this conclusion for strategies to optimize device performance.
In this paper we focus upon the electron injection dynamics in complete dye-sensitized nanocrystalline metal oxide solar cells (DSSCs). Electron injection dynamics are studied by transient absorption ...and emission studies of DSSCs and correlated with device photovoltaic performance and charge recombination dynamics. We find that the electron injection dynamics are dependent upon the composition of the redox electrolyte employed in the device. In a device with an electrolyte composition yielding optimum photovoltaic device efficiency, electron injection kinetics exhibit a half time of 150 ps. This half time is 20 times slower than that for control dye-sensitized films covered in inert organic liquids. This retardation is shown to result from the influence of the electrolyte upon the conduction band energetics of the TiO2 electrode. We conclude that optimum DSSC device performance is obtained when the charge separation kinetics are just fast enough to compete successfully with the dye excited-state decay. These conditions allow a high injection yield while minimizing interfacial charge recombination losses, thereby minimizing “kinetic redundancy” in the device. We show furthermore that the nonexponential nature of the injection dynamics can be simulated by a simple inhomogeneous disorder model and discuss the relevance of our findings to the optimization of both dye-sensitized and polymer based photovoltaic devices.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused a severe, international shortage of N95 respirators, which are essential to protect health care providers from ...infection. Given the contemporary limitations of the supply chain, it is imperative to identify effective means of decontaminating, reusing, and thereby conserving N95 respirator stockpiles. To be effective, decontamination must result in sterilization of the N95 respirator without impairment of respirator filtration or user fit. Although numerous methods of N95 decontamination exist, none are universally accessible. In this work, we describe a microwave-generated steam decontamination protocol for N95 respirators for use in health care systems of all sizes, geographies, and means. Using widely available glass containers, mesh from commercial produce bags, a rubber band, and a 1,100-W commercially available microwave, we constructed an effective, standardized, and reproducible means of decontaminating N95 respirators. Employing this methodology against MS2 phage, a highly conservative surrogate for SARS-CoV-2 contamination, we report an average 6-log
plaque-forming unit (PFU) (99.9999%) and a minimum 5-log
PFU (99.999%) reduction after a single 3-min microwave treatment. Notably, quantified respirator fit and function were preserved, even after 20 sequential cycles of microwave steam decontamination. This method provides a valuable means of effective decontamination and reuse of N95 respirators by frontline providers facing urgent need.
Due to the rapid spread of coronavirus disease 2019 (COVID-19), there is an increasing shortage of protective gear necessary to keep health care providers safe from infection. As of 9 April 2020, the CDC reported 9,282 cumulative cases of COVID-19 among U.S. health care workers (CDC COVID-19 Response Team, MMWR Morb Mortal Wkly Rep 69:477-481, 2020, https://doi.org/10.15585/mmwr.mm6915e6). N95 respirators are recommended by the CDC as the ideal method of protection from COVID-19. Although N95 respirators are traditionally single use, the shortages have necessitated the need for reuse. Effective methods of N95 decontamination that do not affect the fit or filtration ability of N95 respirators are essential. Numerous methods of N95 decontamination exist; however, none are universally accessible. In this study, we describe an effective, standardized, and reproducible means of decontaminating N95 respirators using widely available materials. The N95 decontamination method described in this work will provide a valuable resource for hospitals, health care centers, and outpatient practices that are experiencing increasing shortages of N95 respirators due to the COVID-19 pandemic.
The reported prevalence of thyroid disease in pregnancy varies widely through the published literature. These discrepancies are due to differences in criteria for euthyroidism, nationality, iodine ...status, and gestational age at screening. As a result, currently, an accepted rate of prevalence does not exist for the various thyroid diseases in pregnancy. Understanding the true prevalence rates of these disorders has important implications for clinical management and the ongoing discussion regarding universal screening. The aims of this study were to assess (i) the true prevalence of thyroid disorders in pregnancy and (ii) the impact of diagnostic methodology on these rates.
A systematic review was conducted of the existing literature, including the Pubmed database and references from relevant review articles. Sixty-three studies reporting prevalence of overt hypothyroidism, subclinical hypothyroidism, isolated hypothyroxinemia, subclinical hyperthyroidism, and overt hyperthyroidism in pregnant women were included. Studies were further classified by thyrotropin (TSH) cutoff for diagnosis in hypothyroid disease and timing of screening for hyperthyroid disease. Meta-analysis yielded pooled prevalence rates, with subgroup analyses for TSH cutoff and timing of screening. Analysis of studies using the 97.5th percentile TSH cutoff was assessed to yield the most accurate prevalence rates for hypothyroidism.
Pooled prevalence rates for hypothyroidism calculated from studies using the 97.5th percentile as an upper limit for TSH were 0.50% for overt hypothyroidism, 3.47% for subclinical hypothyroidism, and 2.05% for isolated hypothyroxinemia. Pooled prevalence rates in the first and second trimesters for hyperthyroidism were 0.91% and 0.65%, respectively, for overt hyperthyroidism and 2.18% and 0.98%, respectively, for subclinical hyperthyroidism.
Population-based, trimester-specific TSH cutoffs for diagnosis of hypothyroid disease in pregnancy result in more accurate diagnosis and better estimates for prevalence of disease. Prevalence of hyperthyroidism in pregnancy varies depending on timing of screening. The prevalence rates reported in this study represent the best estimate to date of the true rates of thyroid disease in pregnancy.
The placenta is a vital organ of pregnancy, regulating adaptation to pregnancy, gestational parent/fetal exchange, and ultimately, fetal development and growth. Not surprisingly, in cases of ...placental dysfunction-where aspects of placental development or function become compromised-adverse pregnancy outcomes can result. One common placenta-mediated disorder of pregnancy is preeclampsia (PE), a hypertensive disorder of pregnancy with a highly heterogeneous clinical presentation. The wide array of clinical characteristics observed in pregnant individuals and neonates of a PE pregnancy are likely the result of distinct forms of placental pathology underlying the PE diagnosis, explaining why no one common intervention has proven effective in the prevention or treatment of PE. The historical paradigm of placental pathology in PE highlights an important role for utero-placental malperfusion, placental hypoxia and oxidative stress, and a critical role for placental mitochondrial dysfunction in the pathogenesis and progression of the disease. In the current review, the evidence of placental mitochondrial dysfunction in the context of PE will be summarized, highlighting how altered mitochondrial function may be a common feature across distinct PE subtypes. Further, advances in this field of study and therapeutic targeting of mitochondria as a promising intervention for PE will be discussed.
The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a severe international shortage of the nasopharyngeal swabs that are required for collection of optimal ...specimens, creating a critical bottleneck blocking clinical laboratories' ability to perform high-sensitivity virological testing for SARS-CoV-2. To address this crisis, we designed and executed an innovative, cooperative, rapid-response translational-research program that brought together health care workers, manufacturers, and scientists to emergently develop and clinically validate new swabs for immediate mass production by 3D printing. We performed a multistep preclinical evaluation of 160 swab designs and 48 materials from 24 companies, laboratories, and individuals, and we shared results and other feedback via a public data repository (http://github.com/rarnaout/Covidswab/). We validated four prototypes through an institutional review board (IRB)-approved clinical trial that involved 276 outpatient volunteers who presented to our hospital's drive-through testing center with symptoms suspicious for COVID-19. Each participant was swabbed with a reference swab (the control) and a prototype, and SARS-CoV-2 reverse transcriptase PCR (RT-PCR) results were compared. All prototypes displayed excellent concordance with the control (κ = 0.85 to 0.89). Cycle threshold (
) values were not significantly different between each prototype and the control, supporting the new swabs' noninferiority (Mann-Whitney U MWU test,
> 0.05). Study staff preferred one of the prototypes over the others and preferred the control swab overall. The total time elapsed between identification of the problem and validation of the first prototype was 22 days. Contact information for ordering can be found at http://printedswabs.org Our experience holds lessons for the rapid development, validation, and deployment of new technology for this pandemic and beyond.
Abstract Objective The sodium-glucose transporter 2 (SGLT2) inhibitors Canagliflozin and Dapagliflozin are recently approved medications for type 2 diabetes. Recent studies indicate that SGLT2 ...inhibitors may inhibit the growth of some cancer cells but the mechanism(s) remain unclear. Methods Cellular proliferation and clonogenic survival were used to assess the sensitivity of prostate and lung cancer cell growth to the SGLT2 inhibitors. Oxygen consumption, extracellular acidification rate, cellular ATP, glucose uptake, lipogenesis, and phosphorylation of AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase, and the p70S6 kinase were assessed. Overexpression of a protein that maintains complex-I supported mitochondrial respiration (NDI1) was used to establish the importance of this pathway for mediating the anti-proliferative effects of Canagliflozin. Results Clinically achievable concentrations of Canagliflozin, but not Dapagliflozin, inhibit cellular proliferation and clonogenic survival of prostate and lung cancer cells alone and in combination with ionizing radiation and the chemotherapy Docetaxel. Canagliflozin reduced glucose uptake, mitochondrial complex-I supported respiration, ATP, and lipogenesis while increasing the activating phosphorylation of AMPK. The overexpression of NDI1 blocked the anti-proliferative effects of Canagliflozin indicating reductions in mitochondrial respiration are critical for anti-proliferative actions. Conclusion These data indicate that like the biguanide metformin, Canagliflozin not only lowers blood glucose but also inhibits complex-I supported respiration and cellular proliferation in prostate and lung cancer cells. These observations support the initiation of studies evaluating the clinical efficacy of Canagliflozin on limiting tumorigenesis in pre-clinical animal models as well epidemiological studies on cancer incidence relative to other glucose lowering therapies in clinical populations.
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