The kinetics of energy storage in transition metal oxides are usually limited by solid-state diffusion, and the strategy most often utilized to improve their rate capability is to reduce ion ...diffusion distances by utilizing nanostructured materials. Here, another strategy for improving the kinetics of layered transition metal oxides by the presence of structural water is proposed. To investigate this strategy, the electrochemical energy storage behavior of a model hydrated layered oxide, WO3·2H2O, is compared with that of anhydrous WO3 in an acidic electrolyte. It is found that the presence of structural water leads to a transition from battery-like behavior in the anhydrous WO3 to ideally pseudocapacitive behavior in WO3·2H2O. As a result, WO3·2H2O exhibits significantly improved capacity retention and energy efficiency for proton storage over WO3 at sweep rates as fast as 200 mV s–1, corresponding to charge/discharge times of just a few seconds. Importantly, the energy storage of WO3·2H2O at such rates is nearly 100% efficient, unlike in the case of anhydrous WO3. Pseudocapacitance in WO3·2H2O allows for high-mass loading electrodes (>3 mg cm–2) and high areal capacitances (>0.25 F cm–2 at 200 mV s–1) with simple slurry-cast electrodes. These results demonstrate a new approach for developing pseudocapacitance in layered transition metal oxides for high-power energy storage, as well as the importance of energy efficiency as a metric of performance of pseudocapacitive materials.
There is an urgent global need for electrochemical energy storage that includes materials that can provide simultaneous high power and high energy density. One strategy to achieve this goal is with ...pseudocapacitive materials that take advantage of reversible surface or near-surface Faradaic reactions to store charge. This allows them to surpass the capacity limitations of electrical double-layer capacitors and the mass transfer limitations of batteries. The past decade has seen tremendous growth in the understanding of pseudocapacitance as well as materials that exhibit this phenomenon. The purpose of this Review is to examine the fundamental development of the concept of pseudocapacitance and how it came to prominence in electrochemical energy storage as well as to describe new classes of materials whose electrochemical energy storage behavior can be described as pseudocapacitive.
Normal tissue injury from irradiation is an unfortunate consequence of radiotherapy. Technologic improvements have reduced the risk of normal tissue injury; however, toxicity causing treatment breaks ...or long-term side effects continues to occur in a subset of patients. The molecular events that lead to normal tissue injury are complex and span a variety of biologic processes, including oxidative stress, inflammation, depletion of injured cells, senescence, and elaboration of proinflammatory and profibrogenic cytokines. This article describes selected recent advances in normal tissue radiobiology.
The integrity of the epidermis and mucosal epithelia is highly dependent on resident self-renewing stem cells, which makes them vulnerable to physical and chemical insults compromising the ...repopulating capacity of the epithelial stem cell compartment. This is frequently the case in cancer patients receiving radiation or chemotherapy, many of whom develop mucositis, a debilitating condition involving painful and deep mucosal ulcerations. Here, we show that inhibiting the mammalian target of rapamycin (mTOR) with rapamycin increases the clonogenic capacity of primary human oral keratinocytes and their resident self-renewing cells by preventing stem cell senescence. This protective effect of rapamycin is mediated by the increase in expression of mitochondrial superoxide dismutase (MnSOD), and the consequent inhibition of ROS formation and oxidative stress. mTOR inhibition also protects from the loss of proliferative basal epithelial stem cells upon ionizing radiation in vivo, thereby preserving the integrity of the oral mucosa and protecting from radiation-induced mucositis.
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► Rapamycin increases the repopulating capacity of human epithelial stem cells ► mTOR inhibition prevents epithelial stem cell senescence ► mTOR inhibition protects from oxidative stress by increasing MnSOD expression ► Rapamycin protects from radiation-induced oral ulcers and mucositis
Targeting mTOR with rapamycin, a known drug approved in other contexts, protects human epithelial stem cells from replicative senescence after radiation treatment. These findings highlight a potential treatment approach for mucositis, a common and painful side effect of many forms of cancer therapy.
Summary Background Dual antiplatelet therapy (DAPT) cessation increases the risk of adverse events after percutaneous coronary intervention (PCI). Whether risk changes over time, depends on the ...underlying reason for DAPT cessation, or both is unknown. We assessed associations between different modes of DAPT cessation and cardiovascular risk after PCI. Methods The PARIS (patterns of non-adherence to anti-platelet regimens in stented patients) registry is a prospective observational study of patients undergoing PCI with stent implantation in 15 clinical sites in the USA and Europe between July 1, 2009, and Dec 2, 2010. Adult patients (aged 18 years or older) undergoing successful stent implantation in one or more native coronary artery and discharged on DAPT were eligible for enrolment. Patients were followed up at months 1, 6, 12, and 24 after implantation. Prespecified categories for DAPT cessation included physician-recommended discontinuation, brief interruption (for surgery), or disruption (non-compliance or because of bleeding). All adverse events and episodes of DAPT cessation were independently adjudicated. Using Cox models with time-varying covariates, we examined the effect of DAPT cessation on major adverse events (MACE composite of cardiac death, definite or probable stent thrombosis, myocardial infarction, or target-lesion revascularisation). Incidence rates for DAPT cessation and adverse events were calculated as Kaplan-Meier estimates of time to the first event. This study is registered with ClinicalTrials.gov , number NCT00998127. Findings We enrolled 5031 patients undergoing PCI, including 5018 in the final study population. Over 2 years, the overall incidence of any DAPT cessation was 57·3%. Rate of any discontinuation was 40·8%, of interruption was 10·5%, and of disruption was 14·4%. The corresponding overall 2 year MACE rate was 11·5%, most of which (74%) occurred while patients were taking DAPT. Compared with those on DAPT, the adjusted hazard ratio (HR) for MACE due to interruption was 1·41 (95% CI 0·94–2·12; p=0·10) and to disruption was 1·50 (1·14–1.97; p=0·004). Within 7 days, 8–30 days, and more than 30 days after disruption, adjusted HRs were 7·04 (3·31–14·95), 2·17 (0·97–4·88), and 1·3 (0·97–1·76), respectively. By contrast with patients who remained on DAPT, those who discontinued had lower MACE risk (0·63 0·46–0·86). Results were similar after excluding patients receiving bare metal stents and using an alternative MACE definition that did not include target lesion revascularisation. Interpretation In a real-world setting, for patients undergoing PCI and discharged on DAPT, cardiac events after DAPT cessation depend on the clinical circumstance and reason for cessation and attenuates over time. While most events after PCI occur in patients on DAPT, early risk for events due to disruption is substantial irrespective of stent type. Funding Bristol-Myers Squibb and Sanofi-Aventis.
Hydrous transition metal oxides (TMOs) are redox-active materials that confine structural water within their bulk, organized in 1D, 2D, or 3D networks. In an electrochemical cell, hydrous TMOs can ...interact with electrolyte species not only via their outer surface but also via their hydrous inner surface, which can transport electrolyte species to the interior of the material. Many TMOs operating in an aqueous electrochemical environment transform to hydrous TMOs, which then serve as the electrochemically active phase. This review summarizes the physicochemical properties of hydrous TMOs and recent mechanistic insights into their behavior in electrochemical reactions of interest for energy storage, conversion, and environmental applications. Particular focus is placed on first-principles calculations and operando characterization to obtain an atomistic view of their electrochemical mechanisms. Hydrous TMOs represent an important class of energy and environmental materials in aqueous and nonaqueous environments. Further understanding of their interaction with electrolyte species is likely to yield advancements in electrochemical reactivity and kinetics for energy and environmental applications.
•Patients with chronic ITP had clonal expansions of disease-associated TEMRA CD8+ T cells.•CD8+ T cells bind to platelets and cause their activation and apoptosis, defining an antibody-independent ...mechanism of platelet destruction.
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Immune thrombocytopenia (ITP) is traditionally considered an antibody-mediated disease. However, a number of features suggest alternative mechanisms of platelet destruction. In this study, we use a multidimensional approach to explore the role of cytotoxic CD8+ T cells in ITP. We characterized patients with ITP and compared them with age-matched controls using immunophenotyping, next-generation sequencing of T-cell receptor (TCR) genes, single-cell RNA sequencing, and functional T-cell and platelet assays. We found that adults with chronic ITP have increased polyfunctional, terminally differentiated effector memory CD8+ T cells (CD45RA+CD62L−) expressing intracellular interferon gamma, tumor necrosis factor α, and granzyme B, defining them as TEMRA cells. These TEMRA cells expand when the platelet count falls and show no evidence of physiological exhaustion. Deep sequencing of the TCR showed expanded T-cell clones in patients with ITP. T-cell clones persisted over many years, were more prominent in patients with refractory disease, and expanded when the platelet count was low. Combined single-cell RNA and TCR sequencing of CD8+ T cells confirmed that the expanded clones are TEMRA cells. Using in vitro model systems, we show that CD8+ T cells from patients with ITP form aggregates with autologous platelets, release interferon gamma, and trigger platelet activation and apoptosis via the TCR-mediated release of cytotoxic granules. These findings of clonally expanded CD8+ T cells causing platelet activation and apoptosis provide an antibody-independent mechanism of platelet destruction, indicating that targeting specific T-cell clones could be a novel therapeutic approach for patients with refractory ITP.
The importance of cytotoxic T cells has been recognized in chronic immune thrombocytopenia (ITP), yet how CD8+ T cells evolve and perpetuate chronic ITP is a mystery. This month’s CME article, a Plenary Paper by Malik and colleagues, demonstrates that in chronic ITP, there is clonal expansion of a particular subset of CD8+ T cells, known as terminally differentiated effector memory T cells, which persist over years, are more evident in refractory ITP, and are more prevalent when the platelet count is low. Furthermore, CD8+ T cells induce platelet activation and apoptosis in an antibody-independent mechanism for refractory thrombocytopenia that may be amenable to therapeutic targeting.
Preclinical evidence suggests that high-dose hypofractionated ionizing radiation (IR) can enhance anti-tumor immunity and result in significant tumor control when combined with immune checkpoint ...blockade (ICB). However, low-dose daily fractioned IR used for many tumor types including head and neck squamous cell carcinoma results in lymphopenia and may be immunosuppressive. We compared immune correlates, primary tumor and abscopal tumor control rates following the addition of PD-1 mAb to either high-dose hypofractioned (8Gyx2) or low-dose daily fractionated (2Gyx10) IR in syngeneic models of cancer. When compared to 2Gyx10 IR, 8Gyx2 IR preserved peripheral and tumor-infiltrating CD8
+
T-lymphocyte accumulation and activation and reduced peripheral and tumor gMDSC accumulation. Regulatory T-lymphocytes were largely unaltered. Type I and I IFN levels and expression of IFN-responsive MHC class I and PD-L1 was enhanced in tumors treated with 8Gyx2 compared to 2Gyx10 IR. Functionally, tumor-specific CD8
+
T-lymphocyte IFN responses within tumor draining lymph nodes were enhanced following 8Gyx2 IR but suppressed following 2Gyx10 IR. When combined with PD-1 mAb, reversal of adaptive immune resistance and subsequent enhancement of CD8+ cell dependent primary and abscopal tumor control was observed following 8Gyx2 but not 2Gyx10 IR. These data strongly support that compared to daily fractionated low-dose IR, high-dose hypofractionated IR preserves or enhances anti-tumor immunity and, when combined with PD-1 mAb to reverse adaptive immune resistance, promotes anti-tumor immunity to control primary and distant tumors. These data critically inform the rational design of trials combining IR and ICB.
MicroRNAs (miRNAs) are small, highly conserved, non-coding RNA that alter protein expression and regulate multiple intracellular processes, including those involved in the response to cellular ...stress. Alterations in miRNA expression may occur following exposure to several stress-inducing anticancer agents including ionizing radiation, etoposide, and hydrogen peroxide (H(2)O(2)).
Normal human fibroblasts were exposed to radiation, H(2)O(2), or etoposide at doses determined by clonogenic cell survival curves. Total RNA was extracted and miRNA expression was determined by microarray. Time course and radiation dose responses were determined using RT-PCR for individual miRNA species. Changes in miRNA expression were observed for 17 miRNA species following exposure to radiation, 23 after H(2)O(2) treatment, and 45 after etoposide treatment. Substantial overlap between the miRNA expression changes between agents was observed suggesting a signature miRNA response to cell stress. Changes in the expression of selected miRNA species varied in response to radiation dose and time. Finally, production of reactive oxygen species (ROS) increased with increasing doses of radiation and pre-treatment with the thiol antioxidant cysteine decreased both ROS production and the miRNA response to radiation.
These results demonstrate a common miRNA expression signature in response to exogenous genotoxic agents including radiation, H(2)O(2), and etoposide. Additionally, pre-treatment with cysteine prevented radiation-induced alterations in miRNA expression which suggests that miRNAs are responsive to oxidative stress. Taken together, these results imply that miRNAs play a role in cellular defense against exogenous stress and are involved in the generalized cellular response to genotoxic oxidative stress.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Introgressive hybridization is now recognized as a widespread phenomenon, but its role in evolution remains contested. Here, we use newly available reference genome assemblies to investigate ...phylogenetic relationships and introgression in a medically important group of Afrotropical mosquito sibling species. We have identified the correct species branching order to resolve a contentious phylogeny and show that lineages leading to the principal vectors of human malaria were among the first to split. Pervasive autosomal introgression between these malaria vectors means that only a small fraction of the genome, mainly on the X chromosome, has not crossed species boundaries. Our results suggest that traits enhancing vectorial capacity may be gained through interspecific gene flow, including between nonsister species. Mosquito adaptability across genomesVirtually everyone has first-hand experience with mosquitoes. Few recognize the subtle biological distinctions among these bloodsucking flies that render some bites mere nuisances and others the initiation of a potentially life-threatening infection. By sequencing the genomes of several mosquitoes in depth, Neafsey et al. and Fontaine et al. reveal clues that explain the mystery of why only some species of one genus of mosquitoes are capable of transmitting human malaria (see the Perspective by Clark and Messer).Science, this issue 10.1126/science.1258524 and 10.1126/science.1258522; see also p. 27
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