Direct observation of dynamic lithium diffusion behavior in nickel-rich, LiNi0.8Mn0.1Co0.1O2 (NMC811) cathodes using operando muon spectroscopy

Ni-rich layered oxide cathode materials such as LiNi0.8Mn0.1Co0.1O2 (NMC811) are widely tipped as the next-generation cathodes for lithium-ion batteries. The NMC class offers high capacities but suffers an irreversible first cycle capacity loss, a result of slow Li+ diffusion kinetics at a low state of charge. Understanding the origin of these kinetic hindrances to Li+ mobility inside the cathode is vital to negate the first cycle capacity loss in future materials design. Here, we report on the development of operando muon spectroscopy (μSR) to probe the Å-length scale Li+ ion diffusion in NMC811 during its first cycle and how this can be compared to electrochemical impedance spectroscopy (EIS) and the galvanostatic intermittent titration technique (GITT). Volume-averaged muon implantation enables measurements that are largely unaffected by interface/surface effects, thus providing a specific characterization of the fundamental bulk properties to complement surface-dominated electrochemical methods. First cycle measurements show that the bulk Li+ mobility is less affected than the surface Li+ mobility at full depth of discharge, indicating that sluggish surface diffusion is the likely cause of first cycle irreversible capacity loss. Additionally, we demonstrate that trends in the nuclear field distribution width of the implanted muons during cycling correlate with those observed in differential capacity, suggesting the sensitivity of this μSR parameter to structural changes during cycling

Towards a unified theory of Sobolev inequalities

We discuss our work on pointwise inequalities for the gradient which are connected with the isoperimetric profile associated to a given geometry. We show how they can be used to unify certain aspects of the theory of Sobolev inequalities. In particular, we discuss our recent papers on fractional order inequalities, Coulhon type inequalities, transference and dimensionless inequalities and our forthcoming work on sharp higher order Sobolev inequalities that can be obtained by iteration.Comment: 39 pages, made some changes to section 1

Cell identity and nucleo-mitochondrial genetic context modulate OXPHOS performance and determine somatic heteroplasmy dynamics

Heteroplasmy, multiple variants of mitochondrial DNA (mtDNA) in the same cytoplasm, may be naturally generated by mutations but is counteracted by a genetic mtDNA bottleneck during oocyte development. Engineered heteroplasmic mice with nonpathological mtDNA variants reveal a nonrandom tissue-specific mtDNA segregation pattern, with few tissues that do not show segregation. The driving force for this dynamic complex pattern has remained unexplained for decades, challenging our understanding of this fundamental biological problem and hindering clinical planning for inherited diseases. Here, we demonstrate that the nonrandom mtDNA segregation is an intracellular process based on organelle selection. This cell type-specific decision arises jointly from the impact of mtDNA haplotypes on the oxidative phosphorylation (OXPHOS) system and the cell metabolic requirements and is strongly sensitive to the nuclear context and to environmental cues

From thermal rectifiers to thermoelectric devices

We discuss thermal rectification and thermoelectric energy conversion from the perspective of nonequilibrium statistical mechanics and dynamical systems theory. After preliminary considerations on the dynamical foundations of the phenomenological Fourier law in classical and quantum mechanics, we illustrate ways to control the phononic heat flow and design thermal diodes. Finally, we consider the coupled transport of heat and charge and discuss several general mechanisms for optimizing the figure of merit of thermoelectric efficiency.Comment: 42 pages, 22 figures, review paper, to appear in the Springer Lecture Notes in Physics volume "Thermal transport in low dimensions: from statistical physics to nanoscale heat transfer" (S. Lepri ed.

Operators of harmonic analysis in weighted spaces with non-standard growth

Last years there was increasing an interest to the so-called function spaces with non-standard growth, known also as variable exponent Lebesgue spaces. For weighted such spaces on homogeneous spaces, we develop a certain variant of Rubio de Francia's extrapolation theorem. This extrapolation theorem is applied to obtain the boundedness in such spaces of various operators of harmonic analysis, such as maximal and singular operators, potential operators, Fourier multipliers, dominants of partial sums of trigonometric Fourier series and others, in weighted Lebesgue spaces with variable exponent. There are also given their vector-valued analogues. (C) 2008 Elsevier Inc. All rights reserved.INTAS [06-1000017-8792]; Center CEMAT, Instituto Superior Tecnico, Lisbon, Portugalinfo:eu-repo/semantics/publishedVersio

Building a Healthcare Alliance for Resourceful Medicine Offensive Against Neoplasms in hematologY added value framework for hematologic malignancies: a comparative analysis of existing tools

OBJECTIVES: The Innovative Medicines Initiative-funded, multistakeholders project Healthcare Alliance for Resourceful Medicine Offensive Against Neoplasms in hematologY (HARMONY) created a task force involving patient organizations, medical associations, pharmaceutical companies, and health technology assessment/regulator agencies' representatives to evaluate the suitability of previously established value frameworks (VFs) for assessing the clinical and societal impact of new interventions for hematologic malignancies (HMs). METHODS: Since the HARMONY stakeholders identified the inclusion of patients' points of view on evaluating VFs as a priority, surveys were conducted with the patient organizations active in HMs and part of the HARMONY network, together with key opinion leaders, pharmaceutical companies, and regulators, to establish which outcomes were important for each HM. Next, to evaluate VFs against the sources of information taken into account (randomized clinical trials, registries, real-world data), structured questionnaires were created and filled by HARMONY health professionals to specify preferred data sources per malignancy. Finally, a framework evaluation module was built to analyze existing clinical VFs (American Society of Clinical Oncology, European Society of Medical Oncology, Magnitude of Clinical Benefit Scale, Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen, Institute for Clinical and Economic Review, National Comprehensive Cancer Network Evidence Blocks, and patient-perspective VF). RESULTS: The comparative analysis describes challenges and opportunities for the use of each framework in the context of HMs and drafts possible lines of action for creating or integrating a more specific, patient-focused clinical VF for HMs. CONCLUSIONS: None of the frameworks meets the HARMONY goals for a tool that applies to HMs and assesses in a transparent, reproducible, and systematic way the therapeutic value of innovative health technologies versus available alternatives, taking a patient-centered approach and using real-world evidence

Contourite depositional system after the exit of a strait: Case study from the late Miocene South Rifian Corridor, Morocco

Idealized facies of bottom current deposits (contourites) have been established for fine-grained contourite drifts in modern deep-marine sedimentary environments. Their equivalent facies in the ancient record however are only scarcely recognized due to the weathered nature of most fine-grained deposits in outcrop. Facies related to the erosional elements (i.e. contourite channels) of contourite depositional systems have not yet been properly established and related deposits in outcrop appear non-existent. To better understand the sedimentary facies and facies sequences of contourites, the upper Miocene contourite depositional systems of the South Rifian Corridor (Morocco) is investigated. This contourite depositional system formed by the dense palaeo-Mediterranean Outflow Water. Foraminifera assemblages were used for age-constraints (7.51 to 7.35 Ma) and to determine the continental slope depositional domains. Nine sedimentary facies have been recognized based on lithology, grain-size, sedimentary structures and biogenic structures. These facies were subsequently grouped into five facies associations related to the main interpreted depositional processes (hemipelagic settling, contour currents and gravity flows). The vertical sedimentary facies succession records the tectonically induced, southward migration of the contourite depositional systems and the intermittent behaviour of the palaeo-Mediterranean Outflow Water, which is mainly driven by precession and millennial-scale climate variations. Tides substantially modulated the palaeo-Mediterranean Outflow Water on a sub-annual scale. This work shows exceptional examples of muddy and sandy contourite deposits in outcrop by which a facies distribution model from the proximal continental slope, the contourite channel to its adjacent contourite drift, is proposed. This model serves as a reference for contourite recognition both in modern environments and the ancient record. Furthermore, by establishing the hydrodynamics of overflow behaviour a framework is provided that improves process-based interpretation of deep-water bottom current deposits

In vitro and in vivo antimycobacterial activities of ketone and amide derivatives of quinoxaline 1,4-di-N-oxide

Abstract: Objectives: To evaluate a novel series of quinoxaline 1,4-di-N-oxides for in vitro activity against Mycobacterium tuberculosis and for efficacy in a mouse model of tuberculosis (TB). Methods: Ketone and amide derivatives of quinoxaline 1,4-di-N-oxide were evaluated in in vitro and in vivo tests including: (i) activity against M. tuberculosis resistant to currently used antitubercular drugs including multidrug-resistant strains (MDR-TB resistant to isoniazid and rifampicin); (ii) activity against non-replicating persistent (NRP) bacteria; (iii) MBC; (iv) maximum tolerated dose, oral bioavailability and in vivo efficacy in mice; and (v) potential for cross-resistance with another bioreduced drug, PA-824. Results: Ten compounds were tested on single drug-resistant M. tuberculosis. In general, all compounds were active with ratios of MICs against resistant and non-resistant strains of <= 4.00. One compound, 5, was orally active in a murine model of TB, bactericidal, active against NRP bacteria and active on MDR-TB and poly drug-resistant clinical isolates (resistant to 3-5 antitubercular drugs). Conclusions: Quinoxaline 1,4-di-N-oxides represent a new class of orally active antitubercular drugs. They are likely bioreduced to an active metabolite, but the pathway of bacterial activation was different from PA-824, a bioreducible nitroimidazole in clinical trials. Compound 5 was bactericidal and active on NRP organisms indicating that activation occurred in both growing and non-replicating bacteria leading to cell death. The presence of NRP bacteria is believed to be a major factor responsible for the prolonged nature of antitubercular therapy. If the bactericidal activity and activity on non-replicating bacteria in vitro translate to in vivo conditions, quinoxaline 1,4-di-N-oxides may offer a path to shortened therapy

Efficacy of quinoxaline-2-carboxylate 1,4-di-N-oxide derivatives in experimental tuberculosis

This study extends earlier reports regarding the in vitro efficacies of the 1,4-di-N-oxide quinoxaline derivatives against Mycobacterium tuberculosis and has led to the discovery of a derivative with in vivo efficacy in the mouse model of tuberculosis. Quinoxaline-2-carboxylate 1,4-di-N-oxide derivatives were tested in vitro against a broad panel of single-drug-resistant M. tuberculosis strains. The susceptibilities of these strains to some compounds were comparable to those of strain H(37)Rv, as indicated by the ratios of MICs for resistant and nonresistant strains, supporting the premise that 1,4-di-N-oxide quinoxaline derivatives have a novel mode of action unrelated to those of the currently used antitubercular drugs. Specific derivatives were further evaluated in a series of in vivo assays, including evaluations of the maximum tolerated doses, the levels of oral bioavailability, and the efficacies in a low-dose aerosol model of tuberculosis in mice. One compound, ethyl 7-chloro-3-methylquinoxaline-2-carboxylate 1,4-dioxide, was found to be (i) active in reducing CFU counts in both the lungs and spleens of infected mice following oral administration, (ii) active against PA-824-resistant Mycobacterium bovis, indicating that the pathway of bioreduction/activation is different from that of PA-824 (a bioreduced nitroimidazole that is in clinical trials), and (iii) very active against nonreplicating bacteria adapted to low-oxygen conditions. These data indicate that 1,4-di-N-oxide quinoxalines hold promise for the treatment of tuberculosis

Patients with primary immunodeficiencies are a reservoir of poliovirus and a risk to polio eradication

ABSTARCT: Immunodeficiency-associated vaccine-derived polioviruses (iVDPVs) have been isolated from primary immunodeficiency (PID) patients exposed to oral poliovirus vaccine (OPV). Patients may excrete poliovirus strains for months or years; the excreted viruses are frequently highly divergent from the parental OPV and have been shown to be as neurovirulent as wild virus. Thus, these patients represent a potential reservoir for transmission of neurovirulent polioviruses in the post-eradication era. In support of WHO recommendations to better estimate the prevalence of poliovirus excreters among PIDs and characterize genetic evolution of these strains, 635 patients including 570 with primary antibody deficiencies and 65 combined immunodeficiencies were studied from 13 OPV-using countries. Two stool samples were collected over 4 days, tested for enterovirus, and the poliovirus positive samples were sequenced. Thirteen patients (2%) excreted polioviruses, most for less than 2 months following identification of infection. Five (0.8%) were classified as iVDPVs (only in combined immunodeficiencies and mostly poliovirus serotype 2). Non-polio enteroviruses were detected in 30 patients (4.7%). Patients with combined immunodeficiencies had increased risk of delayed poliovirus clearance compared to primary antibody deficiencies. Usually, iVDPV was detected in subjects with combined immunodeficiencies in a short period of time after OPV exposure, most for less than 6 months. Surveillance for poliovirus excretion among PID patients should be reinforced until polio eradication is certified and the use of OPV is stopped. Survival rates among PID patients are improving in lower and middle income countries, and iVDPV excreters are identified more frequently. Antivirals or enhanced immunotherapies presently in development represent the only potential means to manage the treatment of prolonged excreters and the risk they present to the polio endgame. Keywords: Poliovirus eradication, Immunodeficiency-associated vaccine-derived polioviruses, Oral poliovirus vaccine, Humoral immunodeficiency, Combined immunodeficiency, Primary immunodeficienc