Unraveling the effect of intra- and intercellular processes on acetaminophen-induced liver injury

In high dosages, acetaminophen (APAP) can cause severe liver damage, but susceptibility to liver failure varies across individuals and is influenced by factors such as health status. Because APAP-induced liver injury and recovery is regulated by an intricate system of intra- and extracellular molecular signaling, we here aim to quantify the importance of specific modules in determining the outcome after an APAP insult and of potential targets for therapies that mitigate adversity. For this purpose, we integrated hepatocellular acetaminophen metabolism, DNA damage response induction and cell fate into a multiscale mechanistic liver lobule model which involves various cell types, such as hepatocytes, residential Kupffer cells and macrophages. Our model simulations show that zonal differences in metabolism and detoxification efficiency are essential determinants of necrotic damage. Moreover, the extent of senescence, which is regulated by intracellular processes and triggered by extracellular signaling, influences the potential to recover. In silico therapies at early and late time points after APAP insult indicated that prevention of necrotic damage is most beneficial for recovery, whereas interference with regulation of senescence promotes regeneration in a less pronounced way.Toxicolog

Quantum Convolutional Coding with Shared Entanglement: General Structure

We present a general theory of entanglement-assisted quantum convolutional coding. The codes have a convolutional or memory structure, they assume that the sender and receiver share noiseless entanglement prior to quantum communication, and they are not restricted to possess the Calderbank-Shor-Steane structure as in previous work. We provide two significant advances for quantum convolutional coding theory. We first show how to "expand" a given set of quantum convolutional generators. This expansion step acts as a preprocessor for a polynomial symplectic Gram-Schmidt orthogonalization procedure that simplifies the commutation relations of the expanded generators to be the same as those of entangled Bell states (ebits) and ancilla qubits. The above two steps produce a set of generators with equivalent error-correcting properties to those of the original generators. We then demonstrate how to perform online encoding and decoding for a stream of information qubits, halves of ebits, and ancilla qubits. The upshot of our theory is that the quantum code designer can engineer quantum convolutional codes with desirable error-correcting properties without having to worry about the commutation relations of these generators.Comment: 23 pages, replaced with final published versio

Decoherence of electron spin qubits in Si-based quantum computers

Direct phonon spin-lattice relaxation of an electron qubit bound by a donor impurity or quantum dot in SiGe heterostructures is investigated. The aim is to evaluate the importance of decoherence from this mechanism in several important solid-state quantum computer designs operating at low temperatures. We calculate the relaxation rate $1/T_1$ as a function of [100] uniaxial strain, temperature, magnetic field, and silicon/germanium content for Si:P bound electrons. The quantum dot potential is much smoother, leading to smaller splittings of the valley degeneracies. We have estimated these splittings in order to obtain upper bounds for the relaxation rate. In general, we find that the relaxation rate is strongly decreased by uniaxial compressive strain in a SiGe-Si-SiGe quantum well, making this strain an important positive design feature. Ge in high concentrations (particularly over 85%) increases the rate, making Si-rich materials preferable. We conclude that SiGe bound electron qubits must meet certain conditions to minimize decoherence but that spin-phonon relaxation does not rule out the solid-state implementation of error-tolerant quantum computing.Comment: 8 figures. To appear in PRB-July 2002. Revisions include: some references added/corrected, several typos fixed, a few things clarified. Nothing dramati

Central obesity as a precursor to the metabolic syndrome in the AusDiab study and Mauritius

Evidence from epidemiologic studies that central obesity precedes future metabolic change and does not occur concurrently with the appearance of the blood pressure, glucose, and lipid abnormalities that characterize the metabolic syndrome (MetS) has been lacking. Longitudinal surveys were conducted in Mauritius in 1987, 1992, and 1998, and in Australia in 2000 and 2005 (AusDiab). This analysis included men and women (aged 25 years) in three cohorts: AusDiab 2000&ndash;2005 (n = 5,039), Mauritius 1987&ndash;1992 (n = 2,849), and Mauritius 1987&ndash;1998 (n = 1,999). MetS components included waist circumference, systolic blood pressure, fasting and 2-h postload plasma glucose, high-density lipoprotein (HDL) cholesterol, triglycerides, and homeostasis model assessment of insulin sensitivity (HOMA-S) (representing insulin sensitivity). Linear regression was used to determine which baseline components predicted deterioration in other MetS components over 5 years in AusDiab and 5 and 11 years in Mauritius, adjusted for age, sex, and ethnic group. Baseline waist circumference predicted deterioration (P &lt; 0.01) in four of the other six MetS variables tested in AusDiab, five of six in Mauritius 1987&ndash;1992, and four of six in Mauritius 1987&ndash;1998. In contrast, an increase in waist circumference between baseline and follow-up was only predicted by insulin sensitivity (HOMA-S) at baseline, and only in one of the three cohorts. These results suggest that central obesity plays a central role in the development of the MetS and appears to precede the appearance of the other MetS components.<br /

Policy instruments (‎non-price)‎ for medical innovation

Innovation policy instruments are policy interventions with a specific mechanism of action that influences the innovation process. This Oslo Medicines Initiative technical report presents a broad range of such instruments available to national policy-makers in support of innovation for new medicines (excluding those focused on price, which are covered elsewhere in the report series). This report explores various types of policy instruments, based on reviews of the literature on policies for innovation in the medical and other sectors. For each type identified, the report explores the mechanisms of action, the effects these have and where they occur, and the extent to which these instruments have been implemented globally. It also sets out considerations for their effective implementation. The report demonstrates that the long-established push/pull (supply/ demand) framing that dominates discourse around medical innovation can be broadened, providing policy-makers with instruments to supplement push/pull approaches, by emphasizing the role of communication, collaboration and coordination in supporting the emergence of medicines to address societal needs

UML 1.4 versus UML 2.0 as Languages to Describe Software Architectures.

ML 1.4 is widely accepted as the standard for representing the various software artifacts generated by a development process. For this reason, there have been attempts to use this language to represent the software architec- ture of systems as well. Unfortunately, these attempts have ended in representa- tions (boxes and lines) already criticized by the software architecture commu- nity. Recently, OMG has published a draft that will constitute the future UML 2.0 specification. In this paper we compare the capacities of UML 1.4 and UML 2.0 to describe software architectures. In particular, we study extensions of both UML versions to describe the static view of the C3 architectural style (a simplification of the C2 style). One of the results of this study is the difficulties found when using the UML 2.0 metamodel to describe the concept of connector in a software architecture

Using stereochemistry to control mechanical properties in thiol–yne click-hydrogels

The stereochemistry of polymers has a profound impact on their mechanical properties. While this has been observed in thermoplastics, studies on how stereochemistry affects the bulk properties of swollen networks, such as hydrogels, are limited. Typically, changing the stiffness of a hydrogel is achieved at the cost of changing another parameter, that in turn affects the physical properties of the material and ultimately influences the cellular response. Herein, we report that by manipulating the stereochemistry of a double bond, formed in situ during gelation, materials with diverse mechanical properties but comparable physical properties can be obtained. Click-hydrogels that possess a high % trans content are stiffer than their high % cis analogues by almost a factor of 3. Human mesenchymal stem cells acted as a substrate stiffness cell reporter demonstrating the potential of these platforms to study mechanotransduction without the influence of other external factors

Ultrafast optically induced spin transfer in ferromagnetic alloys

The vision of using light to manipulate electronic and spin excitations in materials on their fundamental time and length scales requires new approaches in experiment and theory to observe and understand these excitations. The ultimate speed limit for all-optical manipulation requires control schemes for which the electronic or magnetic subsystems of the materials are coherently manipulated on the time scale of the laser excitation pulse. In our work, we provide experimental evidence of such a direct, ultrafast, and coherent spin transfer between two magnetic subsystems of an alloy of Fe and Ni. Our experimental findings are fully supported by time-dependent density functional theory simulations and, hence, suggest the possibility of coherently controlling spin dynamics on subfemtosecond time scales, i.e., the birth of the research area of attomagnetism

“It's like giving him a piece of me.”: Exploring UK and Israeli women's accounts of motherhood and feeding

Objective The present study explored how Israeli and UK mothers integrate feeding into their conceptualisations of mothering 2–6 months post-partum. Background The nature and importance of motherhood is subject to differential contextual, cultural, political and historical influences. We set out to compare experiences of motherhood and feeding between these two countries using a qualitative approach. Methods Forty one women (mean age 36.4 ± 2.7 years) from Israel and the UK, mostly married or in a committed relationship were interviewed about their experience of pregnancy, motherhood and feeding. Data were analysed thematically. Results The experience of motherhood in the early postnatal period was dominated, for all mothers, by the experience of breastfeeding and clustered around three representations of mothering, namely; 1) a devoted mother who ignores her own needs; 2) a mother who is available for her infant but acknowledges her needs as well; and 3) a struggling mother for whom motherhood is a burden. Such representations existed within both cultural groups and sometimes coexisted within the same mothers. UK women described more struggles within motherhood whereas a tendency towards idealising motherhood was observed for Israeli women. Conclusion There are similarities in the ways that UK and Israeli women experienced motherhood and feeding. Where family life is strongly emphasized, mothers reported extremes of idealism and burden and associated an “ideal” mother with a breastfeeding mother. Where motherhood is represented as just one of many roles women take up, they are more likely to represent a “good enough” approach to mothering. Understanding the experience of motherhood and feeding in different cultural settings is important to provide the context for postnatal care specifically where mothers are reluctant to share problems or difficulties encountered