Separability problem for multipartite states of rank at most four

One of the most important problems in quantum information is the separability problem, which asks whether a given quantum state is separable. We investigate multipartite states of rank at most four which are PPT (i.e., all their partial transposes are positive semidefinite). We show that any PPT state of rank two or three is separable and has length at most four. For separable states of rank four, we show that they have length at most six. It is six only for some qubit-qutrit or multiqubit states. It turns out that any PPT entangled state of rank four is necessarily supported on a 3x3 or a 2x2x2 subsystem. We obtain a very simple criterion for the separability problem of the PPT states of rank at most four: such a state is entangled if and only if its range contains no product vectors. This criterion can be easily applied since a four-dimensional subspace in the 3x3 or 2x2x2 system contains a product vector if and only if its Pluecker coordinates satisfy a homogeneous polynomial equation (the Chow form of the corresponding Segre variety). We have computed an explicit determinantal expression for the Chow form in the former case, while such expression was already known in the latter case.Comment: 19 page

Translational Modeling in Schizophrenia:Predicting Human Dopamine D2 Receptor Occupancy

OBJECTIVES: To assess the ability of a previously developed hybrid physiology-based pharmacokinetic-pharmacodynamic (PBPKPD) model in rats to predict the dopamine D2 receptor occupancy (D2RO) in human striatum following administration of antipsychotic drugs.METHODS: A hybrid PBPKPD model, previously developed using information on plasma concentrations, brain exposure and D2RO in rats, was used as the basis for the prediction of D2RO in human. The rat pharmacokinetic and brain physiology parameters were substituted with human population pharmacokinetic parameters and human physiological information. To predict the passive transport across the human blood-brain barrier, apparent permeability values were scaled based on rat and human brain endothelial surface area. Active efflux clearance in brain was scaled from rat to human using both human brain endothelial surface area and MDR1 expression. Binding constants at the D2 receptor were scaled based on the differences between in vitro and in vivo systems of the same species. The predictive power of this physiology-based approach was determined by comparing the D2RO predictions with the observed human D2RO of six antipsychotics at clinically relevant doses.RESULTS: Predicted human D2RO was in good agreement with clinically observed D2RO for five antipsychotics. Models using in vitro information predicted human D2RO well for most of the compounds evaluated in this analysis. However, human D2RO was under-predicted for haloperidol.CONCLUSIONS: The rat hybrid PBPKPD model structure, integrated with in vitro information and human pharmacokinetic and physiological information, constitutes a scientific basis to predict the time course of D2RO in man.</p

On The Rate and Extent of Drug Delivery to the Brain

To define and differentiate relevant aspects of blood–brain barrier transport and distribution in order to aid research methodology in brain drug delivery. Pharmacokinetic parameters relative to the rate and extent of brain drug delivery are described and illustrated with relevant data, with special emphasis on the unbound, pharmacologically active drug molecule. Drug delivery to the brain can be comprehensively described using three parameters: Kp,uu (concentration ratio of unbound drug in brain to blood), CLin (permeability clearance into the brain), and Vu,brain (intra-brain distribution). The permeability of the blood–brain barrier is less relevant to drug action within the CNS than the extent of drug delivery, as most drugs are administered on a continuous (repeated) basis. Kp,uu can differ between CNS-active drugs by a factor of up to 150-fold. This range is much smaller than that for log BB ratios (Kp), which can differ by up to at least 2,000-fold, or for BBB permeabilities, which span an even larger range (up to at least 20,000-fold difference). Methods that measure the three parameters Kp,uu, CLin, and Vu,brain can give clinically valuable estimates of brain drug delivery in early drug discovery programmes

Report from the EPAA workshop: In vitro ADME in safety testing used by EPAA industry sectors

AbstractThere are now numerous in vitro and in silico ADME alternatives to in vivo assays but how do different industries incorporate them into their decision tree approaches for risk assessment, bearing in mind that the chemicals tested are intended for widely varying purposes? The extent of the use of animal tests is mainly driven by regulations or by the lack of a suitable in vitro model. Therefore, what considerations are needed for alternative models and how can they be improved so that they can be used as part of the risk assessment process? To address these issues, the European Partnership for Alternative Approaches to Animal Testing (EPAA) working group on prioritisation, promotion and implementation of the 3Rs research held a workshop in November, 2008 in Duesseldorf, Germany. Participants included different industry sectors such as pharmaceuticals, cosmetics, industrial- and agro-chemicals. This report describes the outcome of the discussions and recommendations (a) to reduce the number of animals used for determining the ADME properties of chemicals and (b) for considerations and actions regarding in vitro and in silico assays. These included: standardisation and promotion of in vitro assays so that they may become accepted by regulators; increased availability of industry in vivo kinetic data for a central database to increase the power of in silico predictions; expansion of the applicability domains of in vitro and in silico tools (which are not necessarily more applicable or even exclusive to one particular sector) and continued collaborations between regulators, academia and industry. A recommended immediate course of action was to establish an expert panel of users, developers and regulators to define the testing scope of models for different chemical classes. It was agreed by all participants that improvement and harmonization of alternative approaches is needed for all sectors and this will most effectively be achieved by stakeholders from different sectors sharing data

Serial blood cytokine and chemokine mRNA and microRNA over 48 h are insult specific in a piglet model of inflammation-sensitized hypoxia-ischaemia.

BACKGROUND: Exposure to inflammation exacerbates injury in neonatal encephalopathy (NE). We hypothesized that brain biomarker mRNA, cytokine mRNA and microRNA differentiate inflammation (E. coli LPS), hypoxia (Hypoxia), and inflammation-sensitized hypoxia (LPS+Hypoxia) in an NE piglet model. METHODS: Sixteen piglets were randomized: (i) LPS 2 μg/kg bolus; 1 μg/kg infusion (LPS; n = 5), (ii) Saline with hypoxia (Hypoxia; n = 6), (iii) LPS commencing 4 h pre-hypoxia (LPS+Hypoxia; n = 5). Total RNA was acquired at baseline, 4 h after LPS and 1, 3, 6, 12, 24, 48 h post-insult (animals euthanized at 48 h). Quantitative PCR was performed for cytokines (IL1A, IL6, CXCL8, IL10, TNFA) and brain biomarkers (ENO2, UCHL1, S100B, GFAP, CRP, BDNF, MAPT). MicroRNA was detected using GeneChip (Affymetrix) microarrays. Fold changes from baseline were compared between groups and correlated with cell death (TUNEL) at 48 h. RESULTS: Within 6 h post-insult, we observed increased IL1A, CXCL8, CCL2 and ENO2 mRNA in LPS+Hypoxia and LPS compared to Hypoxia. IL10 mRNA differentiated all groups. Four microRNAs differentiated LPS+Hypoxia and Hypoxia: hsa-miR-23a, 27a, 31-5p, 193-5p. Cell death correlated with TNFA (R = 0.69; p < 0.01) at 1-3 h and ENO2 (R = -0.69; p = 0.01) at 48 h. CONCLUSIONS: mRNA and miRNA differentiated hypoxia from inflammation-sensitized hypoxia within 6 h in a piglet model. This information may inform human studies to enable triage for tailored neuroprotection in NE. IMPACT: Early stratification of infants with neonatal encephalopathy is key to providing tailored neuroprotection. IL1A, CXCL8, IL10, CCL2 and NSE mRNA are promising biomarkers of inflammation-sensitized hypoxia. IL10 mRNA levels differentiated all three pathological states; fold changes from baseline was the highest in LPS+Hypoxia animals, followed by LPS and Hypoxia at 6 h. miR-23, -27, -31-5p and -193-5p were significantly upregulated within 6 h of a hypoxia insult. Functional analysis highlighted the diverse roles of miRNA in cellular processes

Sammenligning av tradisjonelt bæresystem og bæresystem av massivtre.

I dette prosjektet skal det dimensjoneres fagverk, i limtre og stål, over gymsalen til Kolvikbakken ungdomsskole. Det er gjort en beregning av miljøutslipp av LCA, fase A1-A4, og samlet erfaring fra byggebransjen om bruken av de to bæresystemene gjennom intervjuer. Fagverket går over et spenn på 25.8 meter. På grunn av dimensjoner på lett-tak, som plassers over fagverkene, trenger man 10 fagverk på langsiden av gymsalen. Fagverkene er beregnet både for hånd og i EUROCODExpress. Etter gjennomføring av dimensjonering kom fagverket i limtre dårlig ut, grunnet de store dimensjonene på tverrsnittene som var nødvendig for å opprettholde krav til nedbøying. Fagverket i limtre ble for høyt, slik vi har løst oppgaven, og vil i praksis ikke kunne benyttes for Kolvikbakken ungdomsskole. Fagverket i stål er innenfor krav til nedbøying, OK etter gjennomført kontroll, og en mulig løsning for spennet over gymsalen. Miljøutslippene for de to bæresystemene baserer seg på forhold A1-A4 i en LCA. Fasene tar for seg miljøutslipp fra produksjon av materiale til levering på byggeplass. Etter å ha gjennomført beregningene, basert på tilgjengelige EPD-er, fant vi at samlet GWP for bæresystemet i massivtre var -1407405.83 kg CO2-eq og 904362.93 kg CO2-eq for det tradisjonelle bæresystemet. Det er bæresystemet av massivtre som kommer best ut på miljøaspektet hvor det tar opp 1407,4 tonn CO2-eq i bæresystemet. Det ble gjennomført tre intervjuer i prosjektet hvor vi intervjuet prosjektledere med erfaring fra byggeprosjekter med både tradisjonelt bæresystem og bæresystem av massivtre. Intervjuene tok utgangspunkt i arbeidsomfang, tid og kostnader relatert til de to bæresystemene. Ikke uventet kom det frem i intervjuene at store spenn er utfordrende med bæresystem av massivtre, noe som vi også har vist i vår dimensjonering av fagverk over et større spenn

Key comparison of liquid density standards

Hydrostatic density determination for liquids is mainly performed by laboratories to provide means for calibrating liquid density measuring instruments such as oscillation-type density meters. From 2002 to 2005 the CIPM key comparison CCM.D-K2 'comparison of liquid density standards' was carried out piloted by the PTB. The aim was to compare the results of the density determination by the participating laboratories to support entries to the CMC tables in this sub-field. To provide further laboratories the possibility to support their entries to the CMC tables at the meeting of the EUROMET Working Group on Density in 2007 this comparison was agreed on. BEV (Austria) organized the comparison supported by the PTB (Germany). For the comparison samples of pentadecane, water, tetrachloroethylene and of an oil of high viscosity were measured in the temperature range from 5 °C to 60 °C at atmospheric pressure by hydrostatic weighing. The measurements were completed in 2008. The reference values of the first reports based on the draft of the CCM.D-K2. After the official publication of the CCM.D-K2 the reference values were recalculated and the report was finalised in 2015