Effect of RasGAP N2 fragment-derived peptide on tumor growth in mice.

Peptides that interfere with the natural resistance of cancer cells to genotoxin-induced apoptosis may improve the efficacy of anticancer regimens. We have previously reported that a cell-permeable RasGAP-derived peptide (TAT-RasGAP(317-326)) specifically sensitizes tumor cells to genotoxin-induced apoptosis in vitro. Here, we examined the in vivo stability of a protease-resistant D-form of the peptide, RI.TAT-RasGAP(317-326), and its effect on tumor growth in nude mice bearing subcutaneous human colon cancer HCT116 xenograft tumors. After intraperitoneal injection, RI.TAT-RasGAP(317-326) persisted in the blood of nude mice for more than 1 hour and was detectable in various tissues and subcutaneous tumors. Tumor-bearing mice treated daily for 7 days with RI.TAT-RasGAP(317-326) (1.65 mg/kg body weight) and cisplatin (0.5 mg/kg body weight) or doxorubicin (0.25 mg/kg body weight) displayed reduced tumor growth compared with those treated with either genotoxin alone (n = 5-7 mice per group; P = .004 and P = .005, respectively; repeated measures analysis of variance [ANOVA, two-sided]). This ability of the RI.TAT-RasGAP(317-326) peptide to enhance the tumor growth inhibitory effect of cisplatin was still observed at peptide doses that were at least 150-fold lower than the dose lethal to 50% of mice. These findings provide the proof of principle that RI.TAT-RasGAP(317-326) may be useful for improving the efficacy of chemotherapy in patients.

Can resistance to trastuzumab be reversed by endocrine therapy? Combination of trastuzumab and letrozole after resistance to sequential trastuzumab and aromatase inhibitor monotherapies in patients with ER-positive, HER-2 positive, advanced breast cancer: a proof-of-concept trial (SAKK 23/03)

Introduction: Trastuzumab (T) is a cornerstone in the treatment of patients with HER2-overexpressing advanced breast cancer and development of resistance to T is a major therapeutic problem. HER-2 is part of a highly interactive signaling network that may impair efficacy of endocrine therapy. A sequential treatment design was chosen in this trial to ensure complete resistance to single agent therapy before receiving both a non-steroidal aromatase inhibitor (AI) and T. Any kind of clinical activity with combined treatment of AI and T after progression of single agent treatments could indicate restoration of sensitivity as a consequence of cross-talking and networking between both pathways. Methods: Key eligibility criteria included postmenopausal patients (pts.) with advanced, measurable, HER-2 positive (assessed by FISH, ratio (≥2)), HR positive disease and progression on prior treatment with a non-steroidal AI, e.g. letrozole or anastrozole, either in an adjuvant or advanced setting. Pts. received standard dose T monotherapy either weekly or three-weekly in step 1 and upon disease progression, continued T in combination with letrozole in step 2. The primary endpoint was clinical benefit response (CBR: CR, PR or SD for at least 24 weeks (+/- 1 week) according to RECIST) in step 2. Results: Thirteen pts. were enrolled in five centers in Switzerland. In step 1, six pts. (46%) achieved CBR. Median time to progression (TTP) was 161 days (Range: 50 - 627). Based on data collected until the end of May 2010, CBR was observed in seven out of the eleven evaluable pts. (64%) in step 2, including one pt. with partial response. Four of the seven pts. within step 2 that achieved CBR also had CBR in step 1. Seven out of eleven pts. have documented tumor progression during step 2 treatment. Median TTP for all eleven pts. was 184 days (range 61 - 471). Mean time on study treatment (TTP in step 1 plus TTP in step 2) for pts. reaching step 2 was 380 days (range 174 - 864). Adverse events were generally mild. Conclusion: Results of this proof-of-principle trial suggest that complete resistance to both AI and T can be overcome in a proportion of pts. by combined treatment of AI and T, as all pts. served as their own control. Our results appear promising for a new treatment strategy which offers a chemotherapy-free and well-tolerated option for at least a subset of the pts. with HR positive, HER-2 positive breast cancer. Further trials will need to corroborate this finding.

Prevention of vascular dysfunction and arterial hypertension in mice generated by assisted reproductive technologies by addition of melatonin to culture media.

Assisted reproductive technologies (ART) induce vascular dysfunction in humans and mice. In mice, ART-induced vascular dysfunction is related to epigenetic alteration of the endothelial nitric oxide synthase (eNOS) gene, resulting in decreased vascular eNOS expression and nitrite/nitrate synthesis. Melatonin is involved in epigenetic regulation, and its administration to sterile women improves the success rate of ART. We hypothesized that addition of melatonin to culture media may prevent ART-induced epigenetic and cardiovascular alterations in mice. We, therefore, assessed mesenteric-artery responses to acetylcholine and arterial blood pressure, together with DNA methylation of the eNOS gene promoter in vascular tissue and nitric oxide plasma concentration in 12-wk-old ART mice generated with and without addition of melatonin to culture media and in control mice. As expected, acetylcholine-induced mesenteric-artery dilation was impaired (P = 0.008 vs. control) and mean arterial blood pressure increased (109.5 ± 3.8 vs. 104.0 ± 4.7 mmHg, P = 0.002, ART vs. control) in ART compared with control mice. These alterations were associated with altered DNA methylation of the eNOS gene promoter (P < 0.001 vs. control) and decreased plasma nitric oxide concentration (10.1 ± 11.1 vs. 29.5 ± 8.0 μM) (P < 0.001 ART vs. control). Addition of melatonin (10(-6) M) to culture media prevented eNOS dysmethylation (P = 0.005, vs. ART + vehicle), normalized nitric oxide plasma concentration (23.1 ± 14.6 μM, P = 0.002 vs. ART + vehicle) and mesentery-artery responsiveness to acetylcholine (P < 0.008 vs. ART + vehicle), and prevented arterial hypertension (104.6 ± 3.4 mmHg, P < 0.003 vs. ART + vehicle). These findings provide proof of principle that modification of culture media prevents ART-induced vascular dysfunction. We speculate that this approach will also allow preventing ART-induced premature atherosclerosis in humans.

Multi-axis solutions in packaging machines in Europe

The objective of this thesis was to examine the potential of multi-axis solutions in packaging machines produced in Europe. The definition of a multi-axis solution in this study is a construction that uses a common DC bus power supply for different amplifiers running the axes and the intelligence is centralized into one unit. The cost structure of a packaging machine was gained from an automation research, which divided the machines according to automation categories. The automation categories were then further divided into different sub-components by evaluating the ratio of multi-axis solutions compared to other automation components in packaging machines. A global motion control study was used for further information. With the help of the ratio, an estimation of the potential of multi-axis solutions in each country and packaging machine sector was completed. In addition to the research, a specific questionnaire was sent to five companies to gain information about the present situation and possible trends in packaging machinery. The greatest potential markets are in Germany and Italy, which are also the largest producers of packaging machinery in Europe. The greatest growth in the next few years will be seen in Turkey where the annual growth rate equals the general machinery production rate in Asia. The greatest market potential of the Nordic countries is found in Sweden in 35th position on the list. According to the interviews, motion control products in packaging machines will retain their current power levels, as well as the number of axes in the future. Integrated machine safety features together with a universal programming language are the desired attributes of the future. Unlike generally in industry, the energy saving objectives are and will remain insignificant in the packaging industry.

Electrical properties of some single crystal dodecaborides /|nby Jyoti Burte. -- 260 St. Catharines [Ont. : s. n.],

PreVi011.3 ':i or~ : indicat e('. tk~t ho t~)rE's sed ~-Al B 12 1i~2, ~' a semiconductor. r:Toreove r , the s i mpl.(~ electronic t heory also indi cates that ~ -AIB1 2 should be a semico nductor, since thf're is one nonbonding e 'Le ctrofl per AlB12- uni t. JPor these reasons, we decided to measure t he electrical n ropert i ~ s of ~ -AlB1 2 single crystal s . Singl e crystal s of¥- AIB 12 ab ou t 1 x 1 r1n1 . size were grown from a copper mel t at 12500 C. The melt technique coupled. 1,vi th slow cooling vilas used because of i ts advantages such as : siTYInle set- up of the expe rimon t ; only e ;l.sil y available c hemi cals are required and it i s a c omparatively strair::bt forvvard y,le t hod still yielding crystal s big enouGh for OtU' purpose . Copper rms used as a solvent , i nst8ad of previOl.wly used aluminum , because it allows c.l.'ystal growth at hig he r t emneratures. HovlGver, the cry s tals of ] -AlB12 shm'red very hi gh res i s t ance a t r oom temperature . From our neasureJ'lents we conclude that the r esistivity of j3- Al B12 is, at least, given as ~ = 4. x 107 oblD .em •• Those results are inc ons i s t ent wi 'uh the ones .. reported by IIiss Khin fo r bot- pressed j3-AlB12 g i ven a s = 7600 ohm . em . or I e s s . ' Since tbe hot pressing was done at about 800 - ' 9000C i n ~ rap hi te moul ds 1,7i th 97% AlB12- p oVJder, vie thi nk there is pas s ib i 1 i ty th a.t lower borides or borot] carbide are , being formed, ':.Jhich are k11 own to be good semiconductors . v7e tried to ro-pe r-AlB12 by addi'J,'?: agents s uch as l:Ig , IG.-InO 4. ' HgS04 , KI12PO 4·' etc. to t he melt .. However , all these re age 11 t eel either reduced the yield and size of t lJe crystals or r;ave crystals of high r esis'can ce again. We think tba t molten copper keeps t he i mpurities off . There is also a pos s i bil i ty t hc:!,t these doping agents get oxidi~::;ed at '1 250°C • Hence, we co ~ clud e that J -AIB12 has v~ ry high r es i stance at r oom temperature . This was a l s o C011 - fi rmed by checki ng the siYlgle and. polycrystals of .~-AIB12 from Norton Co., Ontario and Cooper Nletallurgical Association. Boron carbide has been reported to be a semiconductor with ~ - 0.3 to 0.8 ohm . cm. for hotpres sed s araples. Boron carbide b e inq: struct urally related to ¥-AIB12 , we de cided to study the electrical prone rties of it~ Single crystals. These crystals were cut from a Single melt grovvn crystal a t Norton Co., Ontario. The resistivity of th," se crystal s was measured by the Van der Pam-v' s ~ nethod, which \vas very c onvenient fo r our crystal sha-pp.s. Some of the crystals showed resistivity ~ == 0.50 ob,Tn.cr] . i n agreement with the previously reported results . However , a few crystals showed lower resistivity e.g . 0 .13 and 0.20 ohm.cra • • The Hall mobility could .not be measured and th8reiore i s lower than 0 .16 em 2 v - 1 sec -1 • This is in agreement \vith t he re1)orted Hall mobility for pyrolytic boron . _ 2 -1 -1 carbide as 0.13 cm v sec • We also studied the orientation of the boron carbide crystals by the Jjaue-method. The inclination of c-axis with res pect to x-ray be81Il was det ermined . This was found to be 100 t o 20° f or normal resistivity sarnples (0.5 ohm . cm.) and 27 - 30° for t he lower r esistivity samples (0.1 ~5 to 0.20 ohm.cm .). This indica tes the possibility that th.e r es if.1tivity of B13C3 i s orientation dependent.

The gender pay gap among university professors: the role of individual and organizational determinants

Cette étude de cas, composée de trois articles, examine les diverses sources d’explication de l’écart salarial selon le genre chez les professeurs d’une grande université de recherche canadienne. Le premier article analyse les écarts selon le genre sur les primes “de marché” à partir de données d’un sondage réalisé auprès des professeurs en 2002. Une analyse des correspondances donne une solution à deux facteurs dans laquelle le second facteur oppose clairement les professeurs qui ont reçu une prime à ceux qui n’en n’ont pas reçue. Le genre est fortement associé à ce facteur, la catégorie “femme” se retrouvant du côté de l’axe associé à l’absence de primes de marché. Les résultats de la régression logistique confirment que le secteur d’activité, la fréquence des contrats de recherche, la valorisation du salaire ainsi que le rang combiné à l’ancienneté sont reliés à la présence de primes de marché, tel que proposé par les hypothèses. Toutefois, même après avoir contrôlé pour ces relations, les femmes sont toujours près de trois fois moins susceptibles de s’être vu attribuer des primes de marché que leurs homologues masculins. Dans l’ensemble, les résultats suggèrent que dans un contexte où les salaires sont déterminés par convention collective, la réindividualisation du processus de détermination des salaires — en particulier le versement de primes de marché aux professeurs d’université — peut favoriser la réapparition d’écarts de salaire selon le genre. Le second article est réalisé à partir de données administratives portant sur les années 1997 à 2006. Les contributions respectives de quatre composantes de la rémunération à l’écart salarial selon le genre y sont analysées, soit le salaire de base, l’accès au rang de professeur titulaire, l’accès aux primes de marché et chaires de recherche du Canada, de même que les montants reçus. Les composantes varient quant à leur degré de formalisation. Ceci permet de tester l’hypothèse selon laquelle l’ampleur de l’écart salarial selon le genre varie en fonction du degré de formalisation des composantes salariales. Nous déterminons également dans quelle mesure l’écart selon le genre sur les diverses composantes de la rémunération varie en fonction de la représentation relative des femmes professeurs au sein des unités. Les résultats démontrent l’existence de variations dans l’ampleur des différences selon le genre en fonction du degré de formalisation des pratiques de rémunération. Qui plus est, après contrôles, la rémunération est plus faible dans les unités où les femmes sont fortement représentées. Le dernier article examine les mécanismes pouvant mener à un écart selon le genre en ce qui a trait à l’accès aux primes de marché chez les professeurs de l’institution. Les processus d’attribution de ces suppléments salariaux sont examinés à partir d’entretiens réalisés avec 17 administrateurs à tous les niveaux hiérarchiques de l’institution et dans une diversité d’unités académiques. Les résultats suggèrent que les différences selon le genre pourraient être liées à des caractéristiques spécifiques du processus d’attribution et à une distribution inégale des primes aux unités à forte représentation féminine. De façon générale, les résultats démontrent que l’écart de rémunération selon le genre chez les professeurs de cette université n’est pas totalement expliqué par des différences dans les caractéristiques individuelles des hommes et femmes. L’analyse révèle que l’écart réside dans des différences selon le genre en ce qui a trait à l’accès aux primes de marché et aux chaires de recherches du Canada et, dans une moindre mesure, au rang de professeur titulaire. Aucune différence n’est observée sur le salaire de base et le montant des primes salariales reçues, que celles-ci soient dites de “marché” ou associées à une chaire de recherche du Canada. Qui plus est, on constate que la rémunération est plus faible dans les unités où les femmes sont le mieux représentées. L’accès différencié selon le genre aux primes de marché qui est observé pourrait être lié à certains processus organisationnels qui limitent les probabilités d’octrois à des femmes. Les femmes pourraient être particulièrement désavantagées dans ce système d’octroi, pour plusieurs raisons. L’existence de différences selon le genre en ce qui a trait aux dispositions ou habiletés des individus à négocier leur salaire est évoquée et supposée par certains administrateurs. Un accès limité aux informations concernant la politique de primes pourrait réduire la probabilité que des femmes tentent d’obtenir ces suppléments salariaux. Les directeurs d’unités, qui sont en majorité des hommes, pourraient être biaisées en faveur des professeurs masculins dans leurs évaluations s’ils tendent à favoriser ceux qui leurs ressemblent. Il est également possible que les directeurs d’unités où les femmes sont les mieux représentées n’aient pas reçu d’information sur les primes de marché ou que des traditions disciplinaires les aient rendu réticents à demander des primes.

Techniques for Enhancing Wind Energy Generation - A CFD Based Multibody Dynamics Approach in Horizontal Axis Wind Turbines

Wind energy has emerged as a major sustainable source of energy.The efficiency of wind power generation by wind mills has improved a lot during the last three decades.There is still further scope for maximising the conversion of wind energy into mechanical energy.In this context,the wind turbine rotor dynamics has great significance.The present work aims at a comprehensive study of the Horizontal Axis Wind Turbine (HAWT) aerodynamics by numerically solving the fluid dynamic equations with the help of a finite-volume Navier-Stokes CFD solver.As a more general goal,the study aims at providing the capabilities of modern numerical techniques for the complex fluid dynamic problems of HAWT.The main purpose is hence to maximize the physics of power extraction by wind turbines.This research demonstrates the potential of an incompressible Navier-Stokes CFD method for the aerodynamic power performance analysis of horizontal axis wind turbine.The National Renewable Energy Laboratory USA-NREL (Technical Report NREL/Cp-500-28589) had carried out an experimental work aimed at the real time performance prediction of horizontal axis wind turbine.In addition to a comparison between the results reported by NREL made and CFD simulations,comparisons are made for the local flow angle at several stations ahead of the wind turbine blades.The comparison has shown that fairly good predictions can be made for pressure distribution and torque.Subsequently, the wind-field effects on the blade aerodynamics,as well as the blade/tower interaction,were investigated.The selected case corresponded to a 12.5 m/s up-wind HAWT at zero degree of yaw angle and a rotational speed of 25 rpm.The results obtained suggest that the present can cope well with the flows encountered around wind turbines.The areodynamic performance of the turbine and the flow details near and off the turbine blades and tower can be analysed using theses results.The aerodynamic performance of airfoils differs from one another.The performance mainly depends on co-efficient of performnace,co-efficient of lift,co-efficient of drag, velocity of fluid and angle of attack.This study shows that the velocity is not constant for all angles of attack of different airfoils.The performance parameters are calculated analytically and are compared with the standardized performance tests.For different angles of ,the velocity stall is determined for the better performance of a system with respect to velocity.The research addresses the effect of surface roughness factor on the blade surface at various sections.The numerical results were found to be in agreement with the experimental data.A relative advantage of the theoretical aerofoil design method is that it allows many different concepts to be explored economically.Such efforts are generally impractical in wind tunnels because of time and money constraints.Thus, the need for a theoretical aerofoil design method is threefold:first for the design of aerofoil that fall outside the range of applicability of existing calalogs:second,for the design of aerofoil that more exactly match the requirements of the intended application:and third,for the economic exploration of many aerofoil concepts.From the results obtained for the different aerofoils,the velocity is not constant for all angles of attack.The results obtained for the aerofoil mainly depend on angle of attack and velocity.The vortex generator technique was meticulously studies with the formulation of the specification for the right angle shaped vortex generators-VG.The results were validated in accordance with the primary analysis phase.The results were found to be in good agreement with the power curve.The introduction of correct size VGs at appropriate locations over the blades of the selected HAWT was found to increase the power generation by about 4%

Principle-Based Parsing

During the past few years, there has been much discussion of a shift from rule-based systems to principle-based systems for natural language processing. This paper outlines the major computational advantages of principle-based parsing, its differences from the usual rule-based approach, and surveys several existing principle-based parsing systems used for handling languages as diverse as Warlpiri, English, and Spanish, as well as language translation.

Display of a Maize cDNA library on baculovirus infected insect cells

Background: Maize is a good model system for cereal crop genetics and development because of its rich genetic heritage and well-characterized morphology. The sequencing of its genome is well advanced, and new technologies for efficient proteomic analysis are needed. Baculovirus expression systems have been used for the last twenty years to express in insect cells a wide variety of eukaryotic proteins that require complex folding or extensive posttranslational modification. More recently, baculovirus display technologies based on the expression of foreign sequences on the surface of Autographa californica ( AcMNPV) have been developed. We investigated the potential of a display methodology for a cDNA library of maize young seedlings. Results: We constructed a full-length cDNA library of young maize etiolated seedlings in the transfer vector pAcTMVSVG. The library contained a total of 2.5 x 10(5) independent clones. Expression of two known maize proteins, calreticulin and auxin binding protein (ABPI), was shown by western blot analysis of protein extracts from insect cells infected with the cDNA library. Display of the two proteins in infected insect cells was shown by selective biopanning using magnetic cell sorting and demonstrated proof of concept that the baculovirus maize cDNA display library could be used to identify and isolate proteins. Conclusion: The maize cDNA library constructed in this study relies on the novel technology of baculovirus display and is unique in currently published cDNA libraries. Produced to demonstrate proof of principle, it opens the way for the development of a eukaryotic in vivo display tool which would be ideally suited for rapid screening of the maize proteome for binding partners, such as proteins involved in hormone regulation or defence.

Eight-plex iTRAQ analysis of variant metastatic human prostate cancer cells identifies candidate biomarkers of progression: an exploratory study.

BACKGROUND: Due to the heterogeneity in the biological behavior of prostate cancer, biomarkers that can reliably distinguish indolent from aggressive disease are urgently needed to inform treatment choices. METHODS: We employed 8-plex isobaric Tags for Relative and Absolute Quantitation (iTRAQ), to profile the proteomes of two distinct panels of isogenic prostate cancer cells with varying growth and metastatic potentials, in order to identify novel biomarkers associated with progression. The LNCaP, LNCaP-Pro5, and LNCaP-LN3 panel of cells represent a model of androgen-responsive prostate cancer, while the PC-3, PC-3M, and PC-3M-LN4 panel represent a model of androgen-insensitive disease. RESULTS: Of the 245 unique proteins identified and quantified (>or=95% confidence; >or=2 peptides/protein), 17 showed significant differential expression (>or=+/-1.5), in at least one of the variant LNCaP cells relative to parental cells. Similarly, comparisons within the PC-3 panel identified 45 proteins to show significant differential expression in at least one of the variant PC-3 cells compared with parental cells. Differential expression of selected candidates was verified by Western blotting or immunocytochemistry, and corresponding mRNA expression was determined by quantitative real-time PCR (qRT-PCR). Immunostaining of prostate tissue microarrays for ERp5, one of the candidates identified, showed a significant higher immunoexpression in pre-malignant lesions compared with non-malignant epithelium (P < 0.0001, Mann-Whitney U-test), and in high Gleason grade (4-5) versus low grade (2-3) cancers (P < 0.05). CONCLUSIONS: Our study provides proof of principle for the application of an 8-plex iTRAQ approach to uncover clinically relevant candidate biomarkers for prostate cancer progression.

Implications of non-cylindrical flux ropes for magnetic cloud reconstruction techniques and the interpretation of double flux rope events

Magnetic clouds (MCs) are a subset of interplanetary coronal mass ejections (ICMEs) which exhibit signatures consistent with a magnetic flux rope structure. Techniques for reconstructing flux rope orientation from single-point in situ observations typically assume the flux rope is locally cylindrical, e.g., minimum variance analysis (MVA) and force-free flux rope (FFFR) fitting. In this study, we outline a non-cylindrical magnetic flux rope model, in which the flux rope radius and axial curvature can both vary along the length of the axis. This model is not necessarily intended to represent the global structure of MCs, but it can be used to quantify the error in MC reconstruction resulting from the cylindrical approximation. When the local flux rope axis is approximately perpendicular to the heliocentric radial direction, which is also the effective spacecraft trajectory through a magnetic cloud, the error in using cylindrical reconstruction methods is relatively small (≈ 10∘). However, as the local axis orientation becomes increasingly aligned with the radial direction, the spacecraft trajectory may pass close to the axis at two separate locations. This results in a magnetic field time series which deviates significantly from encounters with a force-free flux rope, and consequently the error in the axis orientation derived from cylindrical reconstructions can be as much as 90∘. Such two-axis encounters can result in an apparent ‘double flux rope’ signature in the magnetic field time series, sometimes observed in spacecraft data. Analysing each axis encounter independently produces reasonably accurate axis orientations with MVA, but larger errors with FFFR fitting.

Towards a model-based integration of co-registered electroencephalography/functional magnetic resonance imaging data with realistic neural population meshes

Brain activity can be measured with several non-invasive neuroimaging modalities, but each modality has inherent limitations with respect to resolution, contrast and interpretability. It is hoped that multimodal integration will address these limitations by using the complementary features of already available data. However, purely statistical integration can prove problematic owing to the disparate signal sources. As an alternative, we propose here an advanced neural population model implemented on an anatomically sound cortical mesh with freely adjustable connectivity, which features proper signal expression through a realistic head model for the electroencephalogram (EEG), as well as a haemodynamic model for functional magnetic resonance imaging based on blood oxygen level dependent contrast (fMRI BOLD). It hence allows simultaneous and realistic predictions of EEG and fMRI BOLD from the same underlying model of neural activity. As proof of principle, we investigate here the influence on simulated brain activity of strengthening visual connectivity. In the future we plan to fit multimodal data with this neural population model. This promises novel, model-based insights into the brain's activity in sleep, rest and task conditions.

Realistic mean field forward predictions for the integration of co-registered EEG/fMRI

Brain activity can be measured non-invasively with functional imaging techniques. Each pixel in such an image represents a neural mass of about 105 to 107 neurons. Mean field models (MFMs) approximate their activity by averaging out neural variability while retaining salient underlying features, like neurotransmitter kinetics. However, MFMs incorporating the regional variability, realistic geometry and connectivity of cortex have so far appeared intractable. This lack of biological realism has led to a focus on gross temporal features of the EEG. We address these impediments and showcase a "proof of principle" forward prediction of co-registered EEG/fMRI for a full-size human cortex in a realistic head model with anatomical connectivity, see figure 1. MFMs usually assume homogeneous neural masses, isotropic long-range connectivity and simplistic signal expression to allow rapid computation with partial differential equations. But these approximations are insufficient in particular for the high spatial resolution obtained with fMRI, since different cortical areas vary in their architectonic and dynamical properties, have complex connectivity, and can contribute non-trivially to the measured signal. Our code instead supports the local variation of model parameters and freely chosen connectivity for many thousand triangulation nodes spanning a cortical surface extracted from structural MRI. This allows the introduction of realistic anatomical and physiological parameters for cortical areas and their connectivity, including both intra- and inter-area connections. Proper cortical folding and conduction through a realistic head model is then added to obtain accurate signal expression for a comparison to experimental data. To showcase the synergy of these computational developments, we predict simultaneously EEG and fMRI BOLD responses by adding an established model for neurovascular coupling and convolving "Balloon-Windkessel" hemodynamics. We also incorporate regional connectivity extracted from the CoCoMac database [1]. Importantly, these extensions can be easily adapted according to future insights and data. Furthermore, while our own simulation is based on one specific MFM [2], the computational framework is general and can be applied to models favored by the user. Finally, we provide a brief outlook on improving the integration of multi-modal imaging data through iterative fits of a single underlying MFM in this realistic simulation framework.

The role of necessity in international humanitarian and human rights law

The nature of armed conflict has changed dramatically in recent decades. In particular, it is increasingly the case that hostilities now occur alongside ‘everyday’ situations. This has led to a pressing need to determine when a ‘conduct of hostilities’ model (governed by international humanitarian law—IHL) applies and when a ‘law enforcement’ model (governed by international human rights law—IHRL) applies. This in turn raises the question of whether these two legal regimes are incompatible or whether they might be applied in parallel. It is on this question that the current paper focuses, examining it at the level of principle. Whilst most accounts of the principles underlying these two areas of law focus on humanitarian considerations, few have compared the role played by necessity in each. This paper seeks to address this omission. It demonstrates that considerations of necessity play a prominent role in both IHL and IHRL, albeit with differing consequences. It then applies this necessity-based analysis to suggest a principled basis for rationalising the relationship between IHL and IHRL, demonstrating how this approach would operate in practice. It is shown that, by emphasising the role of necessity in IHL and IHRL, an approach can be adopted that reconciles the two in a manner that is sympathetic to their object and purpose.