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Abstract After traumatic brain injury (TBI) cerebral inflammation with invasion of neutrophils and lymphocytes is a crucial factor in the process of secondary brain damage. In TBI the intrinsic renin-angiotensin system is an important mediator of cerebral inflammation, as inhibition of the angiotensin II receptor type 1 (AT1) reduces secondary brain damage and the invasion of neutrophil granulocytes into injured cerebral tissue. The current study explored the involvement of immune cells in neuroprotection mediated by AT1 inhibition following experimental TBI. Four different cohorts of male mice were examined, investigating the effects of neutropenia (anti-Ly6G antibody mediated neutrophil depletion; C57BL/6), lymphopenia (RAG1 deficiency, RAG1−/−), and their combination with candesartan-mediated AT1 inhibition. The present results showed that reduction of neutrophils and lymphocytes, as well as AT1 inhibition in wild type and RAG1−/− mice, reduced brain damage and neuroinflammation after TBI. However, in neutropenic mice, candesartan did not have an effect. Interestingly, AT1 inhibition was found to be neuroprotective in RAG1−/− mice but not in neutropenic mice. The findings suggest that AT1 inhibition may exert neuroprotection by reducing the inflammation caused by neutrophils, ultimately leading to a decrease in their invasion into cerebral tissue.

Abstract Traumatic brain injury (TBI) causes the release of danger-associated molecular patterns (DAMP) from damaged or dead cells, which contribute to secondary brain damage after TBI. Cell-free DNA (cfDNA) is a DAMP known to cause disruption of the blood–brain barrier (BBB), promote procoagulant processes, brain edema, and neuroinflammation. This study tested the hypothesis that administration of deoxyribonuclease-I (DNase-I) has a beneficial effect after TBI. Mice (n = 84) were subjected to controlled cortical impact (CCI) and posttraumatic intraperitoneal injections of low dose (LD) or high dose (HD) of DNase-I or vehicle solution at 30 min and 12 h after CCI. LD was most effective to reduce lesion volume (p = 0.003), brain water content (p

Abstract Antagonism of the angiotensin II type 1 receptor (AT1) improves neurological function and reduces brain damage after experimental traumatic brain injury (TBI), which may be partly a result of enhanced indirect angiotensin II type 2 receptor (AT2) stimulation. AT2 stimulation was demonstrated to be neuroprotective via anti-inflammatory, vasodilatory, and neuroregenerative mechanisms in experimental cerebral pathology models. We recently demonstrated an upregulation of AT2 after TBI suggesting a protective mechanism. The present study investigated the effect of post-traumatic (5 days after TBI) AT2 activation via high and low doses of a selective AT2 agonist, compound 21 (C21), compared to vehicle-treated controls. No differences in the extent of the TBI-induced lesions were found between both doses of C21 and the controls. We then tested AT2-knockdown animals for secondary brain damage after experimental TBI. Lesion volume and neurological outcomes in AT2-deficient mice were similar to those in wild-type control mice at both 24 h and 5 days post-trauma. Thus, in contrast to AT1 antagonism, AT2 modulation does not influence the initial pathophysiological mechanisms of TBI in the first 5 days after the insult, indicating that AT2 plays only a minor role in the early phase following trauma-induced brain damage.

Abstract Traumatic brain injury (TBI) involves primary mechanical damage and delayed secondary damage caused by vascular dysfunction and neuroinflammation. Intracellular components released into the parenchyma and systemic circulation, termed danger-associated molecular patterns (DAMPs), are major drivers of vascular dysfunction and neuroinflammation. These DAMPs include cell-free RNAs (cfRNAs), which damage the blood–brain barrier (BBB), thereby promoting edema, procoagulatory processes, and infiltration of inflammatory cells. We tested the hypothesis that intraperitoneal injection of Ribonuclease-1 (RNase1, two doses of 20, 60, or 180 µg/kg) at 30 min and 12 h after controlled-cortical-impact (CCI) can reduce secondary lesion expansion compared to vehicle treatment 24 h and 120 h post-CCI. The lowest total dose (40 µg/kg) was most effective at reducing lesion volume (− 31% RNase 40 µg/kg vs. vehicle), brain water accumulation (− 5.5%), and loss of BBB integrity (− 21.6%) at 24 h post-CCI. RNase1 also reduced perilesional leukocyte recruitment (− 53.3%) and microglial activation (− 18.3%) at 120 h post-CCI, but there was no difference in lesion volume at this time and no functional benefit. Treatment with RNase1 in the early phase following TBI stabilizes the BBB and impedes leukocyte immigration, thereby suppressing neuroinflammation. RNase1-treatment may be a novel approach to delay brain injury to extend the window for treatment opportunities after TBI.

The electric quadrupole moment of 49Sc was measured by collinear laser spectroscopy at CERN-ISOLDE to be Qs=−0.159(8) eb, and a nearly tenfold improvement in precision was reached for the electromagnetic moments of 47,49Sc. The single-particle behavior and nucleon-nucleon correlations are investigated with the electromagnetic moments of Z=21 isotopes and N=28 isotones as valence neutrons and protons fill the distinctive 0f7/2 orbit, respectively, located between magic numbers, 20 and 28. The experimental data are interpreted with shell-model calculations using an effective interaction, and ab-initio valence-space in-medium similarity renormalization group calculations based on chiral interactions. These results highlight the sensitivity of nuclear electromagnetic moments to different types of nucleon-nucleon correlations, and establish an important benchmark for further developments of theoretical calculations.

The time on task (ToT) effect describes the relationship of the time spent on a cognitive task and the probability of successful task completion. The effect has been shown to vary in size and direction across tests and even within tests, depending on the test taker and item characteristics. Specifically, investing more time has a positive effect on response accuracy for difficult items and low ability test-takers, but a negative effect for easy items and high ability test-takers. The present study sought to test the replicability of this result pattern of the ToT effect across samples independently drawn from the same populations of persons and items. Furthermore, its generalizability was tested in terms of differential correlations across ability tests. To this end, ToT effects were estimated for three different reasoning tests and one test measuring natural sciences knowledge in 10 comparable subsamples with a total N = 2640. Results for the subsamples were highly similar, demonstrating that ToT effects are estimated with sufficient reliability. Generally, faster answers tended to be more accurate, suggesting a relatively effortless processing style. However, with increasing item difficulty and decreasing person ability, the effect flipped to the opposite direction, i.e., higher accuracy with longer processing times. The within-task moderation of the ToT effect can be reconciled with an account on effortful processing or cognitive load. By contrast, the generalizability of the ToT effect across different tests was only moderate. Cross-test relations were stronger in relative terms if performance in the respective tasks was more strongly related. This suggests that individual differences in the ToT effect depend on test characteristics such as their reliabilities but also similarities and differences of their processing requirements.

The task-switching paradigm is deemed a measure of cognitive flexibility. Previous research has demonstrated that individual differences in task-switch costs are moderately inversely related to cognitive ability. However, current theories emphasize multiple component processes of task switching, such as task-set preparation and task-set inertia. The relations of task-switching processes with cognitive ability were investigated in the current study. Participants completed a task-switching paradigm with geometric forms and a visuospatial working memory capacity (WMC) task. The task-switch effect was decomposed with the diffusion model. Effects of task-switching and response congruency were estimated as latent differences using structural equation modeling. Their magnitudes and relations with visuospatial WMC were investigated. Effects in the means of parameter estimates replicated previous findings, namely increased non-decision time in task-switch trials. Further, task switches and response incongruency had independent effects on drift rates, reflecting their differential effects on task readiness. Findings obtained with the figural tasks employed in this study revealed that WMC was inversely related to the task-switch effect in non-decision time. Relations with drift rates were inconsistent. Finally, WMC was moderately inversely related to response caution. These findings suggest that more able participants either needed less time for task-set preparation or that they invested less time for task-set preparation.

Abstract Background Traumatic brain injury (TBI) is a major cause of death and disability. T cells were shown to infiltrate the brain during the first days after injury and to exacerbate tissue damage. The objective of this study was to investigate the hitherto unresolved role of immunosuppressive, regulatory T cells (Tregs) in experimental TBI. Methods “Depletion of regulatory T cell” (DEREG) and wild type (WT) C57Bl/6 mice, treated with diphtheria toxin (DTx) to deplete Tregs or to serve as control, were subjected to the controlled cortical impact (CCI) model of TBI. Neurological and motor deficits were examined until 5 days post-injury (dpi). At the 5 dpi endpoint, (immuno-) histological, protein, and gene expression analyses were carried out to evaluate the consequences of Tregs depletion. Comparison of parametric or non-parametric data between two groups was done using Student’s t test or the Mann-Whitney U test. For multiple comparisons, p values were calculated by one-way or two-way ANOVA followed by specific post hoc tests. Results The overall neurological outcome at 5 dpi was not different between DEREG and WT mice but more severe motor deficits occurred transiently at 1 dpi in DEREG mice. DEREG and WT mice did not differ in the extent of brain damage, blood-brain barrier (BBB) disruption, or neuronal excitotoxicity, as examined by lesion volumetry, immunoglobulin G (IgG) extravasation, or calpain-generated αII-spectrin breakdown products (SBDPs), respectively. In contrast, increased protein levels of glial fibrillary acidic protein (GFAP) and GFAP+ astrocytes in the ipsilesional brain tissue indicated exaggerated reactive astrogliosis in DEREG mice. T cell counts following anti-CD3 immunohistochemistry and gene expression analyses of Cd247 (CD3 subunit zeta) and Cd8a (CD8a) further indicated an increased number of T cells infiltrating the brain injury sites of DEREG mice compared to WT. These changes coincided with increased gene expression of pro-inflammatory interferon-γ (Ifng) in DEREG mice compared to WT in the injured brain. Conclusions The results show that the depletion of Tregs attenuates T cell brain infiltration, reactive astrogliosis, interferon-γ gene expression, and transiently motor deficits in murine acute traumatic brain injury.

Abstract Background Acute subdural hemorrhage (ASDH) is a severe consequence of traumatic brain injury. The occurrence of subdural blood increases the lethality of these patients independent of the amount of blood or elevated intracranial pressure. Thrombin is one of the potential harmful blood components. Possible harmful effects of thrombin are mediated via the Protease-activated-receptor-1 (PAR1) and thus, translating the acute Thrombin release after ASDH into cell loss. The objectives of the present study were twofold, namely to examine (1) the impact of direct thrombin inhibition in the acute phase after hemorrhage on the long-term histological and functional deficits and (2) the early inhibition of PAR1 activation by thrombin with the selective antagonist SCH79797 on lesion volume at 14 days after ASDH. The effects of thrombin on the lesion size were investigated in two separate experiments via (1) direct thrombin inhibition in the subdural infused blood (Argatroban 600 µg) as well as by (2) intraventricular injection of the PAR-1 antagonist SCH79797 (1 µg or 5 µg). Lesion volume and behavior deficits using a neurological deficit score and a motor function test (beam balance test) were analyzed as outcome parameters at 14 days after injury. Results 59 Male Sprague–Dawley rats received a subdural infusion of 300 µl autologous blood or sham operation. Lesion volume at 14 days after ASDH tended to be smaller in the Argatroban-treated group when compared to the vehicle group (8.1 ± 1.1 vs. 10.1 ± 2.3 mm2, n.s.). Motor deficits in the beam balance test were not significantly less severe in the Argatroban-treated group. Animals treated with SCH79797 also showed a trend towards dose-dependent decreased lesion volume in comparison to the vehicle-treated group (1 μg: 4.3 ± 0.7 mm3; 5 μg: 3.8 ± 1.1 mm3; vehicle: 6.5 ± 2.0 mm3, n.s). Conclusions Thrombin inhibition in the subdural blood and local cerebral blockade of PAR-1 cause a tendency towards reduced lesion volume or functional recovery. All results show a trend in favor of the acute treatment on the outcome parameters. Our results suggests that thrombin could be an important blood-derived factor during acute subdural hemorrhage that translates its deleterious effects in concert with other blood-induced factors.

Collinear laser spectroscopy was performed on Zn (Z=30) isotopes at ISOLDE, CERN. The study of hyperfine spectra of nuclei across the Zn isotopic chain, N=33–49, allowed the measurement of nuclear spins for the ground and isomeric states in odd-A neutron-rich nuclei up to N=50. Exactly one long-lived (>10 ms) isomeric state has been established in each 69–79Zn isotope. The nuclear magnetic dipole moments and spectroscopic quadrupole moments are well reproduced by large-scale shell–model calculations in the f5pg9 and fpg9d5 model spaces, thus establishing the dominant term in their wave function. The magnetic moment of the intruder Iπ=1/2+ isomer in 79Zn is reproduced only if the νs1/2 orbital is added to the valence space, as realized in the recently developed PFSDG-U interaction. The spin and moments of the low-lying isomeric state in 73Zn suggest a strong onset of deformation at N=43, while the progression towards 79Zn points to the stability of the Z=28 and N=50 shell gaps, supporting the magicity of 78Ni. Keywords: Zinc, Magnetic dipole moment, Quadrupole moment, Laser, Shell closure

Nuclear charge radii of 62−80Zn have been determined using collinear laser spectroscopy of bunched ion beams at CERN-ISOLDE. The subtle variations of observed charge radii, both within one isotope and along the full range of neutron numbers, are found to be well described in terms of the proton excitations across the Z=28 shell gap, as predicted by large-scale shell model calculations. It comprehensively explains the changes in isomer-to-ground state mean square charge radii of 69−79Zn, the inversion of the odd-even staggering around N=40 and the odd-even staggering systematics of the Zn charge radii. With two protons above Z=28, the observed charge radii of the Zn isotopic chain show a cumulative effect of different aspects of nuclear structure including single particle structure, shell closure, correlations and deformations near the proposed doubly magic nuclei, 68Ni and 78Ni. Keywords: Zinc, Nuclear charge radii, Shell closure, Nuclear deformation, Correlations

Following publication of the original article [1], the authors opted to correct the following mistakes. According to the title and our results, the conclusions in the abstract and at the end of the discussion the term “attenuates” must be corrected to read as “increases”.

In Part 1 of this article we discussed the need for information quality and the systematic management of learning materials and learning arrangements. Digital repositories, often called Learning Object Repositories (LOR), were introduced as a promising answer to this challenge. We also derived technological and pedagogical requirements for LORs from a concretization of information quality criteria for e-learning technology. This second part presents technical solutions that particularly address the demands of open education movements, which aspire to a global reuse and sharing culture. From this viewpoint, we develop core requirements for scalable network architectures for educational content management. We then present edu-sharing, an advanced example of a network of homogeneous repositories for learning resources, and discuss related technology. We conclude with an outlook in terms of emerging developments towards open and networked system architectures in e-learning.

As education providers increasingly integrate digital learning media into their education processes, the need for the systematic management of learning materials and learning arrangements becomes clearer. Digital repositories, often called Learning Object Repositories (LOR), promise to provide an answer to this challenge. This article is composed of two parts. In this part, we derive technological and pedagogical requirements for LORs from a concretization of information quality criteria for e-learning technology. We review the evolution of learning object repositories and discuss their core features in the context of pedagogical requirements, information quality demands, and e-learning technology standards. We conclude with an outlook in Part 2, which presents concrete technical solutions, in particular networked repository architectures.

The first part of this serial paper dealt with the medical criteria used in evaluation of the clinical picture caused by physical stress and the evaluation of other candidate causes and was published in issue no. 3/2005 (pp. 711–752) of Trauma and Berufskrankheit. This follow-up paper (II) presents criteria to be used in the evaluation of whether it is necessary to give up the occupations putting the spine at risk and in estimation of the degree of disability. [ABSTRACT FROM AUTHOR]

Background:Blood pressure-independent (BP) effects of angiotensin (Ang) II and endothelin (ET) on coronaries (remodeling) in high renin hypertension are incompletely understood. Methods:We studied the effects of subdepressor doses of Ang II receptor (AT1) blockade with losartan (10 mg/kg/day gavage) and endothelin A receptor (ETA) blockade with LU135252 (30 mg/kg/day) on the coronaries of rats harboring human renin and angiotensinogen genes (dTGR). Nontransgenic Sprague-Dawley rats were controls. The rats were treated between the ages of 6 and 10 weeks. Coronary cross-sectional area [CSA; 0.79 × (external diameter2 – internal diameter2)], cell proliferation, and infiltration of monocytes/macrophages were determined. Results:Monotherapy did not lower BP while combination treatment did (p < 0.05). All treatments reduced mortality (p < 0.01). CSA was decreased by all treatments compared to vehicle, independent of blood pressure (p < 0.05). Extensive proliferation by PCNA staining and infiltration of ED-1-positive cells was diminished by both treatment and the combination. Conclusions:The data show that Ang II promotes coronary inflammation and remodeling, in part independent of blood pressure but dependent upon ET signaling. Combination treatment directed at both pathways may improve outcome, independent of blood pressure reduction.Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

A negative magnetic moment of 23Mg has been determined by collinear laser spectroscopy at CERN-ISOLDE. The absolute value is in agreement with previous measurements by nuclear magnetic resonance while the sign points at high-seniority configurations. The result is consistent with shell-model predictions for nuclei with valence nucleons in the sd shell. [ABSTRACT FROM AUTHOR]

An experimental setup for sensitive high-resolution measurements of hyperfine structure spectra of exotic calcium isotopes has been developed and commissioned at the COLLAPS beam line at ISOLDE, CERN. The technique is based on the radioactive detection of decaying isotopes after optical pumping and state selective neutralization (ROC) (Vermeeren et al 1992 Phys. Rev. Lett.68 1679). The improvements and developments necessary to extend the applicability of the experimental technique to calcium isotopes produced at rates as low as few ions s–1 are discussed. Numerical calculations of laser-ion interaction and ion-beam simulations were explored to obtain the optimum performance of the experimental setup. Among the implemented features are a multi-step optical pumping region for sensitive measurements of isotopes with hyperfine splitting, a high-voltage platform for adequate control of low-energy ion beams and simultaneous β-detection of neutralized and remaining ions. The commissioning of the experimental setup, and the first online results on neutron-rich calcium isotopes are presented. [ABSTRACT FROM AUTHOR]

We report on improved isotope shift measurements of the isotopes Ca in the (D2) transition using collinear laser spectroscopy. Accurately known isotope shifts in the (D1) transition were used to calibrate the ion beam energy with an uncertainty of The accuracy in the D2 transition was improved by a factor of 5–10. A King-plot analysis of the two transitions revealed that the field shift factor in the D2 line is about 1.8(13)% larger than in the D1 transition which is ascribed to relativistic contributions of the wave function. [ABSTRACT FROM AUTHOR]