A calcium-driven conformational switch of the n-terminal and core domains of annexin A1

In 1993, Huber and co-workers published the structure of an N-terminally truncated version of human annexin A1 lacking the first 32 amino acid residues (PDB code: 1AIN). In 2001, we reported the structure of full-length porcine annexin A1 including the N-terminal domain in the absence of calcium ions (PDB code: 1HM6). The latter structure did not reflect a typical annexin core fold, but rather a surprising interaction of the N-terminal domain and the core domain. Comparing these two structures revealed that in the full-length structure the first 12 residues of the N-terminal domain insert into the core of the protein, thereby replacing and unwinding one of the a-helices (helix D in repeat 3) that is involved in calcium binding. We hypothesized that this Structure in the absence of calcium ions represents the inactive form of the protein. Furthermore, we proposed that upon calcium binding, the N-terminal domain would be expelled from the core domain and that the core D-helix would reform in the proper conformation for calcium coordination. Herein, we report the X-ray structure of full-length porcine annexin A1 in the presence of calcium. This new structure shows a typical annexin core structure as we hypothesized, with the D-helix back in place for calcium coordination while parts of the now exposed N-terminal domain are disordered. We could locate eight calcium ions in this structure, two of which are octa-coordinated and two of which were not observed in the structure of the N-terminally truncated annexin A1. Possible implications of this calcium-induced conformational switch for the membrane aggregation properties of annexin A1 will be discussed. (C) 2003 Elsevier Science Ltd. All rights reserved

Arrangement of Annexin A2 tetramer and its impact on the structure and diffusivity of supported lipid bilayers

Annexins are a family of proteins that bind to anionic phospholipid membranes in a Ca2+-dependent manner. Annexin A2 forms heterotetramers (Anx A2t) with the S100A10 (p11) protein dimer. The tetramer is capable of bridging phospholipid membranes and it has been suggested to play a role in Ca2+-dependent exocytosis and cell-cell adhesion of metastatic cells. Here, we employ x-ray reflectivity measurements to resolve the conformation of Anx A2t upon Ca2+-dependent binding to single supported lipid bilayers (SLBs) composed of different mixtures of anionic (POPS) and neutral (POPC) phospholipids. Based on our results we propose that Anx A2t binds in a side-by-side configuration, i.e., both Anx A2 monomers bind to the bilayer with the p11 dimer positioned on top. Furthermore, we observe a strong decrease of lipid mobility upon binding of Anx A2t to SLBs with varying POPS content. X-ray reflectivity measurements indicate that binding of Anx A2t also increases the density of the SLB. Interestingly, in the protein-facing leaflet of the SLB the lipid density is higher than in the substrate-facing leaflet. This asymmetric densification of the lipid bilayer by Anx A2t and Ca2+ might have important implications for the biochemical mechanism of Anx A2t-induced endo- and exocytosis.Comment: 27 pages, 7 figures; supplementary material available upon request from the author

Assessing language dominance with functional MRI: The role of control tasks and statistical analysis

There is a discrepancy between the brain regions revealed by functional neuroimaging techniques and those brain regions where a loss of function, either by lesion or by electrocortical stimulation, induces language disorders. To differentiate between essential and non-essential language-related processes, we investigated the effects of linguistic control tasks and different analysis methods for functional MRI data. Twelve subjects solved two linguistic generation tasks: (1) a verb generation task and (2) an antonym generation task (each with a linguistic control task on the phonological level) as well as two decision tasks of semantic congruency (each with a cognitive high-level control task). Differential contrasts and conjunction analyses were carried out on the single-subject level and an individual lateralization index (LI) was computed. On the group level we determined the percent signal change in the left inferior frontal gyrus (IFG: BA 44 and BA 45). The conjunction analysis of multiple language tasks led to significantly greater absolute LIs than the LIs based on the single task versus fixation contrasts. A further significant increase of the magnitude of the LIs could be achieved by using the phonological control conditions. Although the decision tasks appear to be more robust to changes in the statistical threshold, the combined generation tasks had an advantage over the decision tasks both for assessing language dominance and locating Broca's area. These results underline the need for conjunction analysis based on several language tasks to suppress highly task-specific processes. They also point to the need for high-level cognitive control tasks to partial out general, language supporting but not language critical processes. Higher absolute LIs, which reflect unambiguously hemispheric language dominance, can be thus obtained

Using magnetic resonance imaging to assess visual deficits : a review

PURPOSE: Over the last two decades, magnetic resonance imaging (MRI) has been widely used in neuroscience research to assess both structure and function in the brain in health and disease. With regard to vision research, prior to the advent of MRI, researchers relied on animal physiology and human post-mortem work to assess the impact of eye disease on visual cortex and connecting structures. Using MRI, researchers can non-invasively examine the effects of eye disease on the whole visual pathway, including the lateral geniculate nucleus, striate and extrastriate cortex. This review aims to summarise research using MRI to investigate structural, chemical and functional effects of eye diseases, including: macular degeneration, retinitis pigmentosa, glaucoma, albinism, and amblyopia. RECENT FINDINGS: Structural MRI has demonstrated significant abnormalities within both grey and white matter densities across both visual and non-visual areas. Functional MRI studies have also provided extensive evidence of functional changes throughout the whole of the visual pathway following visual loss, particularly in amblyopia. MR spectroscopy techniques have also revealed several abnormalities in metabolite concentrations in both glaucoma and age-related macular degeneration. GABA-edited MR spectroscopy on the other hand has identified possible evidence of plasticity within visual cortex. SUMMARY: Collectively, using MRI to investigate the effects on the visual pathway following disease and dysfunction has revealed a rich pattern of results allowing for better characterisation of disease. In the future MRI will likely play an important role in assessing the impact of eye disease on the visual pathway and how it progresses over time

Perceptual learning in patients with macular degeneration

Patients with age-related macular degeneration (AMD) or hereditary macular dystrophies (JMD) rely on an efficient use of their peripheral visual field. We trained eight AMD and five JMD patients to perform a texture-discrimination task (TDT) at their preferred retinal locus (PRL) used for fixation. Six training sessions of approximately one hour duration were conducted over a period of approximately 3 weeks. Before, during and after training twelve patients and twelve age-matched controls (the data from two controls had to be discarded later) took part in three functional magnetic resonance imaging (fMRI) sessions to assess training-related changes in the BOLD response in early visual cortex. Patients benefited from the training measurements as indexed by significant decrease (p = 0.001) in the stimulus onset asynchrony (SOA) between the presentation of the texture target on background and the visual mask, and in a significant location specific effect of the PRL with respect to hit rate (p = 0.014). The following trends were observed: (i) improvement in Vernier acuity for an eccentric line-bisection task; (ii) positive correlation between the development of BOLD signals in early visual cortex and initial fixation stability (r = 0.531); (iii) positive correlation between the increase in task performance and initial fixation stability (r = 0.730). The first two trends were non-significant, whereas the third trend was significant at p = 0.014, Bonferroni corrected. Consequently, our exploratory study suggests that training on the TDT can enhance eccentric vision in patients with central vision loss. This enhancement is accompanied by a modest alteration in the BOLD response in early visual cortex

The use of the sodium fluorescein and YELLOW 560 nm filter for the resection of pediatric posterior fossa lesions

Purpose This study aimed to verify the feasibility, safety, and benefit of using fluorescein sodium (FL) and a YELLOW 560 nm filter in posterior fossa tumors in children. Methods All cases of pediatric posterior fossa tumors that have undergone surgery using fluorescein (2018–2022) have been included and were examined retrospectively. In those cases where resection of the tumor was planned, a blinded neuroradiologist distinguished gross total resection and subtotal resection according to the postoperative MRI findings. The surgical report and medical files were reviewed regarding the intraoperative staining grade and adverse events. The grade of fluorescent staining of the targeted lesion was assessed as described in the surgical reports. The screening was conducted for any reference to the degree of fluorescent staining: “intense,” “medium,” “slight,” and “no staining.” Results 19 cases have been included. In 14 cases, a complete resection was initially intended. In 11 of these cases, a gross total resection could be achieved (78.6%). Staining was described as intense in most cases (58.8%). Except for yellow-colored urine, no side effects obviously related to FL were found throughout the observation period. Conclusion In combination with a specific filter, FL is a reliable, safe, and feasible tool in posterior fossa surgery in children

Symptom burden and surgical outcome in non-skull base meningiomas

Purpose: Non-skull base meningiomas (NSBM) are a distinct entity and frequently present with focal neurological deficits. This study was designed to analyze functional and oncological outcome following microsurgical tumor resection in patients with NSBM. Patients and methods: An analysis of 300 patients that underwent NSBM resection between 2003 and 2013 was performed. Assessment reasures for functional outcome were Karnofsky Performance Scale (KPS), Medical Research Council - Neurological Performance Scale (MRC-NPS), and improvement rates of focal deficits and seizures. The extent of resection; recurrence-free survival (RFS) and tumor-specific survival (TSS) were also determined. Results: Impaired KPS and MRC-NPS were present in 73.3% and 45.7%, respectively. Focal neurological deficits were recorded in 123 patients (41.0%), with hemiparesis (21.7%) and aphasia (9.3%) the most prevalent form of impairment. Most meningiomas were localized at the convexity (64.0%), followed by falcine tumors (20.3%). Both KPI and MRC-NPS scores were significantly improved by surgical resection. Postoperative improvement rates of 96.6%, 89.3%, 72.3%, 57.9%, and 27.3% were observed for aphasia, epilepsy, hemiparesis, cranial nerve, and visual field deficits, respectively. Long-term improvement was achieved in 83.2%, 89.3%, 80.0%, 68.4% and 54.6% of patients, respectively. Gross total resection (GTR) over subtotal resection (STR) significantly improved preoperative seizures and visual field deficits and correlated with reduced risk of new postoperative hemiparesis. Poor Simpson grade was the only significant prognostic factor in multivariate analysis for long-term functional deficit, which occurred in 7.3%. Median RFS was 45.9 months (6.0 - 151.5 months), while median TSS was 53.7 months (3.1 – 153.2 months). Both WHO grade (p= 0.001) and Simpson classification (p= 0.014 and p= 0.031) were independent significant prognostic factors for decreased RFS and TSS by multivariate analysis, respectively. Furthermore, tumor diameter > 50 mm (p= 0.039) significantly correlated with decreased TSS in multivariate analysis. Conclusion: Surgical resection significantly and stably improves neurological deficits in patients with NSBM

fMRI Retinotopic Mapping in Patients with Brain Tumors and Space-occupying Brain Lesions in the Area of the Occipital Lobe

Functional magnetic resonance imaging (fMRI) is a valuable tool in the clinical routine of neurosurgery when planning surgical interventions and assessing the risk of postoperative functional deficits. Here, we examined how the presence of a brain tumor or lesion in the area of the occipital lobe affects the results of fMRI retinotopic mapping. fMRI data were evaluated on a retrospectively selected sample of 12 patients with occipital brain tumors, 7 patients with brain lesions and 19 control subjects. Analyses of the cortical activation, percent signal change, cluster size of the activated voxels and functional connectivity were carried out using Statistical Parametric Mapping (SPM12) and the CONN and Marsbar toolboxes. We found similar but reduced patterns of cortical activation and functional connectivity between the two patient groups compared to a healthy control group. Here, we found that retinotopic organization was well-preserved in the patients and was comparable to that of the age-matched controls. The results also showed that, compared to the tumor patients, the lesion patients showed higher percent signal changes but lower values in the cluster sizes of the activated voxels in the calcarine fissure region. Our results suggest that the lesion patients exhibited results that were more similar to those of the control subjects in terms of the BOLD signal, whereas the extent of the activation was comparable to that of the tumor patients

Attenuation of the BOLD fMRI Signal and Changes in Functional Connectivity Affecting the Whole Brain in Presence of Brain Metastasis

To date, there are almost no investigations addressing functional connectivity (FC) in patients with brain metastases (BM). In this retrospective study, we investigate the influence of BM on hemodynamic brain signals derived from functional magnetic resonance imaging (fMRI) and FC. Motor-fMRI data of 29 patients with BM and 29 matched healthy controls were analyzed to assess percent signal changes (PSC) in the ROIs motor cortex, premotor cortex, and supplementary motor cortex and FC in the sensorimotor, default mode, and salience networks using Statistical Parametric Mapping (SPM12) and marsbar and CONN toolboxes. In the PSC analysis, an attenuation of the BOLD signal in the metastases-affected hemisphere compared to the contralateral hemisphere was significant only in the supplementary motor cortex during hand movement. In the FC analysis, we found alterations in patients’ FC compared to controls in all examined networks, also in the hemisphere contralateral to the metastasis. This indicates a qualitative attenuation of the BOLD signal in the affected hemisphere and also that FC is altered by the presence of BM, similarly to what is known for primary brain tumors. This transformation is not only visible in the infiltrated hemisphere, but also in the contralateral one, suggesting an influence of BM beyond local damage

Clinical Benefits of Combining Different Visualization Modalities in Neurosurgery

The prevailing philosophy in oncologic neurosurgery, has shifted from maximally invasive resection to the preservation of neurologic function. The foundation of safe surgery is the multifaceted visualization of the target region and the surrounding eloquent tissue. Recent advancements in pre-operative and intraoperative visualization modalities have changed the face of modern neurosurgery. Metabolic and functional data can be integrated into intraoperative guidance software, and fluorescent dyes under dedicated filters can potentially visualize patterns of blood flow and better define tumor borders or isolated tumor foci. High definition endoscopes enable the depiction of tiny vessels and tumor extension to the ventricles or skull base. Fluorescein sodium-based confocal endomicroscopy, which is under scientific evaluation, may further enhance the neurosurgical armamentarium. We aim to present our institutional workup of combining different neuroimaging modalities for surgical neuro-oncological procedures. This institutional algorithm (IA) was the basis of the recent publication by Haj et al. describing outcome and survival data of consecutive patients with high grade glioma (HGG) before and after the introduction of our Neuro-Oncology Center