Functionally specific binding regions of microtubule-associated protein 2c exhibit distinct conformations and dynamics

Microtubule-associated protein 2c (MAP2c) is a 49-kDa intrinsically disordered protein regulating the dynamics of microtubules in developing neurons. MAP2c differs from its sequence homologue Tau in the pattern and kinetics of phosphorylation by cAMP-dependent protein kinase (PKA). Moreover, the mechanisms through which MAP2c interacts with its binding partners and the conformational changes and dynamics associated with these interactions remain unclear. Here, we used NMR relaxation and paramagnetic relaxation enhancement techniques to determine the dynamics and long-range interactions within MAP2c. The relaxation rates revealed large differences in flexibility of individual regions of MAP2c, with the lowest flexibility observed in the known and proposed binding sites. Quantitative conformational analyses of chemical shifts, small-angle X-ray scattering (SAXS), and paramagnetic relaxation enhancement measurements disclosed that MAP2c regions interacting with important protein partners, including Fyn tyrosine kinase, plectin, and PKA, adopt specific conformations. High populations of polyproline II and alpha-helices were found in Fyn- and plectin-binding sites of MAP2c, respectively. The region binding the regulatory subunit of PKA consists of two helical motifs bridged by a more extended conformation. Of note, although MAP2c and Tau did not differ substantially in their conformations in regions of high sequence identity, we found that they differ significantly in long-range interactions, dynamics, and local conformation motifs in their N-terminal domains. These results highlight that the N-terminal regions of MAP2c provide important specificity to its regulatory roles and indicate a close relationship between MAP2c's biological functions and conformational behavior

The Way to a Man's Heart Is through His Stomach: What about Horses?

International audienceBACKGROUND: How do we bond to one another? While in some species, like humans, physical contact plays a role in the process of attachment, it has been suggested that tactile contact's value may greatly differ according to the species considered. Nevertheless, grooming is often considered as a pleasurable experience for domestic animals, even though scientific data is lacking. On another hand, food seems to be involved in the creation of most relationships in a variety of species. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we used the horse training context to test the effects of food versus grooming during repeated human-horse interactions. The results reveal that food certainly holds a key role in the attachment process, while tactile contact was here clearly insufficient for bonding to occur. CONCLUSION/SIGNIFICANCE: This study raises important questions on the way tactile contact is perceived, and shows that large inter-species differences are to be expected

Plos Med

Background The ε4 allele of apolipoprotein E (APOE) gene and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The diagnosis of AD based on clinical symptoms alone is known to have poor specificity; recently developed diagnostic criteria based on biomarkers that reflect underlying AD neuropathology allow better assessment of the strength of the associations of risk factors with AD. Accordingly, we examined the global and age-specific association between APOE genotype and AD by using the A/T/N classification, relying on the cerebrospinal fluid (CSF) levels of β-amyloid peptide (A, β-amyloid deposition), phosphorylated tau (T, pathologic tau), and total tau (N, neurodegeneration) to identify patients with AD. Methods and findings This case–control study included 1,593 white AD cases (55.4% women; mean age 72.8 [range = 44–96] years) with abnormal values of CSF biomarkers from nine European memory clinics and the American Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. A total of 11,723 dementia-free controls (47.1% women; mean age 65.6 [range = 44–94] years) were drawn from two longitudinal cohort studies (Whitehall II and Three-City), in which incident cases of dementia over the follow-up were excluded from the control population. Odds ratio (OR) and population attributable fraction (PAF) for AD associated with APOE genotypes were determined, overall and by 5-year age categories. In total, 63.4% of patients with AD and 22.6% of population controls carried at least one APOE ε4 allele. Compared with non-ε4 carriers, heterozygous ε4 carriers had a 4.6 (95% confidence interval 4.1–5.2; p < 0.001) and ε4/ε4 homozygotes a 25.4 (20.4–31.2; p < 0.001) higher OR of AD in unadjusted analysis. This association was modified by age (p for interaction < 0.001). The PAF associated with carrying at least one ε4 allele was greatest in the 65–70 age group (69.7%) and weaker before 55 years (14.2%) and after 85 years (22.6%). The protective effect of APOE ε2 allele for AD was unaffected by age. Main study limitations are that analyses were based on white individuals and AD cases were drawn from memory centers, which may not be representative of the general population of patients with AD. Conclusions In this study, we found that AD diagnosis based on biomarkers was associated with APOE ε4 carrier status, with a higher OR than previously reported from studies based on only clinical AD criteria. This association differs according to age, with the strongest effect at 65–70 years. These findings highlight the need for early interventions for dementia prevention to mitigate the effect of APOE ε4 at the population level

The influence of Mg2+coordination on13C and15N chemical shifts in CKI1RDprotein domain from experiment and molecular dynamics/density functional theory calculations

Sequence dependence of13C and15N chemical shifts in the receiver domain of CKI1 protein from Arabidopsis thaliana, CKI1RD, and its complexed form, CKI1RD•Mg2+, was studied by means of MD/DFT calculations. MD simulations of a 20-ns production run length were performed. Nine explicitly hydrated structures of increasing complexity were explored, up to a 40-amino-acid structure. The size of the model necessary depended on the type of nucleus, the type of amino acid and its sequence neighbors, other spatially close amino acids, and the orientation of amino acid NH groups and their surface/interior position. Using models covering a 10 and a 15 Å environment of Mg2+, a semi-quantitative agreement has been obtained between experiment and theory for the V67-I73 sequence. The influence of Mg2+binding was described better by the 15 Å as compared to the 10 Å model. Thirteen chemical shifts were analyzed in terms of the effect of Mg2+insertion and geometry preparation. The effect of geometry was significant and opposite in sign to the effect of Mg2+binding. The strongest individual effects were found for15N of D70, S74, and V68, where the electrostatics dominated; for13Cβ of D69 and15N of K76, where the influences were equal, and for13Cα of F72 and13Cβ of K76, where the geometry adjustment dominated. A partial correlation between dominant geometry influence and torsion angle shifts upon the coordination has been observed. © 2016 Wiley Periodicals, Inc

Commissioning Monte Carlo algorithm for robotic radiosurgery using cylindrical 3D-array with variable density inserts.

peer reviewed[en] INTRODUCTION: To commission the Monte Carlo (MC) algorithm based model of CyberKnife robotic stereotactic system (CK) and evaluate the feasibility of patient specific QA using the ArcCHECK cylindrical 3D-array (AC) with Multiplug inserts (MP). RESULTS: Four configurations were used for simple beam setup and two for patient QA, replacing water equivalent inserts by lung. For twelve collimators (5-60mm) in simple setup, mean (SD) differences between MC and RayTracing algorithm (RT) of the number of points failing the 3%/1mmgamma criteria were 1(1), 1(3), 1(2) and 1(2) for the four MP configurations. Tracking fiducials were placed within AC for patient QA. Single lung insert setup resulted in mean gamma-index 2%/2mm of 90.5% (range [74.3-95.9]) and 82.3% ([66.8-94.5]) for MC and RT respectively, while 93.5% ([86.8-98.2]) and 86.2% ([68.7-95.4]) in presence of largest inhomogeneities, showing significant differences (p<0.05). DISCUSSION: After evaluating the potential effects, 1.12g/cc PMMA and 0.09g/cc lung material assignment showed the best results. Overall, MC-based model showed superior results compared to RT for simple and patient specific testing, using a 2%/2mm criteria. Results are comparable with other reported commissionings for flattening filter free (FFF) delivery. Further improvement of MC calculation might be challenging as Multiplan has limited material library. CONCLUSIONS: The AC with Multiplug allowed for comprehensive commissioning of CyberKnife MC algorithm and is useful for patient specific QA for stereotactic body radiation therapy. MC calculation accuracy might be limited due to Multiplan's insufficient material library; still results are comparable with other reported commissioning measurements using FFF beams

Prediction of GTV median dose differences eases Monte Carlo re-prescription in lung SBRT.

peer reviewed[en] BACKGROUND AND PURPOSE: The use of Monte Carlo (MC) dose calculation algorithm for lung patients treated with stereotactic body radiotherapy (SBRT) can be challenging. Prescription in low density media and time-consuming optimization conducted CyberKnife centers to propose an equivalent path length (EPL)-to-MC re-prescription method based on GTV median dose. Unknown at the time of planning, GTV D50% practical application remains difficult. The current study aims at creating a re-prescription predictive model in order to limit conflicting dose value during EPL optimization. MATERIAL AND METHODS: 129 patients planned with EPL algorithm were recalculated with MC. Relative GTV_D50% discrepancies were assessed and influencing parameters identified using wrapper feature selection. Based on best descriptive parameters, predictive nomogram was built from multivariate linear regression. EPL-to-MC OARs near max-dose discrepancies were reported. RESULTS: The differences in GTV_D50% (median 10%, SD: 9%) between MC and EPL were significantly (p < .001) impacted by the lesion's surface-to-volume ratio and the average relative electronic density of the GTV and the GTV's 15 mm shell. Built upon those parameters, a nomogram (R2 = 0.79, SE = 4%) predicting the GTV_D50% discrepancies was created. Furthermore EPL-to-MC OAR dose tolerance limit showed a strong linear correlation with coefficient range [0.84-0.99]. CONCLUSION: Good prediction on the required re-prescription can be achieved prior planning using our nomogram. Based on strong linear correlation between EPL and MC for OARs near max-dose, further restriction on dose constraints during the EPL optimization can be warranted. This a priori knowledge eases the re-prescription process in limiting conflicting dose value

Structure and Functions of Microtubule Associated Proteins Tau and MAP2c: Similarities and Differences

The stability and dynamics of cytoskeleton in brain nerve cells are regulated by microtubule associated proteins (MAPs), tau and MAP2. Both proteins are intrinsically disordered and involved in multiple molecular interactions important for normal physiology and pathology of chronic neurodegenerative diseases. Nuclear magnetic resonance and cryo-electron microscopy recently revealed propensities of MAPs to form transient local structures and long-range contacts in the free state, and conformations adopted in complexes with microtubules and filamentous actin, as well as in pathological aggregates. In this paper, we compare the longest, 441-residue brain isoform of tau (tau40), and a 467-residue isoform of MAP2, known as MAP2c. For both molecules, we present transient structural motifs revealed by conformational analysis of experimental data obtained for free soluble forms of the proteins. We show that many of the short sequence motifs that exhibit transient structural features are linked to functional properties, manifested by specific interactions. The transient structural motifs can be therefore classified as molecular recognition elements of tau40 and MAP2c. Their interactions are further regulated by post-translational modifications, in particular phosphorylation. The structure-function analysis also explains differences between biological activities of tau40 and MAP2c

« In partibus fidelium ». Missions du Levant et connaissance de l’Orient chrétien (XIXe-XXIe siècles)

En quoi les missions chrétiennes du Levant ont-elles été des lieux de production de savoirs « orientaux » ? Comment ces connaissances ont-elles circulé de part et d’autre de la Méditerranée ? Comment ont-elles été reformulées et réappropriées localement ? Cet ouvrage se penche sur l’assimilation en Europe de connaissances relatives aux cultures chrétiennes-orientales et sur le rôle que les missions ont joué dans ce processus. Collectés et élaborés dans les grandes bibliothèques et universités européennes, puis intégrés par les structures de gouvernance des Églises, ces nouveaux savoirs ont aussi été réappropriés dans l’espace d’où ils étaient issus. Ils ont donné lieu à des prises de conscience patrimoniales à côté des expériences tragiques de la fin de l’Empire ottoman et de l’établissement de nouveaux États. Ce travail éclaire ainsi la dimension intellectuelle des dynamiques d’arabisation des Églises locales, de reformulation des frontières confessionnelles et de construction d’identités communautaires et nationales au Moyen-Orient. Il montre enfin comment les missions contribuent à la mise en valeur du patrimoine culturel oriental, et comment le domaine du savoir participe d’une évolution de la notion de mission depuis la période ottomane. In what ways were the Christian missions in the Levant places of production of 'oriental' knowledge? Many late nineteenth and early twentieth-century academics utilised knowledge production from Christian missions, notably by way of scholarly Orientalism. However, the history of this knowledge is also a history of representations: while missionary knowledge helped showcase the cultural and religious traditions of Eastern Christianity, what were the underlying motives and especially the consequences? This book examines the formulation and circulation of Eastern Christian knowledge on either side of the Mediterranean, the study of which is sometimes rooted in non-Anglophone academic traditions. The aim is to shed light on how knowledge relating to Eastern Christianity was assimilated in Europe, as well as the role missions played in this process, especially from the last third of the nineteenth century, when the institutions and instruments for the circulation of knowledge emerged. Another objective is to address the circulations and transformations of this knowledge on either side of the Mediterranean: collected and developed in major European libraries and universities, it was integrated by the governance structures of churches, but quite often also returned to the space it originated from, where it was reappropriated and gave rise to patrimonial processes, notably alongside the sometimes tragic experiences of certain communities during the end of the Ottoman Empire and the establishment of new states. Christian missions, at the intersection of East and West, were at the heart of this dynamic

Dispersal strategies, few dominating or many coexisting: the effect of environmental spatial structure and multiple sources of mortality.

Interspecific competition, life history traits, environmental heterogeneity and spatial structure as well as disturbance are known to impact the successful dispersal strategies in metacommunities. However, studies on the direction of impact of those factors on dispersal have yielded contradictory results and often considered only few competing dispersal strategies at the same time. We used a unifying modeling approach to contrast the combined effects of species traits (adult survival, specialization), environmental heterogeneity and structure (spatial autocorrelation, habitat availability) and disturbance on the selected, maintained and coexisting dispersal strategies in heterogeneous metacommunities. Using a negative exponential dispersal kernel, we allowed for variation of both species dispersal distance and dispersal rate. We showed that strong disturbance promotes species with high dispersal abilities, while low local adult survival and habitat availability select against them. Spatial autocorrelation favors species with higher dispersal ability when adult survival and disturbance rate are low, and selects against them in the opposite situation. Interestingly, several dispersal strategies coexist when disturbance and adult survival act in opposition, as for example when strong disturbance regime favors species with high dispersal abilities while low adult survival selects species with low dispersal. Our results unify apparently contradictory previous results and demonstrate that spatial structure, disturbance and adult survival determine the success and diversity of coexisting dispersal strategies in competing metacommunities