Robust Plug-and-Play Joint Axis Estimation Using Inertial Sensors.

Inertial motion capture relies on accurate sensor-to-segment calibration. When two segments are connected by a hinge joint, for example in human knee or finger joints as well as in many robotic limbs, then the joint axis vector must be identified in the intrinsic sensor coordinate systems. Methods for estimating the joint axis using accelerations and angular rates of arbitrary motion have been proposed, but the user must perform sufficiently informative motion in a predefined initial time window to accomplish complete identifiability. Another drawback of state of the art methods is that the user has no way of knowing if the calibration was successful or not. To achieve plug-and-play calibration, it is therefore important that 1) sufficiently informative data can be extracted even if large portions of the data set consist of non-informative motions, and 2) the user knows when the calibration has reached a sufficient level of accuracy. In the current paper, we propose a novel method that achieves both of these goals. The method combines acceleration- and angular rate information and finds a globally optimal estimate of the joint axis. Methods for sample selection, that overcome the limitation of a dedicated initial calibration time window, are proposed. The sample selection allows estimation to be performed using only a small subset of samples from a larger data set as it deselects non-informative and redundant measurements. Finally, an uncertainty quantification method that assures validity of the estimated joint axis parameters, is proposed. Experimental validation of the method is provided using a mechanical joint performing a large range of motions. Angular errors in the order of 2 ∘ were achieved using 125-1000 selected samples. The proposed method is the first truly plug-and-play method that overcome the need for a specific calibration phase and, regardless of the user's motions, it provides an accurate estimate of the joint axis as soon as possible.

Rapid and improved characterization of therapeutic antibodies and antibody related products using IdeS digestion and subunit analysis.

The immunoglobulin degrading enzyme from Streptococcus pyogenes, IdeS, was discovered as a mechanism by which pathogenic bacteria circumvent antibody mediated immune defense. IdeS was found to rapidly and specifically cleave IgG into F(ab')2 and Fc/2 fragments. The enzymatic specificity has led to a range of recent developments in the analytical strategies for characterization of monoclonal therapeutic antibodies and related products such as antibody-drug conjugates, bispecific antibodies, antibody mixtures and Fc-fusion proteins. In this review article we describe the discovery and properties of IdeS, discuss the current challenges in characterizing antibody therapeutics and review the methodologies using IdeS to improve the characterization of therapeutic antibodies. The review is focused on critical quality attributes of the final antibody product as studied by IdeS fragmentation such as Fab- and Fc-glycosylation, oxidation, glycation, C-terminal lysine and others. In summary, this review presents a wide range of IdeS-based applications for improved characterization of originator, biosimilar and next generation antibody-based therapeutics.

Characterization of intermediate steps in amyloid beta (Aß) production under near-native conditions.

Processing of the amyloid precursor protein (APP) by γ-secretase results in generation of Aß peptides of different lengths ranging from 51 to 30 residues. Accumulation of Aß and in particular Aß42 is enhanced by familial Alzheimer disease (FAD) causing mutations in APP and is believed to play a pivotal role. The molecular mechanism underlying normal Aß production, the impact of FAD mutations on this process and how anti-amyloidogenic γ-secretase modulators (GSMs) cause a selective decrease in Aß40 and Aß42 and an increase in shorter Aß peptides, however, is poorly understood. By using a combined immuno- and LC-MS-based assay we identify several major intermediates, i.e. 3- and 4-peptides that line up head to head across the entire APP transmembrane sequence from Aß51 to Aß31/Aß30 and from Aß49 to Aß30/31. FAD APP mutations displayed a relative increase in 3- and 4-peptides from Aß48 to Aß38 compared with Aß49 to Aß37. These findings correlate with an increase in the Aß42/40 ratio. GSMs caused a decrease in Aß40 and Aß42 and an increase in Aß37 and Aß38 paralleled by an increase of the intermediates Aß40-38 and Aß42-39. Collectively, these data provide a thorough characterization of all intermediate steps in Aß production in native cell membranes and provide key mechanistic insights to genetic and pharmacological modulation of Aß generation.

EndoS and EndoS2 hydrolyze Fc-glycans on therapeutic antibodies with different glycoform selectivity and can be used for rapid quantification of high-mannose glycans.

Enzymes that affect glycoproteins of the human immune system, and thereby modulate defense responses, are abundant among bacterial pathogens. Two endoglycosidases from the human pathogen Streptococcus pyogenes, EndoS and EndoS2, have recently been shown to hydrolyze N-linked glycans of human immunoglobulin G. However, detailed characterization and comparison of the hydrolyzing activities have not been performed. In the present study, we set out to characterize the enzymes by comparing the activities of EndoS and EndoS2 on a selection of therapeutic monoclonal antibodies (mAbs), cetuximab, adalimumab, panitumumab and denosumab. By analyzing the glycans hydrolyzed by EndoS and EndoS2 from the antibodies using matrix-assisted laser desorption ionization time of flight, we found that both the enzymes cleaved complex glycans and that EndoS2 hydrolyzed hybrid and oligomannose structures to a greater extent compared with EndoS. A comparison of ultra-high-performance liquid chromatography (LC) profiles of the glycan pool of cetuximab hydrolyzed with EndoS and EndoS2 showed that EndoS2 hydrolyzed hybrid and oligomannose glycans, whereas these peaks were missing in the EndoS chromatogram. We utilized this difference in glycoform selectivity, in combination with the IdeS protease, and developed a LC separation method to quantify high mannose content in the Fc fragments of the selected mAbs. We conclude that EndoS and EndoS2 hydrolyze different glycoforms from the Fc-glycosylation site on therapeutic mAbs and that this can be used for rapid quantification of high mannose content.

Estimation of the variance effective population size in age structured populations.

The variance effective population size for age structured populations is generally hard to estimate and the temporal method often gives biased estimates. Here, we give an explicit expression for a correction factor which, combined with estimates from the temporal method, yield approximately unbiased estimates. The calculation of the correction factor requires knowledge of the age specific offspring distribution and survival probabilities as well as possible correlation between survival and reproductive success. In order to relax these requirements, we show that only first order moments of these distributions need to be known if the time between samples is large, or individuals from all age classes which reproduce are sampled. A very explicit approximate expression for the asymptotic coefficient of standard deviation of the estimator is derived, and it can be used to construct confidence intervals and optimal ways of weighting information from different markers. The asymptotic coefficient of standard deviation can also be used to design studies and we show that in order to maximize the precision for a given sample size, individuals from older age classes should be sampled since their expected variance of allele frequency change is higher and easier to estimate. However, for populations with fluctuating age class sizes, the accuracy of the method is reduced when samples are taken from older age classes with high demographic variation. We also present a method for simultaneous estimation of the variance effective and census population size.

Metapopulation inbreeding dynamics, effective size and subpopulation differentiation--A general analytical approach for diploid organisms.

Motivated by problems in conservation biology we study genetic dynamics in structured populations of diploid organisms (monoecious or dioecious). Our analysis provides an analytical framework that unifies substantial parts of previous work in terms of exact identity by descent (IBD) and identity by state (IBS) recursions. We provide exact conditions under which two structured haploid and diploid populations are equivalent, and some sufficient conditions under which a dioecious diploid population can be treated as a monoecious diploid one. The IBD recursions are used for computing local and metapopulation inbreeding and coancestry effective population sizes and for predictions of several types of fixation indices over different time horizons.

Mutations in mouse Ift144 model the craniofacial, limb and rib defects in skeletal ciliopathies.

Mutations in components of the intraflagellar transport (IFT) machinery required for assembly and function of the primary cilium cause a subset of human ciliopathies characterized primarily by skeletal dysplasia. Recently, mutations in the IFT-A gene IFT144 have been described in patients with Sensenbrenner and Jeune syndromes, which are associated with short ribs and limbs, polydactyly and craniofacial defects. Here, we describe an N-ethyl-N-nitrosourea-derived mouse mutant with a hypomorphic missense mutation in the Ift144 gene. The mutant twinkle-toes (Ift144(twt)) phenocopies a number of the skeletal and craniofacial anomalies seen in patients with human skeletal ciliopathies. Like other IFT-A mouse mutants, Ift144 mutant embryos display a generalized ligand-independent expansion of hedgehog (Hh) signalling, in spite of defective ciliogenesis and an attenuation of the ability of mutant cells to respond to upstream stimulation of the pathway. This enhanced Hh signalling is consistent with cleft palate and polydactyly phenotypes in the Ift144(twt) mutant, although extensive rib branching, fusion and truncation phenotypes correlate with defects in early somite patterning and may reflect contributions from multiple signalling pathways. Analysis of embryos harbouring a second allele of Ift144 which represents a functional null, revealed a dose-dependent effect on limb outgrowth consistent with the short-limb phenotypes characteristic of these ciliopathies. This allelic series of mouse mutants provides a unique opportunity to uncover the underlying mechanistic basis of this intriguing subset of ciliopathies.

Alzheimer's disease: presenilin 2-sparing γ-secretase inhibition is a tolerable Aß peptide-lowering strategy.

γ-Secretase inhibition represents a major therapeutic strategy for lowering amyloid ß (Aß) peptide production in Alzheimer's disease (AD). Progress toward clinical use of γ-secretase inhibitors has, however, been hampered due to mechanism-based adverse events, primarily related to impairment of Notch signaling. The γ-secretase inhibitor MRK-560 represents an exception as it is largely tolerable in vivo despite displaying only a small selectivity between Aß production and Notch signaling in vitro. In exploring the molecular basis for the observed tolerability, we show that MRK-560 displays a strong preference for the presenilin 1 (PS1) over PS2 subclass of γ-secretases and is tolerable in wild-type mice but causes dose-dependent Notch-related side effect in PS2-deficient mice at drug exposure levels resulting in a substantial decrease in brain Aß levels. This demonstrates that PS2 plays an important role in mediating essential Notch signaling in several peripheral organs during pharmacological inhibition of PS1 and provide preclinical in vivo proof of concept for PS2-sparing inhibition as a novel, tolerable and efficacious γ-secretase targeting strategy for AD.

First and second generation γ-secretase modulators (GSMs) modulate amyloid-ß (Aß) peptide production through different mechanisms.

γ-Secretase-mediated cleavage of amyloid precursor protein (APP) results in the production of Alzheimer disease-related amyloid-ß (Aß) peptides. The Aß42 peptide in particular plays a pivotal role in Alzheimer disease pathogenesis and represents a major drug target. Several γ-secretase modulators (GSMs), such as the nonsteroidal anti-inflammatory drugs (R)-flurbiprofen and sulindac sulfide, have been suggested to modulate the Alzheimer-related Aß production by targeting the APP. Here, we describe novel GSMs that are selective for Aß modulation and do not impair processing of Notch, EphB2, or EphA4. The GSMs modulate Aß both in cell and cell-free systems as well as lower amyloidogenic Aß42 levels in the mouse brain. Both radioligand binding and cellular cross-competition experiments reveal a competitive relationship between the AstraZeneca (AZ) GSMs and the established second generation GSM, E2012, but a noncompetitive interaction between AZ GSMs and the first generation GSMs (R)-flurbiprofen and sulindac sulfide. The binding of a (3)H-labeled AZ GSM analog does not co-localize with APP but overlaps anatomically with a γ-secretase targeting inhibitor in rodent brains. Combined, these data provide compelling evidence of a growing class of in vivo active GSMs, which are selective for Aß modulation and have a different mechanism of action compared with the original class of GSMs described.

Characteristics of the variance effective population size over time using an age structured model with variable size.

The variance effective population size (NeV) is a key concept in population biology, because it quantifies the microevolutionary process of random genetic drift, and understanding the characteristics of NeV is thus of central importance. Current formulas for NeV for populations with overlapping generations weight age classes according to their reproductive values (i.e. reflecting the contribution of genes from separate age classes to the population growth) to obtain a correct measure of genetic drift when computing the variance of the allele frequency change over time. In this paper, we examine the effect of applying different weights to the age classes using a novel analytical approach for exploring NeV. We consider a haploid organism with overlapping generations and populations of increasing, declining, or constant expected size and stochastic variation with respect to the number of individuals in the separate age classes. We define NeV, as a function of how the age classes are weighted, and of the span between the two points in time, when measuring allele frequency change. With this model, time profiles for NeV can be calculated for populations with various life histories and with fluctuations in life history composition, using different weighting schemes. We examine analytically and by simulations when NeV, using a weighting scheme with respect to reproductive contribution of separate age classes, accurately reflect the variance of the allele frequency change due to genetic drift over time. We show that the discrepancy of NeV, calculated with reproductive values as weights, compared to when individuals are weighted equally, tends to a constant when the time span between the two measurements increases. This constant is zero only for a population with a constant expected population size. Our results confirm that the effect of ignoring overlapping generations, when empirically assessing NeV from allele frequency shifts, gets smaller as the time interval between samples increases. Our model has empirical applications including assessment of (i) time intervals necessary to permit ignoring the effect of overlapping generations for NeV estimation by means of the temporal method, and (ii) effects of life table manipulation on NeV over varying time periods.

Has inhibition of Aß production adequately been tested as therapeutic approach in mild AD? A model-based meta-analysis of γ-secretase inhibitor data.

PURPOSE: To date, γ-secretase inhibition is the most frequently studied mechanism of reducing Aß in clinical trials with as yet no therapeutic success for AD patients, as measured by the slowing down of cognitive decline or an improvement in cognitive function. The aims of this investigation were to evaluate whether the amyloid hypothesis has been tested clinically, and to explore whether preclinical data are predictive of clinical Aß effects. METHODS: A model-based-meta analysis on Aß levels and drug exposure over time was performed on published and in-house (pre-)clinical data with γ-secretase inhibitors (GSIs; semagacestat, avagacestat, begacestat, PF-3074014, and MK0752). RESULTS: The clinical data available did not show any significant or robust reduction of CNS Aß over time at dose levels intended for AD patients. In contrast, these doses resulted in an average increase in plasma Aß levels over a 24-h interval. A general agreement between preclinical and clinical data was found and allowed for interspecies extrapolations. CONCLUSIONS: More substantially, CNS Aß-lowering drugs are needed to test whether inhibition of Aß production is efficacious in mild AD. Predictions based on preclinical data could assist in the selection of drug candidates and trial design.

Neuromuscular Controller Models for Quantifying Standing Balance in Older People: A Systematic Review.

Objective quantification of the balancing mechanisms in humans is strongly needed in health care of older people, yet is largely missing among current clinical balance assessment methods. Hence, the main goal of this literature review is to identify methods that have the potential to meet that need. We searched in the PubMed and IEEE Xplore databases using predefined criteria, screened 1064 articles, and systematically reviewed and categorized methods from 73 studies that deal with identification of neuromuscular controller models of human upright standing from empirical data. These studies were then analyzed with the particular aim to understand to what degree such methods would be useful solutions for assessing the balance of older individuals aged above 60 years. The 16 studies that included an older subject population were especially examined with this in mind. The majority of the reviewed articles focused on research questions related to the general function of human balance control rather than clinical applicability. Further efforts need to be made to adapt these methods for more accessible and mobile technologies and to ensure that the outcomes are valid for balance assessment of a general older population.

The large hydrophilic loop of presenilin 1 is important for regulating gamma-secretase complex assembly and dictating the amyloid beta peptide (Abeta) Profile without affecting Notch processing.

Gamma-secretase is an enzyme complex that mediates both Notch signaling and beta-amyloid precursor protein (APP) processing, resulting in the generation of Notch intracellular domain, APP intracellular domain, and the amyloid beta peptide (Abeta), the latter playing a central role in Alzheimer disease (AD). By a hitherto undefined mechanism, the activity of gamma-secretase gives rise to Abeta peptides of different lengths, where Abeta42 is considered to play a particular role in AD. In this study we have examined the role of the large hydrophilic loop (amino acids 320-374, encoded by exon 10) of presenilin 1 (PS1), the catalytic subunit of gamma-secretase, for gamma-secretase complex formation and activity on Notch and APP processing. Deletion of exon 10 resulted in impaired PS1 endoproteolysis, gamma-secretase complex formation, and had a differential effect on Abeta-peptide production. Although the production of Abeta38, Abeta39, and Abeta40 was severely impaired, the effect on Abeta42 was affected to a lesser extent, implying that the production of the AD-related Abeta42 peptide is separate from the production of the Abeta38, Abeta39, and Abeta40 peptides. Interestingly, formation of the intracellular domains of both APP and Notch was intact, implying a differential cleavage activity between the epsilon/S3 and gamma sites. The most C-terminal amino acids of the hydrophilic loop were important for regulating APP processing. In summary, the large hydrophilic loop of PS1 appears to differentially regulate the relative production of different Abeta peptides without affecting Notch processing, two parameters of significance when considering gamma-secretase as a target for pharmaceutical intervention in AD.

The Effect of Forward Testing as a Function of Test Occasions and Study Material.

It has long been known that one of the most effective study techniques is to be tested on the to-be-remembered material, a phenomenon known as the testing effect. Recent research has also shown that testing of previous materials promotes the learning of new materials, a phenomenon known as the forward testing effect. In this paper, as of yet unexplored aspects of the forward testing effect related to face-name learning are examined; continuous and initial testing are compared to restudying, the effects of an initial test on subsequent learning, and whether an initial change of domain (change from one topic to another) regarding study material affects the robustness of the effect. An experiment (N = 94) was performed according to a 2 (Material: word pairs/face-name pairs in Block 1) × 3 (Test occasions: Blocks 1-4/Blocks 1 and 4/Block 4) complex between-groups design. The results showed that no difference between testing and repetition could be observed regarding the recall of faces and names. The restudy groups incorrectly recalled more names from previous lists in the last interim test compared to the tested groups, which supports the theory that interim tests reduce proactive interference. The results also suggest that the number of test occasions correlates with the number of incorrect recalls from previous lists. These results, in contrast to previous studies, highlight a potential uncertainty about the forward testing effect linked to the robustness of the phenomenon, the specificity in execution, and generalizability.

Influence of nano-VC on the structural and magnetic properties of MnAlC-alloy.

Alloys of Mn55Al45C2 with additions of VC nano-particles have been synthesized and their properties evaluated. The Mn55Al45C2(VC)x (x = 0.25, 0.5 and 1) alloys have been prepared by induction melting resulting in a high content of the ferromagnetic τ-phase (> 94 wt.%). Powder X-ray diffraction indicates that nano-VC can be dissolved in the alloy matrix up to 1 at.%. On the other side, metallography investigations by scanning electron microscopy and scanning transmission electron microscope show inclusions of the nanosized additives in the microstructure. The effect of nano-VC on the grain and twin boundaries has been studied by electron backscattering diffraction. The magnetization has been measured by magnetometry up to 9 T while the domain structure has been studied using both magnetic force microscopy as well as Kerr-microscopy. For nano-VC contents above 0.25 at.%, a clear increase of the coercive force is observed, from 57 to 71 kA/m. The optimum appears to be for 0.5 at.% nano-VC which shows a 25% increase in coercive force without losing any saturation magnetization. This independent increase in coercivity is believed to originate from the nano-VC reducing the overall magnetic domain size. Overall, we observe that addition of nano-VC could be an interesting route to increase the coercive force of MnAl, without sacrificing saturation magnetization.

Extraction of gait parameters from marker-free video recordings of Timed Up-and-Go tests: Validity, inter- and intra-rater reliability.

BACKGROUND: We study dual-task performance with marker-free video recordings of Timed Up-and-Go tests (TUG) and TUG combined with a cognitive/verbal task (TUG dual-task, TUGdt). RESEARCH QUESTION: Can gait parameters be accurately estimated from video-recorded TUG tests by a new semi-automatic method aided by a technique for human 2D pose estimation based on deep learning? METHODS: Thirty persons aged 60-85 years participated in the study, conducted in a laboratory environment. Data were collected by two synchronous video-cameras and a marker-based optoelectronic motion capture system as gold standard, to evaluate the gait parameters step length (SL), step width (SW), step duration (SD), single-stance duration (SSD) and double-stance duration (DSD). For reliability evaluations, data processing aided by a deep neural network model, involved three raters who conducted three repetitions of identifying anatomical keypoints in recordings of one randomly selected step from each of the participants. Validity was analysed using 95 % confidence intervals (CI) and p-values for method differences and Bland-Altman plots with limits of agreement. Inter- and intra-rater reliability were calculated as intraclass correlation coefficients (ICC) and standard errors of measurement. Smallest detectable change was calculated for inter-rater reliability. RESULTS: Mean ddifferences between video and the motion capture system data for SW, DSD, and SSD were significant (p < 0.001). However, mean differences for all parameters were small (-6.4%-13.0% of motion capture system) indicating good validity. Concerning reliability, almost all 95 % CI of the ICC estimates exceeded 0.90, indicating excellent reliability. Only inter-rater reliability for SW (95 % CI = 0.892;0.973) and one rater's intra-rater reliability for SSD (95 % CI = 0.793;0.951) were lower, but still showed good to excellent reliability. SIGNIFICANCE: The presented method for extraction of gait parameters from video appears suitable for valid and reliable quantification of gait. This opens up for analyses that may contribute to the knowledge of cognitive-motor interference in dual-task testing.

Interleukin-13 regulates secretion of the tumor growth factor-{beta} superfamily cytokine activin A in allergic airway inflammation.

Activin A is a member of the TGF-beta superfamily and plays a role in allergic inflammation and asthma pathogenesis. Recent evidence suggests that activin A regulates proinflammatory cytokine production and is regulated by inflammatory mediators. In a murine model of acute allergic airway inflammation, we observed previously that increased activin A concentrations in bronchoalveolar lavage (BAL) fluid coincide with Th2 cytokine production in lung-draining lymph nodes and pronounced mucus metaplasia in bronchial epithelium. We therefore hypothesized that IL-13, the key cytokine for mucus production, regulates activin A secretion into BAL fluid in experimental asthma. IL-13 increased BAL fluid activin A concentrations in naive mice and dose dependently induced activin A secretion from cultured human airway epithelium. A key role for IL-13 in the secretion of activin A into the BAL fluid during allergic airway inflammation was confirmed in IL-13-deficient mice. Eosinophils were not involved in this response because there was no difference in BAL fluid activin A concentrations between wild-type and eosinophil-deficient mice. Our data highlight an important role for IL-13 in the regulation of activin A intraepithelially and in BAL fluid in naive mice and during allergic airway inflammation. Given the immunomodulatory and fibrogenic effects of activin A, our findings suggest an important role for IL-13 regulation of activin A in asthma pathogenesis.

Antibody Conjugations via Glycosyl Remodeling.

The antibody Fc-glycans are interesting targets for conjugation of cytotoxic compounds due to their localization and their chemical composition. In striving to obtain site-specific conjugates, the antibody Fc-glycans have been explored in numerous ways. Here we present a two-step enzymatic methodology coupled to click-chemistry for conjugation at the core GlcNAc of the Fc-glycan resulting in ADCs that are homogenous with a DAR 2.0, retain antigen binding, and display cytotoxic anti-tumor effects both in vitro and in vivo.

Analysis of the network of feeding neuroregulators using the Allen Brain Atlas.

The Allen Brain Atlas, the most comprehensive in situ hybridization database, covers over 21,000 genes expressed in the mouse brain. Here we discuss the feasibility to utilize the ABA in research pertaining to the central regulation of feeding and we define advantages and vulnerabilities associated with the use of the atlas as a guidance tool. We searched for 57 feeding-related genes in the ABA, and of those 42 display distribution consistent with that described in previous reports. Detailed analyses of these 42 genes in the nucleus accumbens, ventral tegmental area, nucleus of the solitary tract, lateral hypothalamus, arcuate, paraventricular, ventromedial and dorsomedial nuclei suggests that molecules involved in feeding stimulation and termination are coexpressed in multiple consumption-related sites. Gene systems linked to energy needs, reward or satiation display a remarkably high level of overlap. This conclusion calls into question the classical concept of brain sites viewed as independent hunger or reward "centers" and favors the theory of a widespread feeding network comprising multiple neuroregulators affecting numerous aspects of consumption.

Expression profile of the entire family of Adhesion G protein-coupled receptors in mouse and rat.

BACKGROUND: The Adhesion G protein-coupled receptors (GPCRs) are membrane-bound receptors with long N termini. This family has 33 members in humans. Several Adhesion GPCRs are known to have important physiological functions in CNS development and immune system response mediated by large cell surface ligands. However, the majority of Adhesion GPCRs are still poorly studied orphans with unknown functions. RESULTS: In this study we performed the extensive tissue localization analysis of the entire Adhesion GPCR family in rat and mouse. By applying the quantitative real-time PCR technique we have produced comparable expression profile for each of the members in the Adhesion family. The results are compared with literature data and data from the Allen Brain Atlas project. Our results suggest that the majority of the Adhesion GPCRs are either expressed in the CNS or ubiquitously. In addition the Adhesion GPCRs from the same phylogenetic group have either predominant CNS or peripheral expression, although each of their expression profile is unique. CONCLUSION: Our findings indicate that many of Adhesion GPCRs are expressed, and most probably, have function in CNS. The related Adhesion GPCRs are well conserved in their structure and interestingly have considerable overlap in their expression profiles, suggesting similarities among the physiological roles for members within many of the phylogenetically related clusters.