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Head and pelvis vertical movement asymmetries in horses are often evaluated under different conditions yet better understanding is required of how these asymmetries are altered by factors such as surface type or circle size. This study investigated how stride duration, surface and lungeing in circles of different sizes influenced objectively measured head and pelvis movement asymmetries in riding horses in full training. Movement asymmetries were recorded with body mounted accelerometers and were based on the differences between the two vertical displacement minima or maxima of head (HDmin, HDmax) and pelvis (PDmin, PDmax) within a stride cycle. Each horse was evaluated during straight-line trot and during lungeing (d = 10m/15m) on hard and soft surfaces at slow and fast speed (determined by stride duration). All horses (N = 76) had at least one movement asymmetry parameter above a predefined thresholds (|HDmin| or |HDmax| >6mm, |PDmin| or |PDmax| >3mm) during a straight line trot on hard surface (baseline). The horses were assigned to a ‘predominant asymmetry’ group (HDmin, HDmax, PDmin, PDmax) based on which movement asymmetry parameter was the greatest during the baseline condition; the head movement asymmetry values were divided by two to account for the difference in magnitude of the thresholds. Analysis was carried out for each predominant asymmetry group separately using linear mixed models—outcome variable: predominant asymmetry parameter; random factor: horse; fixed factors: surface, direction with stride duration as covariate (P<0.05, Bonferroni post-hoc correction). The ‘direction’ conditions were either a straight-line locomotion (‘straight’) or lungeing with lungeing conditions further classified by circle diameter and by whether the limb which the predominant asymmetry was assigned to (‘assigned limb’) was on the inside or outside of the circle (‘inside10’, ‘inside15’, ‘outside10’, ‘outside15’). Only parameters related to asymmetrical weight-bearing between contralateral limbs (HDmin, PDmin) were affected by changes in stride duration–the most common pattern was an increase in asymmetries as stride duration decreased. Only pelvic movement asymmetries were affected by lungeing. When the assigned hindlimb was on the inside of the circle, the PDmin asymmetries increased and PDmax asymmetries decreased compared to the straight-line condition. With the assigned hindlimb on the outside, PDmin asymmetries decreased but PDmax asymmetries did not change. Trotting on 10 m circle compared to 15 m circle did not increase movement asymmetries. In conclusion, circular motion and changes in stride duration altered movement asymmetries identified in horses in full ridden work but no changes were seen between the soft and hard surfaces. These patterns should be further investigated in clinically lame horses.

Although spontaneous protein crystallization is a rare event in vivo, Charcot-Leyden crystals (CLCs) consisting of galectin-10 (Gal10) protein are frequently observed in eosinophilic diseases, such as asthma. We found that CLCs derived from patients showed crystal packing and Gal10 structure identical to those of Gal10 crystals grown in vitro. When administered to the airways, crystalline Gal10 stimulated innate and adaptive immunity and acted as a type 2 adjuvant. By contrast, a soluble Gal10 mutein was inert. Antibodies directed against key epitopes of the CLC crystallization interface dissolved preexisting CLCs in patient-derived mucus within hours and reversed crystal-driven inflammation, goblet-cell metaplasia, immunoglobulin E (IgE) synthesis, and bronchial hyperreactivity (BHR) in a humanized mouse model of asthma. Thus, protein crystals may promote hallmark features of asthma and are targetable by crystal-dissolving antibodies.

A high proportion of horses in training, perceived as free from lameness by their owner, exhibit vertical movement asymmetries. These types of asymmetries are sensitive measures of lameness, but their specificity as indicators of orthopaedic pathology or locomotor function remains unclear. Equine athletes performing at a high level could be assumed to exhibit a higher degree of movement symmetry compared with the general horse population, but this has not been confirmed. This study investigated the prevalence of movement asymmetries in horses performing at a high level in three equestrian disciplines; show jumping, dressage and eventing, as well as the association between riders’ perception of horse sidedness and said movement asymmetries. Using an inertial measurement unit-based system (Equinosis), gait analysis was performed on 123 high-performing horses. The mean difference between the two vertical minimum and between the two maximum values of each stride was recorded for the head (HD min , HD max ) and pelvis (PD min , PD max ). The horses were defined as asymmetric if one or multiple asymmetry parameters exceeded an absolute trial mean of: >6mm for HD min or HD max , and >3mm for PD min or PD max , with standard deviation less than the respective mean value. Based on the results, 70% of the horses were classified as asymmetric, which is similar to previous findings for young riding horses and horses competing at a lower level. More than one-third of these high-performing horses had asymmetry values of similar magnitude to those seen in clinically lame horses. No clear associations were observed between rider-perceived sidedness and the vertical movement asymmetry values, indicating that the perceived unevenness between sides is not a determinant of vertical movement asymmetry. Longitudinal studies on movement asymmetries in relation to training intensity and full clinical examinations with local or systemic analgesic testing are desired as further research to determine whether these movement asymmetries indicate a welfare problem.

Skeletal metastatic disease is a deleterious consequence of dissemination of tumor cells from numerous primary sites, such as prostate, lung and breast. Skeletal metastases are still incurable, resulting in development of clinical complications and decreased survival for cancer patients with metastatic disease. During the last decade, tumor cell-derived microvesicles have been identified and suggested to be involved in cancer disease progression. Whether cancer exosomes are involved in tumor and bone cell interactions in the metastatic site is still, however, a rather unexplored field. Here we show that exosomes isolated from the murine prostate cancer cell line TRAMP-C1 dramatically decrease fusion and differentiation of monocytic osteoclast precursors to mature, multinucleated osteoclasts. The presence of tumor cell-derived exosomes also clearly decreased the expression of established markers for osteoclast fusion and differentiation, including DC-STAMP, TRAP, cathepsin K, and MMP-9. In contrast, exosomes derived from murine fibroblastic cells did not affect osteoclast formation. Our findings suggest that exosomes released from tumor cells in the tumor-bone interface are involved in pathological regulation of bone cell formation in the metastatic site. This further strengthens the role of tumor cell-derived microvesicles in cancer progression and disease aggressiveness.

Many horses, just before and during their athletic career, show vertical movement asymmetries, to the same degree as clinically lame horses. It is unknown whether these asymmetries are caused by pain or have alternative explanations, such as inherent biological variation. In the latter case, movement asymmetries would be expected to be present at a very young age. This study aimed to investigate the prevalence of movement asymmetries in foals. Motion analysis, using an inertial measurement unit-based system (Equinosis), was performed on 54 foals (31 Swedish Warmbloods, 23 Standardbreds) during straight-line trot. The foals were between 4–13 weeks old and considered sound by their owners. Differences between the vertical minimum and maximum values recorded for the head (HD min , HD max ) and pelvis (PD min , PD max ) between left and right stance were calculated for each stride and an average was computed for each trial. Thresholds for asymmetry were defined as absolute trial mean >6 mm for HD min and HD max , and >3 mm for PD min and PD max . These thresholds were exceeded for one or several parameters by 83% of Standardbred foals and 45% of Swedish Warmblood foals, demonstrating surprisingly high prevalence of asymmetries in young foals, although the risk of repetitive strain injuries and cumulative risk of trauma injuries was expected to be low in this age group. Standardbred foals showed similar prevalence of asymmetries to that reported previously for yearling Standardbred trotters, so relatively higher prevalence of movement asymmetries may be expected among trotters as a breed. In general, vertical head and pelvic movement asymmetries can be anticipated among foals considered sound by their owners. A better understanding of the aetiology of asymmetries is needed for correct interpretation of objective symmetry measurements in different populations of horses.

The prevalence of vertical asymmetries is high in “owner-sound” warmblood riding horses, however the origin of these asymmetries is unknown. This study investigated correlations between vertical asymmetries and motor laterality. Young warmblood riding horses (N = 65), perceived as free from lameness were evaluated on three visits, each comprising objective gait analysis (inertial measurement units system) and a rider questionnaire on perceived sidedness of the horse. A subgroup (N = 40) of horses were also subjected to a forelimb protraction preference test intended as an assessment of motor laterality. We hypothesized associations between vertical asymmetry and motor laterality as well as rider-perceived sidedness. Vertical asymmetry was quantified as trial means of the stride-by-stride difference between the vertical displacement minima and maxima of the head (HDmin, HDmax) and pelvis (PDmin, PDmax). Laterality indexes, based on counts of which limb was protracted, and binomial tests were used to draw conclusions from the preference tests. In the three visits, 60–70% of horses exhibited vertical asymmetries exceeding clinically used thresholds for ≥1 parameter, and 22% of horses exhibited a side preference in the preference test as judged by binomial tests. Linear mixed models identified a weak but statistically significant correlation between perceived hindlimb weakness and higher PDmin values attributable to either of the hindlimbs (p = 0.023). No other statistically significant correlations to vertical asymmetry were seen for any of the questionnaire answers tested. Tests of correlation between the absolute values of laterality index and asymmetry parameters (HDmin, HDmax, PDmin, PDmax) identified a weak correlation (p = 0.049) with PDmax, but when accounting for the direction of asymmetry and motor laterality, no correlations were seen for either of the asymmetry parameters. No convincing evidence of associations between vertical asymmetries and motor laterality were seen and further studies investigating motor laterality and the origin of vertical asymmetries are needed.

Detailed knowledge of how a rider's seating style and riding on a circle influences the movement symmetry of the horse's head and pelvis may aid rider and trainer in an early recognition of low grade lameness. Such knowledge is also important during both subjective and objective lameness evaluations in the ridden horse in a clinical setting. In this study, inertial sensors were used to assess how different rider seating styles may influence head and pelvic movement symmetry in horses trotting in a straight line and on the circle in both directions. A total of 26 horses were subjected to 15 different conditions at trot: three unridden conditions and 12 ridden conditions where the rider performed three different seating styles (rising trot, sitting trot and two point seat). Rising trot induced systematic changes in movement symmetry of the horses. The most prominent effect was decreased pelvic rise that occurred as the rider was actively rising up in the stirrups, thus creating a downward momentum counteracting the horses push off. This mimics a push off lameness in the hindlimb that is in stance when the rider sits down in the saddle during the rising trot. On the circle, the asymmetries induced by rising trot on the correct diagonal counteracted the circle induced asymmetries, rendering the horse more symmetrical. This finding offers an explanation to the equestrian tradition of rising on the 'correct diagonal.' In horses with small pre-existing movement asymmetries, the asymmetry induced by rising trot, as well as the circular track, attenuated or reduced the horse's baseline asymmetry, depending on the sitting diagonal and direction on the circle. A push off hindlimb lameness would be expected to increase when the rider sits during the lame hindlimb stance whereas an impact hindlimb lameness would be expected to decrease. These findings suggest that the rising trot may be useful for identifying the type of lameness during subjective lameness assessment of hindlimb lameness. This theory needs to be studied further in clinically lame horses.

Activation of classical and lectin complement pathways contributes to several human diseases. Empasiprubart is a humanized recycling monoclonal antibody that inhibits both pathways by binding to the CCP2 domain of complement factor 2 (C2), an interaction that is dependent on both Ca 2+ and pH. Here, we resolve the crystal structure of empasiprubart complexed with C2, providing the molecular basis of its Ca 2+ dependency, and report a randomized, double-blind, placebo-controlled trial to assess the safety and tolerability (primary objectives) in addition to pharmacokinetics, pharmacodynamics, and immunogenicity (secondary objectives) of empasiprubart in 78 healthy participants (NCT04532125). A single intravenous (IV) dose of empasiprubart reduces circulating C2 levels by up to 99% and dose-dependently inhibits the classical and lectin pathways. Multiple IV empasiprubart doses reinforce reductions in free C2 levels, which persist until the endpoint of the study at 41 weeks. This prolonged reduction is in line with the empasiprubart elimination half-life (70–88 days). Single and multiple ascending doses of empasiprubart are generally safe and well tolerated. Overall, our results reveal in atomic detail the mechanism of empasiprubart and demonstrate that it is a first-in-class anti-C2 therapeutic antibody for use in complement-mediated diseases. Though the complement system is pivotal in the defence against infections, pathologic activation of the system contributes to disease. Here, authors show that their recently developed monoclonal antibody against complement factor 2, empasiprubart, inhibits the classical and lectin pathways in a clinical trial, and its crystal structure provides basis for its inhibitory properties, such as Ca 2+ binding.

Objectively assessing horse movement symmetry as an adjunctive to the routine lameness evaluation is on the rise with several commercially available systems on the market. Prerequisites for quantifying such symmetries include knowledge of the gait and gait events, such as hoof to ground contact patterns over consecutive strides. Extracting this information in a robust and reliable way is essential to accurately calculate many kinematic variables commonly used in the field. In this study, optical motion capture was used to measure 222 horses of various breeds, performing a total of 82 664 steps in walk and trot under different conditions, including soft, hard and treadmill surfaces as well as moving on a straight line and in circles. Features were extracted from the pelvis and withers vertical movement and from pelvic rotations. The features were then used in a quadratic discriminant analysis to classify gait and to detect if the left/right hind limb was in contact with the ground on a step by step basis. The predictive model achieved 99.98% accuracy on the test data of 120 horses and 21 845 steps, all measured under clinical conditions. One of the benefits of the proposed method is that it does not require the use of limb kinematics making it especially suited for clinical applications where ease of use and minimal error intervention are a priority. Future research could investigate the extension of this functionality to classify other gaits and validating the use of the algorithm for inertial measurement units.

Background Orthology inference is normally based on full-length protein sequences. However, most proteins contain independently folding and recurring regions, domains. The domain architecture of a protein is vital for its function, and recombination events mean individual domains can have different evolutionary histories. It has previously been shown that orthologous proteins may differ in domain architecture, creating challenges for orthology inference methods operating on full-length sequences. We have developed Domainoid, a new tool aiming to overcome these challenges faced by full-length orthology methods by inferring orthology on the domain level. It employs the InParanoid algorithm on single domains separately, to infer groups of orthologous domains. Results This domain-oriented approach allows detection of discordant domain orthologs, cases where different domains on the same protein have different evolutionary histories. In addition to domain level analysis, protein level orthology based on the fraction of domains that are orthologous can be inferred. Domainoid orthology assignments were compared to those yielded by the conventional full-length approach InParanoid, and were validated in a standard benchmark. Conclusions Our results show that domain-based orthology inference can reveal many orthologous relationships that are not found by full-length sequence approaches. Availability https://bitbucket.org/sonnhammergroup/domainoid/