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1.  Genetic regulation of canine skeletal traits: trade-offs between the hind limbs and forelimbs in the fox and dog 
Genetic variation in functionally integrated skeletal traits can be maintained over 10 million years despite bottlenecks and stringent selection. Here, we describe an analysis of the genetic architecture of the canid axial skeleton using populations of the Portuguese Water Dog Canis familiaris) and silver fox (Vulpes vulpes). Twenty-one skeletal metrics taken from radiographs of the forelimbs and hind limbs of the fox and dog were used to construct separate anatomical principal component (PC) matrices of the two species. In both species, 15 of the 21 PCs exhibited significant heritability, ranging from 25% to 70%. The second PC, in both species, represents a trade-off in which limb-bone width is inversely correlated with limb-bone length. PC2 accounts for approximately 15% of the observed skeletal variation, ~30% of the variation in shape. Many of the other significant PCs affect very small amounts of variation (e.g., 0.2–2%) along trade-off axes that partition function between the forelimbs and hind limbs. These PCs represent shape axes in which an increase in size of an element of the forelimb is associated with a decrease in size of an element of the hind limb and vice versa. In most cases, these trade-offs are heritable in both species and genetic loci have been identified in the Portuguese Water Dog for many of these. These PCs, present in both the dog and the fox, include ones that affect lengths of the forelimb versus the hind limb, length of the forefoot versus that of the hind foot, muscle moment (i.e., lever) arms of the forelimb versus hind limb, and cortical thickness of the bones of the forelimb versus hind limb. These inverse relationships suggest that genetic regulation of the axial skeleton results, in part, from the action of genes that influence suites of functionally integrated traits. Their presence in both dogs and foxes suggests that the genes controlling the regulation of these PCs of the forelimb versus hind limb may be found in other tetrapod taxa.
PMCID: PMC2367254  PMID: 18458753
2.  Heritabilities of Directional Asymmetry in the Fore- and Hindlimbs of Rabbit Fetuses 
PLoS ONE  2013;8(10):e76358.
Directional asymmetry (DA), where at the population level symmetry differs from zero, has been reported in a wide range of traits and taxa, even for traits in which symmetry is expected to be the target of selection such as limbs or wings. In invertebrates, DA has been suggested to be non-adaptive. In vertebrates, there has been a wealth of research linking morphological asymmetry to behavioural lateralisation. On the other hand, the prenatal expression of DA and evidences for quantitative genetic variation for asymmetry may suggest it is not solely induced by differences in mechanic loading between sides. We estimate quantitative genetic variation of fetal limb asymmetry in a large dataset of rabbits. Our results showed a low but highly significant level of DA that is partially under genetic control for all traits, with forelimbs displaying higher levels of asymmetry. Genetic correlations were positive within limbs, but negative across bones of fore and hind limbs. Environmental correlations were positive for all, but smaller across fore and hind limbs. We discuss our results in light of the existence and maintenance of DA in locomotory traits.
PMCID: PMC3794934  PMID: 24130770
3.  Brief Communication: Locomotor Limb Preferences in Captive Chimpanzees (Pan troglodytes): Implications for Morphological Asymmetries in Limb Bones 
Understanding the evolutionary origins of hemispheric specialization remains a topic of considerable interest in a variety of scientific disciplines. Whether nonhuman primates exhibit population-level limb preferences continues to be a controversial topic. In this study, limb preferences for ascending and descending locomotion were assessed as a means of examining the hypothesis that asymmetries in forelimb bones might be attributed to asymmetries in posture. The results indicated that captive chimpanzees showed a population-level leftward asymmetry in descending locomotion but no group bias for ascending locomotion. The results are consistent with previous behavioral studies in captive chimpanzees as well as studies on skeletal asymmetries of the forelimbs of chimpanzees.
PMCID: PMC2654328  PMID: 18446855
laterality; posture; locomotion; chimpanzees
4.  Adaptive wing asymmetry in males of the speckled wood butterfly (Pararge aegeria)? 
We analysed asymmetry in the wings of the speckled wood butterfly (Pararge aegeria)by measuring area, length and width of fore- and hindwings. The type of asymmetry is fluctuating except for fore- and hindwing area, and forewing width in males, where asymmetry is directional. The amount of asymmetry (variance of the left wing minus the right wing) is less in males than in females. Within males asymmetry was directional and less in pale, predominantly territorial males than in melanic, predominantly non-territorial males. Asymmetry was negatively related to growth rate within females, but not within males. Females grew faster than males, but had higher asymmetry, whereas the more asymmetrical melanic males grew more slowly than pale males. The differences in the type and amount of asymmetry between the sexes and colour classes suggest a relationship with sex-specific flight patterns such as the territorial spiralling flight of males. We hypothesize that slightly asymmetrical males turn faster, and therefore are superior in territorial disputes over more symmetrical or extremely asymmetrical males. This implies that sexual selection via male–male competition influences the type and amount of asymmetry. The existence of more extremely asymmetrical individuals in females, and to a lesser extent in non-territorial males, may indicate that there are costs in reducing asymmetry.
PMCID: PMC1690082
Foot placement during walking is closely linked to the body position, yet it is typically quantified relative to the other foot. The purpose of this study was to quantify foot placement patterns relative to body post-stroke and investigate its relationship to hemiparetic walking performance.
Thirty-nine participants with hemiparesis walked on a split-belt treadmill at their self-selected speeds and twenty healthy participants walked at matched slow speeds. Anterior-posterior and medial-lateral foot placements (foot center-of-mass) relative to body (pelvis center-of-mass) quantified stepping in body reference frame. Walking performance was quantified using step length asymmetry ratio, percent of paretic propulsion and paretic weight support.
Participants with hemiparesis placed their paretic foot further anterior than posterior during walking compared to controls walking at matched slow speeds (p < .05). Participants also placed their paretic foot further lateral relative to pelvis than non-paretic (p < .05). Anterior-posterior asymmetry correlated with step length asymmetry and percent paretic propulsion but some persons revealed differing asymmetry patterns in the translating reference frame. Lateral foot placement asymmetry correlated with paretic weight support (r = .596; p < .001), whereas step widths showed no relation to paretic weight support.
Post-stroke gait is asymmetric when quantifying foot placement in a body reference frame and this asymmetry related to the hemiparetic walking performance and explained motor control mechanisms beyond those explained by step lengths and step widths alone. We suggest that biomechanical analyses quantifying stepping performance in impaired populations should investigate foot placement in a body reference frame.
PMCID: PMC2881577  PMID: 20193972
6.  Molecular and histopathological detection of Hepatozoon canis in red foxes (Vulpes vulpes) from Portugal 
Parasites & Vectors  2014;7:113.
Hepatozoon canis is a protozoan tick-borne pathogen of dogs and wild canids. Hepatozoon spp. have been reported to infect foxes in different continents and recent studies have mostly used the polymerase chain reaction (PCR) for the detection and characterization of the infecting species. Surveying red foxes (Vulpes vulpes) may contribute to better understanding the epidemiology of canine vector-borne diseases, including hepatozoonosis caused by H. canis in domestic dogs. The present study investigated the prevalence of Hepatozoon spp. by means of histopathology and molecular analysis of different tissues in red foxes from different parts of Portugal.
Blood and tissues including bone marrow, heart, hind leg muscle, jejunum, kidney, liver, lung, popliteal or axillary lymph nodes, spleen and/or tongue were collected from 91 red foxes from eight districts in northern, central and southern Portugal. Tissues were formalin-fixed, paraffin-embedded, cut and stained with hematoxylin and eosin. Polymerase chain reaction (PCR) amplified a ~650 bp fragment of the 18S rRNA gene of Hepatozoon spp. and the DNA products were sequenced.
Hepatozoon canis was detected in 68 out of 90 foxes (75.6%) from all the sampled areas by PCR and sequencing. Histopathology revealed H. canis meronts similar in shape to those found in dogs in the bone marrow of 11 (23.4%) and in the spleen of two (4.3%) out of 47 foxes (p = 0.007). All the 11 foxes found positive by histopathology were also positive by PCR of bone marrow and/or blood. Positivity by PCR (83.0%) was significantly higher (p < 0.001) than by histopathological examination (23.4%) in paired bone marrow samples from the same 47 foxes. Sequences of the 18S rRNA gene of H. canis were 98–99% identical to those in GenBank.
Hepatozoon canis was found to be highly prevalent in red fox populations from northern, central and southern Portugal. Detection of the parasite by histopathology was significantly less sensitive than by PCR. Red foxes are a presumptive reservoir of H. canis infection for domestic dogs.
PMCID: PMC3994325  PMID: 24655375
Canine vector-borne diseases; Hepatozoon canis; Histopathology; Polymerase chain reaction; Portugal; Red fox; Vulpes vulpes
7.  Gait analysis in patients with idiopathic scoliosis 
European Spine Journal  2004;13(5):449-456.
The goal of this study was to observe scoliotic subjects during level walking to identify asymmetries—which may be related to a neurological dysfunction or the spinal deformity itself—and to correlate these to the severity of the scoliotic curve.
We assessed the gait pattern of ten females (median age 14.4) with idiopathic scoliosis characterised by a left-lumbar and a right-thoracic curve component. Gait analysis consisted of 3D kinematic (VICON) and kinetic (Kistler force plates) measurements. The 3D-segment positions of the head, trunk and pelvis, as well as the individual joint angles of the upper and lower extremities, were computed during walking and static standing. Calculation of pertinent kinetic and kinematic parameters allowed statistical comparison.
All subjects walked at a normal velocity (median: 1.22 m/s; range:1.08–1.30 m/s; height-adjusted velocity: 0.75 m/s; range: 0.62–0.88 m/s). The timing of the individual gait phases was normal and symmetrical for the whole group. Sagittal plane hip, knee and ankle motion followed a physiological pattern. Significant asymmetry was observed in the trunk’s rotational behaviour in the transverse plane. During gait, the pelvis and the head rotated symmetrically to the line of progression, whereas trunk rotation was asymmetric, with increased relative forward rotation of the right upper body in relation to the pelvis. This produced a torsional offset to the line of progression. Minimal torsion (at right heel strike) measured: median 1.0° (range: 5.1°–8.3°), and maximal torsion (at left heel strike) measured 11.4° (range 6.9°–17.9°). The magnitude of the torsional offset during gait correlated to the severity of the thoracic deformity and to the standing posture, whereas the range of the rotational movement was not affected by the severity of the deformity. The ground reaction forces revealed a significant asymmetry of [Msz], the free rotational moment around the vertical axis going through the point of equivalent force application. On the right side, the initial endo-rotational moment was lower, followed by a higher exo-rotational moment than on the left. All the other force parameters (vertical, medio–lateral, anterior–posterior), did not show a significant side difference for the whole group. The use of a brace stiffened torsional motion. However the torsional offset and the asymmetry of the free rotational moment remained unchanged.
The most significant and marked asymmetry was seen in the transverse plane, denoted as a torsional offset of the upper trunk in relation to the symmetrically rotating pelvis. This motion pattern was reflected by a ground-reaction-force asymmetry of the free rotational moment. Further studies are needed to investigate whether this behaviour is solely an expression of the structural deformity or whether it could enhance the progression of the torsional deformity.
PMCID: PMC3476595  PMID: 15064994
Idiopathic scoliosis; Gait analysis; Biomechanics; Asymmetry
8.  Developmental Stability: A Major Role for Cyclin G in Drosophila melanogaster 
PLoS Genetics  2011;7(10):e1002314.
Morphological consistency in metazoans is remarkable given the pervasive occurrence of genetic variation, environmental effects, and developmental noise. Developmental stability, the ability to reduce developmental noise, is a fundamental property of multicellular organisms, yet its genetic bases remains elusive. Imperfect bilateral symmetry, or fluctuating asymmetry, is commonly used to estimate developmental stability. We observed that Drosophila melanogaster overexpressing Cyclin G (CycG) exhibit wing asymmetry clearly detectable by sight. Quantification of wing size and shape using geometric morphometrics reveals that this asymmetry is a genuine—but extreme—fluctuating asymmetry. Overexpression of CycG indeed leads to a 40-fold increase of wing fluctuating asymmetry, which is an unprecedented effect, for any organ and in any animal model, either in wild populations or mutants. This asymmetry effect is not restricted to wings, since femur length is affected as well. Inactivating CycG by RNAi also induces fluctuating asymmetry but to a lesser extent. Investigating the cellular bases of the phenotypic effects of CycG deregulation, we found that misregulation of cell size is predominant in asymmetric flies. In particular, the tight negative correlation between cell size and cell number observed in wild-type flies is impaired when CycG is upregulated. Our results highlight the role of CycG in the control of developmental stability in D. melanogaster. Furthermore, they show that wing developmental stability is normally ensured via compensatory processes between cell growth and cell proliferation. We discuss the possible role of CycG as a hub in a genetic network that controls developmental stability.
Author Summary
Developing organisms face genetic, environmental, and stochastic variations, and yet their ability to reach stereotyped phenotypes is pervasive. Although genetic bases of this robustness are actively investigated, no consensus has been achieved, some authors attributing it to particular genes such as Hsp90, while others to emerging properties of complex genetic networks. A particularly puzzling component of robustness is developmental stability, i.e. the reduction of developmental noise. Genetic bases of developmental stability have remained equally elusive. In bilaterians, developmental stability is commonly measured by fluctuating asymmetry (FA), where the same organ is compared on both sides of the same individual. Here, we show that ubiquitous overexpression of the Cyclin G gene induces a 40-fold increase of wing size FA, which is an unprecedented effect, for any organ and in any animal model. Investigating the cellular bases of this asymmetry, we show that the tight negative correlation between cell size and cell number that occurs in wild-type flies was lost. Since not only wings but also legs were affected, Cyclin G appears a candidate gene for a general mechanism of developmental stability in Drosophila, suggesting that phenotypic robustness can be strongly influenced by individual genes.
PMCID: PMC3188557  PMID: 21998598
9.  Craniofacial Asymmetry in Adults With Neglected Congenital Muscular Torticollis 
Annals of Rehabilitation Medicine  2015;39(3):440-450.
To evaluate the craniofacial asymmetry in adults with neglected congenital muscular torticollis (CMT) by quantitative assessment based on craniofacial three-dimensional computed tomography (3D-CT).
Preoperative craniofacial asymmetry was measured by 3D-CT for 31 CMT subjects ≥18 years of age who visited a tertiary medical center and underwent 3D-CT between January 2009 and December 2013. The relationship between the age and the severity of craniofacial asymmetry was analyzed in reference to anteroposterior length asymmetry of the frontal bone and zygomatic arch, vertical and lateral displacements of the facial landmarks, and mandibular axis rotation.
The age at CT was 27.71±7.02 years (range, 18-44 years). All intra-class correlation coefficients were higher than 0.7, suggesting good inter-rater reliability (p<0.05) of all the measurements. The frontal and the zygomatic length ratio (i.e., the anteroposterior length asymmetry on the axial plane) was 1.06±0.03 and 1.07±0.03, respectively, which was increased significantly with age in the linear regression analysis (r2=0.176, p=0.019 and r2=0.188, p=0.015, respectively). The vertical or lateral displacement of the facial landmarks and rotation of the mandibular axis did not significantly correlate with age (p>0.05).
Craniofacial asymmetry of neglected CMT became more severe with age in terms of anteroposterior length asymmetry of the ipsilateral frontal bone and zygomatic arch on the axial plane even after growth cessation. This finding may enhance the understanding of therapeutic strategies for craniofacial asymmetry in adults with neglected CMT.
PMCID: PMC4496516  PMID: 26161351
Craniofacial abnormalities; Facial asymmetry; Computed tomography; Congenital muscular torticollis
10.  Balance Training Exercises Decrease Lower-Limb Strength Asymmetry in Young Tennis Players 
The issue of functional asymmetries in the lower-limbs has been the subject of numerous recent investigations concerning many different contact, limited-contact and non-contact sports. The presence of strength asymmetries in the lower-limbs of young athletes practicing various sporting disciplines is considered an intrinsic risk factor for injury; in such cases, compensation strategies should thus be implemented aimed at eliminating, or at least limiting, the degree of asymmetry in order to avoid the negative consequences asymmetries can have upon the health of young sportsmen and women on the long-term. The aim of the present study was to examine the presence of functional asymmetries in the lower-limbs of young tennis players in strength and speed drill performance and to test a specific balance-training programme in its capacity to effectively reduce such asymmetries. Twenty-three young tennis players were randomly assigned to the Experimental Group (EG) (n = 11: 4 females, 7 males; 13.2 ± 0.9 years; 50.8 ± 8.9 Kg; 1.63 ± 0.08 m) or Comparison Group (CG) (n = 12: 4 females, 8 males; 13.0 ± 0.9 years; 51.1 ± 9.2 Kg; 1.61 ± 0.09 m). To quantify percent asymmetries in lower-limb strength before (T0) and following (T1) training, performances were assessed in the one-leg hop test (OLH), side-hop test (SH) and side steps and forward 4.115-m test (4m-SSF). Performances in the 10 and 20m sprint tests and the Foran test were also assessed. The EG completed a total of 12 training sessions directed at balance training: two 30-minute sessions/week over a 6-week period. The CG followed an identical training schedule, but training sessions consisted of tennis-specific drills only. The results reveal significant differences between pre- and post-training tests in the EG only: the degree of lower-limb asymmetry was decreased in the EG following completion of the training programme, as assessed using the OLH test (p < 0.001), SH test (p < 0.001) and 4m-SSF test (p < 0.05). A significant interaction and main effect of training was also observed in the EG: balance training led to a significant reduction in the percent of asymmetry in lower-limb strength, as measured using the SH (p < 0.01), 4m-SSF (p < 0.01) and OLH (p < 0.05) tests. These results confirm that balance training exercises are able to counteract/reduce the degree of asymmetry in lower-limb strength in young tennis players.
Key pointsThe determination of functional asymmetries in the lower-limbs has been the subject of numerous recent investigations aimed at the prevention of injuries in many different contact, limited-contact and non-contact sports.Sport-specific movements in tennis impose different loads upon the two lower-limbs and can cause the development of lower-limb strength asymmetries in young tennis players.The planning of athletic conditioning in young tennis players requires that strength in the lower-limbs is evaluated such that appropriate injury prevention strategies may be inserted into training programmes.Balance training exercises, and indeed all tasks performed on unstable surfaces, lead to benefits in sport-specific performance.
PMCID: PMC3990896  PMID: 24790496
Strength asymmetry; risk of injury; speed; lateral/side movements
11.  Rib length asymmetry in thoracic adolescent idiopathic scoliosis: is it primary or secondary? 
European Spine Journal  2010;20(2):254-259.
The development of scoliosis in animal models after inducing asymmetric rib growth suggests the possible role of asymmetric rib growth in the etiopathogenesis of adolescent idiopathic scoliosis (AIS). Asymmetric rib length is well recognized in idiopathic scoliosis; however, whether this rib asymmetry is primary or secondary has not been clearly documented. The objectives of this study were to investigate any rib length asymmetry in patients with AIS and compare those with scoliosis with syringomyelia (SS) with the intention of elucidating any relationship between rib growth and pathogenesis of AIS. Forty-eight AIS and 29 SS with apical vertebrae located between T7 and T9 were recruited. The average age was 13.5 ± 2.3 versus 12.5 ± 3.4 years, and the average Cobb angle of thoracic curve was 43.3° ± 16.4° versus 45.6° ± 22.6° in patients with AIS or SS, respectively. The length of all ribs was measured from the tip of costal head to the end of the same rib by built-in software on spiral computed tomography. At the levels of the apical vertebrae, the vertebrae above and below the apex, the mean discrepancy in rib length (concave minus convex rib) was 7, 4 and 7 mm, respectively, in AIS group (p < 0.01), and 6, 5 and 7 mm in SS group, respectively (p < 0.01). The rib length discrepancy between concave and convex sides was significantly correlated with the magnitude of the Cobb angle of thoracic curve in both AIS and SS groups (p < 0.01). Similar findings of the asymmetry of rib length in both AIS and SS patients pointed strongly to the fact that the rib length asymmetry in apical region is most likely secondary to the scoliosis deformity rather than playing a primary role in the etiopathogenesis.
PMCID: PMC3030715  PMID: 21120673
Idiopathic scoliosis; Rib length; Asymmetry
12.  Asymmetry and structural system analysis of the proximal femur meta-epiphysis: osteoarticular anatomical pathology 
The human femur is commonly considered as a subsystem of the locomotor apparatus with four conspicuous levels of organization. This phenomenon is the result of the evolution of the locomotor apparatus, which encompasses both constitutional and individual variability. The work therein reported, therefore, underlies the significance of observing anatomical system analysis of the proximal femur meta-epiphysis in normal conditions, according to the anatomic positioning with respect to the right or left side of the body, and the presence of system asymmetry in the meta-epiphysis structure, thus indicating structural and functional asymmetry.
A total of 160 femur bones of both sexes were compiled and a morphological study of 15 linear and angulated parameters of proximal femur epiphysis was produced, thus defining the linear/angulated size of tubular bones. The parameters were divided into linear and angulated groups, while maintaining the motion of the hip joint and transmission of stress to the unwanted parts of the limb. Furthermore, the straight and vertical diameters of the femoral head and the length of the femoral neck were also studied. The angle between the neck and diaphysis, the neck antiversion and angle of rotation of the femoral neck were subsequently measured. Finally, the condylo-diaphyseal angle with respect to the axis of extremity was determined. To visualize the force of intersystem ties, we have used the method of correlation galaxy construction.
The absolute numeral values of each linear parameter were transformed to relative values. The values of superfluity coefficient for each parameter in the right and left femoral bone groups were estimated and Pearson's correlation coefficient has been calculated (> 0.60). Retrospectively, the observed results have confirmed the presence of functional asymmetry in the proximal femur meta-epiphysis. On the basis of compliance or insignificant difference in the confidence interval of the linear parameters, we have revealed, therefore, a discrepancy in values between the neck and the diaphysis angle and the angle of femoral neck rotation (range displacement of confident interval to a greater degree to the right).
This study assessed the observations of a systemic anatomical study encompassing the proximal femur meta-epiphysis behavior in normal condition. This work has significance in medical practice as the theoretical basis is also required in knowing the decreased frequency and degree of severity of osteoarthritic pathologies in the dominant lower extremity.
PMCID: PMC2291035  PMID: 18304331
13.  Gait in adolescent idiopathic scoliosis: kinematics and electromyographic analysis 
European Spine Journal  2009;18(4):512-521.
Adolescent idiopathic scoliosis (AIS) is a progressive growth disease that affects spinal anatomy, mobility, and left-right trunk symmetry. Consequently, AIS can modify human locomotion. Very few studies have investigated a simple activity like walking in a cohort of well-defined untreated patients with scoliosis. The first goal of this study is to evaluate the effects of scoliosis and scoliosis severity on kinematic and electromyographic (EMG) gait variables compared to an able-bodied population. The second goal is to look for any asymmetry in these parameters during walking. Thirteen healthy girls and 41 females with untreated AIS, with left thoracolumbar or lumbar primary structural curves were assessed. AIS patients were divided into three clinical subgroups (group 1 < 20°, group 2 between 20 and 40°, and group 3 > 40°). Gait analysis included synchronous bilateral kinematic and EMG measurements. The subjects walked on a treadmill at 4 km/h (comfortable speed). The tridimensional (3D) shoulder, pelvis, and lower limb motions were measured using 22 reflective markers tracked by four infrared cameras. The EMG timing activity was measured using bipolar surface electrodes on quadratus lumborum, erector spinae, gluteus medius, rectus femoris, semitendinosus, tibialis anterior, and gastrocnemius muscles. Statistical comparisons (ANOVA) were performed across groups and sides for kinematic and EMG parameters. The step length was reduced in AIS compared to normal subjects (7% less). Frontal shoulder, pelvis, and hip motion and transversal hip motion were reduced in scoliosis patients (respectively, 21, 27, 28, and 22% less). The EMG recording during walking showed that the quadratus lumborum, erector spinae, gluteus medius, and semitendinosus muscles contracted during a longer part of the stride in scoliotic patients (46% of the stride) compared with normal subjects (35% of the stride). There was no significant difference between scoliosis groups 1, 2, and 3 for any of the kinematic and EMG parameters, meaning that severe scoliosis was not associated with increased differences in gait parameters compared to mild scoliosis. Scoliosis was not associated with any kinematic or EMG left–right asymmetry. In conclusion, scoliosis patients showed significant but slight modifications in gait, even in cases of mild scoliosis. With the naked eye, one could not see any difference from controls, but with powerful gait analysis technology, the pelvic frontal motion (right–left tilting) was reduced, as was the motion in the hips and shoulder. Surprisingly, no asymmetry was noted but the spine seemed dynamically stiffened by the longer contraction time of major spinal and pelvic muscles. Further studies are needed to evaluate the origin and consequences of these observations.
PMCID: PMC2899459  PMID: 19224255
Scoliosis; Gait; Asymmetry; Electromyography
14.  Exploratory genotype–phenotype correlations of facial form and asymmetry in unaffected relatives of children with non-syndromic cleft lip and/or palate 
Journal of anatomy  2014;224(6):688-709.
Family relatives of children with nonsyndromic cleft lip with or without cleft palate (NSCL/P) who presumably carry a genetic risk yet do not manifest overt oral clefts, often present with distinct facial morphology of unknown genetic etiology. This study investigates distinct facial morphology among unaffected relatives and examines whether candidate genes previously associated with overt NSCL/P and left–right body patterning are correlated with such facial morphology. Cases were unaffected relatives of individuals with NSCL/P (n = 188) and controls (n = 194) were individuals without family history of NSCL/P. Cases and controls were genotyped for 20 SNPs across 13 candidate genes for NSCL/P (PAX7, ABCA4-ARHGAP29, IRF6, MSX1, PITX2, 8q24, FOXE1, TGFB3 and MAFB) and left–right body patterning (LEFTY1, LEFTY2, ISL1 and SNAI1). Facial shape and asymmetry phenotypes were obtained via principal component analyses and Procrustes analysis of variance from 32 coordinate landmarks, digitized on 3D facial images. Case–control comparisons of phenotypes obtained were performed via multivariate regression adjusting for age and gender. Phenotypes that differed significantly (P < 0.05) between cases and controls were regressed on the SNPs one at a time. Cases had significantly (P < 0.05) more profile concavity with upper face retrusion, upturned noses with obtuse nasolabial angles, more protrusive chins, increased lower facial heights, thinner and more retrusive lips and more protrusive foreheads. Furthermore, cases showed significantly more directional asymmetry compared to controls. Several of these phenotypes were significantly associated with genetic variants (P < 0.05). Facial height and width were associated with SNAI1. Midface antero-posterior (AP) projection was associated with LEFTY1. The AP position of the chin was related to SNAI1, IRF6, MSX1 and MAFB. The AP position of the forehead and the width of the mouth were associated with ABCA4–ARHGAP29 and MAFB. Lastly, facial asymmetry was related to LEFTY1, LEFTY2 and SNAI1. This study demonstrates that, genes underlying lip and palate formation and left–right patterning also contribute to facial features characteristic of the NSCL/P spectrum.
PMCID: PMC4025896  PMID: 24738728
facial asymmetry; genotype-phenotype correlations; morphometrics; NSCL/P; 3D morphology
15.  FoxM1B transcriptionally regulates vascular endothelial growth factor expression and promotes the angiogenesis and growth of glioma cells 
Cancer research  2008;68(21):8733-8742.
We previously found that FoxM1B is overexpressed in human glioblastomas (GBMs) and that forced FoxM1B expression in anaplastic astrocytoma cells leads to the formation of highly angiogenic GBM in nude mice. However, the molecular mechanisms by which FoxM1B enhances glioma angiogenesis are currently unknown. In this study, we found that vascular endothelial growth factor (VEGF) is a direct transcriptional target of FoxM1B. FoxM1B overexpression increased VEGF expression, while blockade of FoxM1 expression suppressed VEGF expression in glioma cells. Transfection of FoxM1 into glioma cells directly activated the VEGF promoter, and inhibition of FoxM1 expression by FoxM1-siRNA suppressed VEGF promoter activation. We identified two FoxM1-binding sites in the VEGF promoter that specifically bound to the FoxM1 protein. Mutation of these FoxM1-binding sites significantly attenuated VEGF promoter activity. Furthermore, FoxM1 overexpression increased and inhibition of FoxM1 expression suppressed the angiogenic ability of glioma cells. Finally, an immunohistochemical analysis of 59 human GBM specimens also showed a significant correlation between FoxM1 overexpression and elevated VEGF expression. Our findings provide both clinical and mechanistic evidence that FoxM1 contributes to glioma progression by enhancing VEGF gene transcription and thus tumor angiogenesis.
PMCID: PMC2597644  PMID: 18974115
FoxM1; VEGF; angiogenesis; tumorigenicity; glioblastoma
16.  FoxM1 overexpression promotes epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma 
AIM: To investigate the expression of forkhead box protein M1 (FoxM1) in the process of epithelial mesenchymal transition in hepatocellular carcinoma (HCC) and its role in metastasis.
METHODS: FoxM1 and E-cadherin expression in HCC tissue microarray specimens was evaluated by immunohistochemical staining, and statistical methods were applied to analyze the correlation between FoxM1 and epithelial-mesenchymal transition (EMT). Kaplan-Meier analysis of the correlation between the FoxM1 expression level and recurrence or overall survival of HCC patients was performed. The expression of FoxM1, E-cadherin and snail homologue 1 (SNAI1) in HCC cell lines was evaluated by real-time reverse transcription-polymerase chain reaction and Western blot. Hepatocyte growth factor (HGF) was used to induce EMT and stimulate cell migration in HCC cells. The expression of FoxM1 and SNAI1 was regulated by transfection with plasmids pcDNA3.1 and siRNAs in vitro. The occurrence of EMT was evaluated by Transwell assay, morphologic analysis and detection of the expression of EMT markers (E-cadherin and vimentin). Luciferase and chromatin immunoprecipitation assays were used to evaluate whether SNAI1 is a direct transcriptional target of FoxM1.
RESULTS: FoxM1 expression was increased significantly in HCC compared with para-carcinoma (10.7 ± 0.9 vs 8.2 ± 0.7, P < 0.05) and normal hepatic (10.7 ± 0.9 vs 2.7 ± 0.4, P < 0.05) tissues. Overexpression of FoxM1 was correlated with HCC tumor size, tumor number, macrovascular invasion and higher TNM stage, but was negatively correlated with E-cadherin expression in microarray specimens and in cell lines. FoxM1 overexpression was correlated significantly with HCC metastasis and EMT. In vitro, we found that FoxM1 plays a key role in HGF-induced EMT, and overexpression of FoxM1 could suppress E-cadherin expression and induce EMT changes, which were associated with increased HCC cell invasiveness. Next, we confirmed that FOXM1 directly binds to and activates the SNAI1 promoter, and we identified SNAI1 as a direct transcriptional target of FOXM1. Moreover, inhibiting the expression of SNAI1 significantly inhibited FoxM1-mediated EMT.
CONCLUSION: FoxM1 overexpression promotes EMT and metastasis of HCC, and SNAI1 plays a critical role in FoxM1-mediated EMT.
PMCID: PMC4284335  PMID: 25574092
Forkhead box protein M1; Epithelial-mesenchymal transition; Hepatocellular carcinoma; Snail homolog 1; E-cadherin
17.  Handedness of a Motor Program in C. elegans Is Independent of Left-Right Body Asymmetry 
PLoS ONE  2012;7(12):e52138.
Complex animals display bilaterally asymmetric motor behavior, or “motor handedness,” often revealed by preferential use of limbs on one side. For example, use of right limbs is dominant in a strong majority of humans. While the mechanisms that establish bilateral asymmetry in motor function are unknown in humans, they appear to be distinct from those for other handedness asymmetries, including bilateral visceral organ asymmetry, brain laterality, and ocular dominance. We report here that a simple, genetically homogeneous animal comprised of only ∼1000 somatic cells, the nematode C. elegans, also shows a distinct motor handedness preference: on a population basis, males show a pronounced right-hand turning bias during mating. The handedness bias persists through much of adult lifespan, suggesting that, as in more complex animals, it is an intrinsic trait of each individual, which can differ from the population mean. Our observations imply that the laterality of motor handedness preference in C. elegans is driven by epigenetic factors rather than by genetic variation. The preference for right-hand turns is also seen in animals with mirror-reversed anatomical handedness and is not attributable to stochastic asymmetric loss of male sensory rays that occurs by programmed cell death. As with C. elegans, we also observed a substantial handedness bias, though not necessarily the same preference in direction, in several gonochoristic Caenorhabditis species. These findings indicate that the independence of bilaterally asymmetric motor dominance from overall anatomical asymmetry, and a population-level tendency away from ambidexterity, occur even in simple invertebrates, suggesting that these may be common features of bilaterian metazoans.
PMCID: PMC3531390  PMID: 23300601
18.  Sequence comparison of prefrontal cortical brain transcriptome from a tame and an aggressive silver fox (Vulpes vulpes) 
BMC Genomics  2011;12:482.
Two strains of the silver fox (Vulpes vulpes), with markedly different behavioral phenotypes, have been developed by long-term selection for behavior. Foxes from the tame strain exhibit friendly behavior towards humans, paralleling the sociability of canine puppies, whereas foxes from the aggressive strain are defensive and exhibit aggression to humans. To understand the genetic differences underlying these behavioral phenotypes fox-specific genomic resources are needed.
cDNA from mRNA from pre-frontal cortex of a tame and an aggressive fox was sequenced using the Roche 454 FLX Titanium platform (> 2.5 million reads & 0.9 Gbase of tame fox sequence; >3.3 million reads & 1.2 Gbase of aggressive fox sequence). Over 80% of the fox reads were assembled into contigs. Mapping fox reads against the fox transcriptome assembly and the dog genome identified over 30,000 high confidence fox-specific SNPs. Fox transcripts for approximately 14,000 genes were identified using SwissProt and the dog RefSeq databases. An at least 2-fold expression difference between the two samples (p < 0.05) was observed for 335 genes, fewer than 3% of the total number of genes identified in the fox transcriptome.
Transcriptome sequencing significantly expanded genomic resources available for the fox, a species without a sequenced genome. In a very cost efficient manner this yielded a large number of fox-specific SNP markers for genetic studies and provided significant insights into the gene expression profile of the fox pre-frontal cortex; expression differences between the two fox samples; and a catalogue of potentially important gene-specific sequence variants. This result demonstrates the utility of this approach for developing genomic resources in species with limited genomic information.
PMCID: PMC3199282  PMID: 21967120
19.  Lean Mass Asymmetry Influences Force and Power Asymmetry During Jumping in Collegiate Athletes 
The purpose of this investigation was to: (1) examine how asymmetry in lower extremity lean mass influenced force and power asymmetry during jumping, (2) determine how power and force asymmetry affected jump height, and (3) report normative values in collegiate athletes. Force and power were assessed from each limb using bilateral force plates during a countermovement jump in 167 Division 1 athletes (mass=85.7±20.3kg, age=20.0±1.2years, 103M/64F). Lean mass of the pelvis, thigh, and shank was assessed via dual-energy X-ray absorptiometry. Percent asymmetry was calculated for lean mass at each region (pelvis, thigh, and shank) as well as force and power. Forward stepwise regressions were performed to determine the influence of lean mass asymmetry on force and power asymmetry. Thigh and shank lean mass asymmetry explained 20% of the variance in force asymmetry (R2=0.20, P<0.001), while lean mass asymmetry of the pelvis, thigh and shank explained 25% of the variance in power asymmetry (R2=0.25, P<0.001). Jump height was compared across level of force and power asymmetry (P>0.05) and greater than 10% asymmetry in power tended to decrease performance (effect size>1.0). Ninety-five percent of this population (2.5th to 97.5th percentile) displayed force asymmetry between −11.8 to 16.8% and a power asymmetry between −9.9 to 11.5%. A small percentage (<4%) of these athletes displayed more than 15% asymmetry between limbs. These results demonstrate that lean mass asymmetry in the lower extremity is at least partially responsible for asymmetries in force and power. However, a large percentage remains unexplained by lean mass asymmetry.
PMCID: PMC4370170  PMID: 24402449
Imbalance; Vertical jump; bilateral; DXA; Body composition
20.  Analysis and simulation of progressive adolescent scoliosis by biomechanical growth modulation 
European Spine Journal  2007;16(10):1621-1628.
Scoliosis is thought to progress during growth because spinal deformity produces asymmetrical spinal loading, generating asymmetrical growth, etc. in a ‘vicious cycle.’ The aim of this study was to test quantitatively whether calculated loading asymmetry of a spine with scoliosis, together with measured bone growth sensitivity to altered compression, can explain the observed rate of scoliosis progression in the coronal plane during adolescent growth. The simulated spinal geometry represented a lumbar scoliosis of different initial magnitudes, averaged and scaled from measurements of 15 patients’ radiographs. Level-specific stresses acting on the vertebrae were estimated for each of 11 external loading directions (‘efforts’) from published values of spinal loading asymmetry. These calculations assumed a physiologically plausible muscle activation strategy. The rate of vertebral growth was obtained from published reports of growth of the spine. The distribution of growth across vertebrae was modulated according to published values of growth sensitivity to stress. Mechanically modulated growth of a spine having an initial 13° Cobb scoliosis at age 11 with the spine subjected to an unweighted combination of eleven loading conditions (different effort direction and magnitude) was predicted to progress during growth. The overall shape of the curve was retained. The averaged final lumbar spinal curve magnitude was 32° Cobb at age 16 years for the lower magnitude of effort (that produced compressive stress averaging 0.48 MPa at the curve apex) and it was 38° Cobb when the higher magnitudes of efforts (that produced compressive stress averaging 0.81 MPa at the apex). An initial curve of 26° progressed to 46° and 56°, respectively. The calculated stresses on growth plates were within the range of those measured by intradiscal pressures in typical daily activities. These analyses predicted that a substantial component of scoliosis progression during growth is biomechanically mediated. The rationale for conservative management of scoliosis during skeletal growth assumes a biomechanical mode of deformity progression (Hueter-Volkmann principle). The present study provides a quantitative basis for this previously qualitative hypothesis. The findings suggest that an important difference between progressive and non-progressive scoliosis might lie in the differing muscle activation strategies adopted by individuals, leading to the possibility of improved prognosis and conservative or less invasive interventions.
PMCID: PMC2078290  PMID: 17653775
Scoliosis; Progression; Simulation; Growth; Biomechanics
21.  Amniotic Fluid Deficiency and Congenital Abnormalities both Influence Fluctuating Asymmetry in Developing Limbs of Human Deceased Fetuses 
PLoS ONE  2013;8(11):e81824.
Fluctuating asymmetry (FA), as an indirect measure of developmental instability (DI), has been intensively studied for associations with stress and fitness. Patterns, however, appear heterogeneous and the underlying causes remain largely unknown. One aspect that has received relatively little attention in the literature is the consequence of direct mechanical effects on asymmetries. The crucial prerequisite for FA to reflect DI is that environmental conditions on both sides should be identical. This condition may be violated during early human development if amniotic fluid volume is deficient, as the resulting mechanical pressures may increase asymmetries. Indeed, we showed that limb bones of deceased human fetuses exhibited increased asymmetry, when there was not sufficient amniotic fluid (and, thus, space) in the uterine cavity. As amniotic fluid deficiency is known to cause substantial asymmetries and abnormal limb development, these subtle asymmetries are probably at least in part caused by the mechanical pressures. On the other hand, deficiencies in amniotic fluid volume are known to be associated with other congenital abnormalities that may disturb DI. More specifically, urogenital abnormalities can directly affect/reduce amniotic fluid volume. We disentangled the direct mechanical effects on FA from the indirect effects of urogenital abnormalities, the latter presumably representing DI. We discovered that both factors contributed significantly to the increase in FA. However, the direct mechanical effect of uterine pressure, albeit statistically significant, appeared less important than the effects of urogenital abnormalities, with an effect size only two-third as large. We, thus, conclude that correcting for the relevant direct factors allowed for a representative test of the association between DI and stress, and confirmed that fetuses form a suitable model system to increase our understanding in patterns of FA and symmetry development.
PMCID: PMC3842303  PMID: 24312362
22.  Distinct Roles of Hand2 in Initiating Polarity and Posterior Shh Expression during the Onset of Mouse Limb Bud Development 
PLoS Genetics  2010;6(4):e1000901.
The polarization of nascent embryonic fields and the endowment of cells with organizer properties are key to initiation of vertebrate organogenesis. One such event is antero-posterior (AP) polarization of early limb buds and activation of morphogenetic Sonic Hedgehog (SHH) signaling in the posterior mesenchyme, which in turn promotes outgrowth and specifies the pentadactylous autopod. Inactivation of the Hand2 transcriptional regulator from the onset of mouse forelimb bud development disrupts establishment of posterior identity and Shh expression, which results in a skeletal phenotype identical to Shh deficient limb buds. In wild-type limb buds, Hand2 is part of the protein complexes containing Hoxd13, another essential regulator of Shh activation in limb buds. Chromatin immunoprecipitation shows that Hand2-containing chromatin complexes are bound to the far upstream cis-regulatory region (ZRS), which is specifically required for Shh expression in the limb bud. Cell-biochemical studies indicate that Hand2 and Hoxd13 can efficiently transactivate gene expression via the ZRS, while the Gli3 repressor isoform interferes with this positive transcriptional regulation. Indeed, analysis of mouse forelimb buds lacking both Hand2 and Gli3 reveals the complete absence of antero-posterior (AP) polarity along the entire proximo-distal axis and extreme digit polydactyly without AP identities. Our study uncovers essential components of the transcriptional machinery and key interactions that set-up limb bud asymmetry upstream of establishing the SHH signaling limb bud organizer.
Author Summary
During early limb bud development, posterior mesenchymal cells are selected to express Sonic Hedgehog (Shh), which controls antero-posterior (AP) limb axis formation (axis from thumb to little finger). We generated a conditional loss-of-function Hand2 allele to inactivate Hand2 specifically in mouse limb buds. This genetic analysis reveals the pivotal role of Hand2 in setting up limb bud asymmetry as initiation of posterior identity and establishment of the Shh expression domain are completely disrupted in Hand2 deficient limb buds. The resulting loss of the ulna and digits mirror the skeletal malformations observed in Shh-deficient limbs. We show that Hand2 is part of the chromatin complexes that are bound to the cis-regulatory region that controls Shh expression specifically in limb buds. In addition, we show that Hand2 is part of a protein complex containing Hoxd13, which also participates in limb bud mesenchymal activation of Shh expression. Indeed, Hand2 and Hoxd13 stimulate ZRS–mediated transactivation in cells, while the Gli3 repressor form (Gli3R) interferes with this up-regulation. Interestingly, limb buds lacking both Hand2 and Gli3 lack AP asymmetry and are severely polydactylous. Molecular analysis reveals some of the key interactions and hierarchies that govern establishment of AP limb asymmetries upstream of SHH.
PMCID: PMC2851570  PMID: 20386744
23.  Establishment and expression of cellular polarity in fucoid zygotes. 
Microbiological Reviews  1992;56(2):316-339.
Zygotes of fucoid algae have long been studied as a paradigm for cell polarity. Polarity is established early in the first cell cycle and is then expressed as localized growth and invariant cell division. The fertilized egg is a spherical cell and, by all accounts, bears little or no asymmetry. Polarity is acquired epigenetically a few hours later in the form of a rhizoid/thallus axis. The initial stage of polarization is axis selection, during which zygotes monitor environment gradients to determine the appropriate direction for rhizoid formation. In their natural setting in the intertidal zone, sunlight is probably the most important polarizing vector; rhizoids form away from the light. The mechanism by which zygotes perceive environmental gradients and transduce that information into an intracellular signal is unknown but may involve a phosphatidylinositol cycle. Once positional information has been recorded, the cytoplasm and membrane are reorganized in accordance with the vectorial information. The earliest detectable asymmetries in the polarizing zygote are localized secretion and generation of a transcellular electric current. Vesicle secretion and the inward limb of the current are localized at the presumptive rhizoid. The transcellular current may establish a cytoplasmic Ca2+ gradient constituting a morphogenetic field, but this remains controversial. Localized secretion and establishment of transcellular current are sensitive to treatment with cytochalasins, indicating that cytoplasmic reorganization is dependent on the actin cytoskeleton. The nascent axis at first is labile and susceptible to reorientation by subsequent environmental vectors but soon becomes irreversibly fixed in its orientation. Locking the axis in place requires both cell wall and F-actin and is postulated to involve an indirect transmembrane bridge linking cortical actin to cell wall. This bridge anchors relevant structures at the presumptive rhizoid and thereby stabilizes the axis. Approximately halfway through the first cell cycle, the latent polarity is expressed morphologically in the form of rhizoid growth. Elongation is by tip growth and does not appear to be fundamentally different from tip growth in other organisms. The zygote always divides perpendicular to the growth axis, and this is controlled by the microtubule cytoskeleton. Two microtubule-organizing centers on the nuclear envelope rotate such that they align with the growth axis. They then serve as spindle poles during mitosis. Cytokinesis bisects the axial spindle, resulting in a transverse crosswall. Although the chronology of cellular events associated with polarity is by now rather detailed, causal mechanisms remain obscure.
PMCID: PMC372870  PMID: 1620068
24.  Divergence in Male and Female Manipulative Behaviors with the Intensification of Metallurgy in Central Europe 
PLoS ONE  2014;9(11):e112116.
Humeral morphology has been shown to reflect, in part, habitual manipulative behaviors in humans. Among Central European agricultural populations, long-term social change, increasing task specialization, and technological innovation all had the potential to impact patterns of habitual activity and upper limb asymmetry. However, systematic temporal change in the skeletal morphology of agricultural populations in this region has not been well-characterized. This study investigates diachronic patterns in humeral biomechanical properties and lengths among 174 adult Central European agriculturalists through the first ∼5400 years of farming in the region. Greater asymmetry in biomechanical properties was expected to accompany the introduction of metallurgy, particularly in males, while upper limb loading patterns were expected to be more similar between the Bronze and Iron Ages. Results revealed a divergence in the lateralization of upper limb biomechanical properties by sex between the Early/Middle Neolithic and Early/Middle Bronze Age. Neolithic females had significantly more variable properties than males in both humeri, while Bronze Age female properties became homogeneous and very symmetrical relative to the right-biased lateralization of contemporaneous males. The Bronze Age to Iron Age transition was associated with morphological change among females, with a significant increase in right-biased asymmetry and a concomitant reduction in sexual dimorphism. Relative to biomechanical properties, humeral length variation and asymmetry were low though some significant sexual dimorphism and temporal change was found. It was among females that the lateralization of humeral biomechanical properties, and variation within them, changed most profoundly through time. This suggests that the introduction of the ard and plow, metallurgical innovation, task specialization, and socioeconomic change through ∼5400 years of agriculture impacted upper limb loading in Central European women to a greater extent than men.
PMCID: PMC4229139  PMID: 25389972
25.  Supra-threshold Asymmetries in Human Motion Perception 
Detection of asymmetries has been a mainstay of using vestibular reflexes to assess semicircular canal function. However, there has been relatively little work on how vestibular stimuli are perceived. Suprathreshold vestibular perception was measured in 13 normal healthy controls by having them compare the relative sizes of two yaw (vertical-axis rotation) or sway (right-left translation) stimuli. Both stimuli were 1.5 s in duration with a staircase used to adjust the relative size of the stimuli to find a pair of stimuli perceived as equal. Motion stimuli were delivered in darkness using a hexapod motion platform, and visual stimuli simulating motion were presented on a screen in the absence of platform motion. Both same direction (SD) and opposite direction (OD) stimuli were delivered in separate runs. After a two-interval stimulus, subjects reported which movement they perceived as larger. Cumulative distribution functions were fit to the responses so that the relative magnitudes of the two stimuli perceived as equal could be determined. For OD trial blocks, a directional asymmetry index (DAI) was calculated to compare the relative size of perceived rightward and leftward motion. For all trial blocks, a temporal asymmetry index (TAI) was used to compare the relative size of the first and second intervals. Motion OD stimuli were perceived as equal in all subjects in yaw and all but one in sway. For visual OD stimuli, two subjects had slightly asymmetric responses for both sway and yaw. The TAI demonstrated asymmetry in 54% in yaw, in which the second interval was perceived to be larger in all but one subject who had an asymmetry. For sway, only two subjects had a significant asymmetry. Visual stimuli produced a similar rate of asymmetry. The direction and magnitude of these asymmetries were not significantly correlated with those seen for motion stimuli. Asymmetries were found in a fraction with the TAI in SD stimuli for motion in yaw (42%) and sway (33%), as well as for vision in yaw (60%) and sway (43%). The precision at discriminating SD motion stimuli decreased significantly with age, but there was no difference with OD motion or visual stimuli.
PMCID: PMC3365573  PMID: 22562587
Vestibular; semi-circular canals; otoliths

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