Glypican-6 and Glypican-4 stimulate embryonic stomach growth by regulating Hedgehog and noncanonical Wnt signaling.

BACKGROUND: Glypicans are a family of proteoglycans that play important roles in embryonic morphogenesis. The mammalian genome contains six glypicans (GPC1 to GPC6). GPC6 and GPC4 are the pair of glypicans that show the highest degree of homology within the family. GPC6-null embryos display bone abnormalities and severely shortened intestines. RESULTS: We show that GPC6-null embryos display significantly smaller stomachs, and that Hedgehog and noncanonical Wnt signaling are dysregulated in GPC6-null stomachs. Like GPC6, GPC4 is expressed by the developing stomach. However, GPC4-null embryos have normal stomachs. To investigate whether GPC6 and GPC4 display functional overlap in the developing stomach, we crossed GPC4-null mice with GPC6 conditional mutants in which the expression of this glypican is severely reduced in the stomach. Notably, we found that the compound mutants display stomachs that are smaller than those of the GPC6 conditional mutants. We also found that this functional overlap between GPC6 and GPC4 is mediated by the noncanonical Wnt pathway. CONCLUSION: This study demonstrates that GPC6 stimulates the growth of the embryonic stomach via Wnt and Hh signaling. In addition, we uncovered a Wnt-mediated functional overlap between GPC6 and GPC4 in the developing stomach.

Single-minded 2 is required for left-right asymmetric stomach morphogenesis.

The morphogenesis of left-right (LR) asymmetry is a crucial phase of organogenesis. In the digestive tract, the development of anatomical asymmetry is first evident in the leftward curvature of the stomach. To elucidate the molecular events that shape this archetypal laterality, we performed transcriptome analyses of the left versus right sides of the developing stomach in frog embryos. Besides the known LR gene pitx2, the only gene found to be expressed asymmetrically throughout all stages of curvature was single-minded 2 (sim2), a Down Syndrome-related transcription factor and homolog of a Drosophila gene (sim) required for LR asymmetric looping of the fly gut. We demonstrate that sim2 functions downstream of LR patterning cues to regulate key cellular properties and behaviors in the left stomach epithelium that drive asymmetric curvature. Our results reveal unexpected convergent cooption of single-minded genes during the evolution of LR asymmetric morphogenesis, and have implications for dose-dependent roles of laterality factors in non-laterality-related birth defects.

Decreased neonatal morbidity in 'stomach-down' left congenital diaphragmatic hernia: implications of prenatal ultrasound diagnosis for counseling and postnatal management.

OBJECTIVE: To evaluate the influence of stomach position on postnatal outcome in cases of left congenital diaphragmatic hernia (CDH) without liver herniation, diagnosed and characterized on prenatal ultrasound (US), by comparing those with ('stomach-up' CDH) to those without ('stomach-down' CDH) intrathoracic stomach herniation. METHODS: Infants with left CDH who underwent prenatal US and postnatal repair at our institution between January 2008 and March 2017 were eligible for inclusion in this retrospective study. Detailed prenatal US examinations, fetal magnetic resonance imaging (MRI) studies, operative reports and medical records of infants enrolled in the pulmonary hypoplasia program at our institution were reviewed. Cases with liver herniation and those with an additional anomaly were excluded. Cases in which bowel loops were identified within the fetal chest on US while the stomach was intra-abdominal were categorized as having stomach-down CDH. Cases in which bowel loops and the stomach were visualized within the fetal chest on US were categorized as having stomach-up CDH. Prenatal imaging findings and postnatal outcomes were compared between the two groups. RESULTS: In total, 152 patients with left CDH were initially eligible for inclusion. Seventy-eight patients had surgically confirmed liver herniation and were excluded. Of the 74 included CDH cases without liver herniation, 28 (37.8%) had stomach-down CDH and 46 (62.2%) had stomach-up CDH. Of the 28 stomach-down CDH cases, 10 (35.7%) were referred for a suspected lung lesion. Sixty-eight (91.9%) cases had postnatal outcome data available for analysis. There was no significant difference in median observed-to-expected (o/e) lung-area-to-head-circumference ratio (LHR) between cases with stomach-down CDH and those with stomach-up CDH (41.5% vs 38.4%; P = 0.41). Furthermore, there was no difference in median MRI o/e total lung volume (TLV) between the two groups (49.5% vs 44.0%; P = 0.22). Compared with stomach-up CDH patients, stomach-down CDH patients demonstrated lower median duration of intubation (18 days vs 9.5 days; P < 0.01), median duration of extracorporeal membrane oxygenation (495 h vs 223.5 h; P < 0.05), rate of supplemental oxygen requirement at 30 days of age (20/42 (47.6%) vs 3/26 (11.5%); P < 0.01) and rate of pulmonary hypertension at initial postnatal echocardiography (28/42 (66.7%) vs 9/26 (34.6%); P = 0.01). No neonatal death occurred in stomach-down CDH patients and one neonatal death was seen in a patient with intrathoracic stomach herniation. CONCLUSIONS: In infants with left CDH without liver herniation, despite similar o/e-LHR and o/e-TLV, those with stomach-down CDH have decreased neonatal morbidity compared to those with stomach herniation. Progressive or variable physiological distension of the stomach over the course of gestation may explain these findings. Stomach-down left CDH is mistaken for a lung mass in a substantial proportion of cases. Accurate prenatal US characterization of CDH is crucial for appropriate prenatal counseling and patient management. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Esophageal atresia and tracheoesophageal fistula: prenatal sonographic manifestation from early to late pregnancy.

OBJECTIVE: Esophageal atresia and/or tracheoesophageal fistula (EA/TEF) remains one of the most frequently missed congenital anomalies prenatally. The aim of our study was to elucidate the sonographic manifestation of EA/TEF throughout pregnancy. METHODS: This was a retrospective study of data obtained from a tertiary center over a 12-year period. The prenatal ultrasound scans of fetuses with EA/TEF were assessed to determine the presence and timing of detection of three principal signs: small/absent stomach and worsening polyhydramnios, both of which were considered as 'suspected' EA/TEF, and esophageal pouch, which was considered as 'detected' EA/TEF. We assessed the yield of the early (14-16 weeks' gestation), routine mid-trimester (19-26 weeks) and third-trimester (≥ 27 weeks) anomaly scans in the prenatal diagnosis of EA/TEF. RESULTS: Seventy-five cases of EA/TEF with available ultrasound images were included in the study. A small/absent stomach was detected on the early anomaly scan in 3.6% of fetuses scanned, without a definitive diagnosis. On the mid-trimester scan, 19.4% of scanned cases were suspected and 4.3% were detected. On the third-trimester anomaly scan, 43.9% of scanned cases were suspected and 33.9% were detected. An additional case with an esophageal pouch was detected on magnetic resonance imaging (MRI) in the mid-trimester and a further two were detected on MRI in the third trimester. In total, 44.0% of cases of EA/TEF in our cohort were suspected, 33.3% were detected and 10.7% were suspected but, eventually, not detected prenatally. CONCLUSIONS: Prenatal diagnosis of EA/TEF on ultrasound is not feasible before the late second trimester. A small/absent stomach may be visualized as early as 15 weeks' gestation. Polyhydramnios does not develop before the mid-trimester. An esophageal pouch can be detected as early as 22 weeks on a targeted scan in suspected cases. The detection rates of all three signs increase with advancing pregnancy, peaking in the third trimester. The early and mid-trimester anomaly scans perform poorly as a screening and diagnostic test for EA/TEF. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Initial morphological symmetry breaking in the foregut and development of the omental bursa in human embryos.

Bilaterally symmetrical primordia of visceral organs undergo asymmetrical morphogenesis leading to typical arrangement of visceral organs in the adult. Asymmetrical morphogenesis within the upper abdomen leads, among others, to the formation of the omental bursa dorsally to the rotated stomach. A widespread view of this process assumes kinking of thin mesenteries as a main mechanism. This view is based on a theory proposed already by Johannes Müller in 1830 and was repeatedly criticized, but some of the most plausible alternative views (initially proposed by Swaen in 1897 and Broman in 1904) still remain to be proven. Here, we analyzed serial histological sections of human embryos between stages 12 and 15 at high light microscopical resolution to reveal the succession of events giving rise to the development of the omental bursa and its relation to the emerging stomach asymmetry. Our analysis indicates that morphological symmetry breaking in the upper abdomen occurs within a wide mesenchymal plate called here mesenteric septum and is based on differential behavior of the coelomic epithelium which causes asymmetric paragastric recess formation and, importantly, precedes initial rotation of stomach. Our results thus provide the first histological evidence of breaking the symmetry of the early foregut anlage in the human embryo and pave the way for experimental studies of left-right symmetry breaking in the upper abdomen in experimental model organisms.

[Application of membrane anatomy in key technologies during gastric cancer surgery: guidance and compromise].

Different from classical surgical anatomy which only pays attention to the morphology and structure of human organs, modern membrane anatomy focuses on not only the relationship between morphology and structure, but also the biological behavior characteristics of tumors. Membrane antomy is a theoretical system with interpretation on both the structural and disease function, so it has been accepted by more and more gastrointestinal surgeons. However, the theoretical system of gastric membrane anatomy is not mature yet. The stomach and its mesentery have undergone complex rotation and fusion in the process of embryonic development, so that surgeons have different understandings of the gastric membrane anatomy. Therefore, it is easy to cause various confusion and misunderstanding, resulting in deviations between the theory of membrane anatomy and the practice of surgery. In the present study, the mesentery of the stomach is divided into different regions, and the embryonic development process is traced back. The application and compromise encountered in the radical gastrectomy of gastric cancer will be expounded according to the membrane anatomy theory combined with the author's experience of operation.

The embryonic development of the bovine stomach revisited.

The adult anatomy and physiology of the bovine (Bos taurus) stomach have been investigated extensively. Despite the many studies, however, the early development of the stomach has not yet been fully elucidated. The goal of the present study, therefore, was to review the available literature, to visualize the embryonic and early foetal development of the bovine stomach and to shed light on unresolved issues. The stomachs of fifteen bovine embryos and eleven foetuses from 26 to 80 days of gestation were photographed both in situ and after exenteration and critical point drying. A series of photographs was obtained that yielded a contiguous and comprehensive view of all the developmental changes that occurred until the virtually final configuration of the stomach was attained. In addition, the serosal surface was studied by electron microscopy, thus revealing subtle regional differences in the lining of the peritoneal cavity. Our observations corroborate the contention that all the compartments evolve from the fusiform primordium and that no outgrowth at the level of the oesophagus occurs. The greater curvature as well as the attachment line of the dorsal mesogastrium shift to the left, which is similar to the process in monogastrians. The rumen and reticulum develop from separate protrusions, and further compartmentalization results from constrictions and bulges and not from folding. Between 55 and 60 days of gestation, the entire bovine stomach except for the abomasum eventually relocates to its final position. In summary, previously debated key issues were addressed and integrated with current findings.

Using three-dimensional ultrasound in predicting complex gastroschisis: A longitudinal, prospective, multicenter cohort study.

OBJECTIVE: To determine whether complex gastroschisis (ie, intestinal atresia, perforation, necrosis, or volvulus) can prenatally be distinguished from simple gastroschisis by fetal stomach volume and stomach-bladder distance, using three-dimensional (3D) ultrasound. METHODS: This multicenter prospective cohort study was conducted in the Netherlands between 2010 and 2015. Of seven university medical centers, we included the four centers that performed longitudinal 3D ultrasound measurements at a regular basis. We calculated stomach volumes (n = 223) using Sonography-based Automated Volume Count. The shortest stomach-bladder distance (n = 241) was determined using multiplanar visualization of the volume datasets. We used linear mixed modelling to evaluate the effect of gestational age and type of gastroschisis (simple or complex) on fetal stomach volume and stomach-bladder distance. RESULTS: We included 79 affected fetuses. Sixty-six (84%) had been assessed with 3D ultrasound at least once; 64 of these 66 were liveborn, nine (14%) had complex gastroschisis. With advancing gestational age, stomach volume significantly increased, and stomach-bladder distance decreased (both P < .001). The developmental changes did not differ significantly between fetuses with simple and complex gastroschisis, neither for fetal stomach volume (P = .85), nor for stomach bladder distance (P = .78). CONCLUSION: Fetal stomach volume and stomach-bladder distance, measured during pregnancy using 3D ultrasonography, do not predict complex gastroschisis.

Standardization and reproducibility of sonographic stomach position grades in fetuses with congenital diaphragmatic hernia.

OBJECTIVES: The purpose of this study was to evaluate the reproducibility of stomach position grading in congenital diaphragmatic hernia (CDH) as proposed by Cordier et al and Basta et al after standardization of the methods at our center. METHODS: We collected sonographic images from 23 fetuses with left-sided CDH at our center from 2010 to 2018. Nine operators (one maternal fetal medicine expert and eight sonographers) reviewed the selected images and graded the stomach position according to the methods of Cordier et al and Basta et al. We assessed the interoperator agreement with Fleiss's kappa statistics. RESULTS: Overall agreement amongst all operators was moderate for both methods proposed by Cordier et al (k = 0.60, SE 0.07, 95% CI 0.47-0.73, P < .0001) and Basta et al (k = 0.60, SE 0.06, 95% CI 0.47-0.73, P < .0001). Interoperator agreement was moderate for grade 3 with the method by Cordier et al (k = 0.45, SE 0.09, 95% CI 0.27-0.64, P < .0001) and fair for grade 4 with the method by Basta et al (k = 0.33, SE 0.08, 95% CI 0.18-0.49 P < .0001). CONCLUSIONS: Our study demonstrates a fair to moderate interoperator agreement of the stomach position grading methods proposed in the literature after standardization of the methods at our center. Further multicenter studies are needed to confirm our results.

Molecular ontogeny of the stomach in the catshark Scyliorhinus canicula.

The origin of extracellular digestion in metazoans was accompanied by structural and physiological alterations of the gut. These adaptations culminated in the differentiation of a novel digestive structure in jawed vertebrates, the stomach. Specific endoderm/mesenchyme signalling is required for stomach differentiation, involving the growth and transcription factors: 1) Shh and Bmp4, required for stomach outgrowth; 2) Barx1, Sfrps and Sox2, required for gastric epithelium development and 3) Cdx1 and Cdx2, involved in intestinal versus gastric identity. Thus, modulation of endoderm/mesenchyme signalling emerges as a plausible mechanism linked to the origin of the stomach. In order to gain insight into the ancient mechanisms capable of generating this structure in jawed vertebrates, we characterised the development of the gut in the catshark Scyliorhinus canicula. As chondrichthyans, these animals retained plesiomorphic features of jawed vertebrates, including a well-differentiated stomach. We identified a clear molecular regionalization of their embryonic gut, characterised by the expression of barx1 and sox2 in the prospective stomach region and expression of cdx1 and cdx2 in the prospective intestine. Furthermore, we show that gastric gland development occurs close to hatching, accompanied by the onset of gastric proton pump activity. Our findings favour a scenario in which the developmental mechanisms involved in the origin of the stomach were present in the common ancestor of chondrichthyans and osteichthyans.

Development and growth of digestive system organs of European and Japanese quail at 14 days post-hatch.

The objective of this study was to evaluate the development and growth of the digestive system organs, from the 11th day of incubation until the 14 d post-hatch in European and Japanese quail. On days 11, 13 and 15 of incubation at hatch and at 4, 7, 10 and 14 d post-hatch, embryos or chicks of European and Japanese quail were analyzed. After 15 d of incubation, samples from stomach and small intestine were analyzed by microscopy. European quail had significantly heavier body weight at 15 d of incubation and after 4 d post-hatch. The digestive system weight progressively increased with age and was similar between European and Japanese quail at 11, 13, and 15 d of incubation and 10 d post-hatch, while relative weight of digestive system was similar between quail type with great values at 4 d post-hatch. For relative weight of the small intestine + pancreas, the weight of the proventriculus and of the gastric ventricle increased significant by among ages analyzed in both types of quail. At hatch, proventriculus had functional secretory cells and mucosa of gastric ventricle had a thin coilin membrane. In small intestine segments, at 15 d of incubation the height of the villi was similar among duodenum, jejunum, and ileum (80 µm). Villi had elongated shape towards the intestinal lumen, covered by enterocytes and dispersed goblet cells with PAS+ and AB+ contend in all segments. The number of goblet cell/villi increased in segments until 7 to 10 d post-hatch. Duodenum increases the villi up to 14 d, while the jejunum and ileum up to 10 and 4 d, respectively. Based on our data in digestive system growth, a shorter period of post-hatch fast and specific diets to quail during first days of growth is recommended to both quail types. It is concluded that the development and growth of different organs of the digestive system up to 14 d of age was similar between European and Japanese quail.

A time-resolved multi-omic atlas of the developing mouse stomach.

The mammalian stomach is structurally highly diverse and its organ functionality critically depends on a normal embryonic development. Although there have been several studies on the morphological changes during stomach development, a system-wide analysis of the underlying molecular changes is lacking. Here, we present a comprehensive, temporal proteome and transcriptome atlas of the mouse stomach at multiple developmental stages. Quantitative analysis of 12,108 gene products allows identifying three distinct phases based on changes in proteins and RNAs and the gain of stomach functions on a longitudinal time scale. The transcriptome indicates functionally important isoforms relevant to development and identifies several functionally unannotated novel splicing junction transcripts that we validate at the peptide level. Importantly, many proteins differentially expressed in stomach development are also significantly overexpressed in diffuse-type gastric cancer. Overall, our study provides a resource to understand stomach development and its connection to gastric cancer tumorigenesis.

Proposal for standardized prenatal ultrasound assessment of the fetus with congenital diaphragmatic hernia by the European reference network on rare inherited and congenital anomalies (ERNICA).

Congenital diaphragmatic hernia is a rare disease associated with high mortality and morbidity. Antenatal ultrasound screening identifies more than 70% of cases, providing the opportunity for in utero referral to a tertiary care center for expert assessment and perinatal management. Additional genetic and morphologic assessment may be used to rule out associated anomalies. In isolated cases, the outcome may be predicted prenatally by medical imaging. The combination of lung size and liver herniation is a widely accepted method to stratify fetuses into groups with an increasing degree of pulmonary hypoplasia and corresponding mortality rates. Ultrasound measurement of the observed to expected lung-to-head ratio (o/e LHR) is most widely used. The o/e LHR is an independent predictor of survival and short-term morbidity. Finally, evaluation of stomach position has recently been introduced as an indirect method to estimate severity of the disease in left-sided defects, as it has been shown to correlate with the proportion of intrathoracic liver. Herein, we propose a protocol for the standardized ultrasound assessment of fetuses with isolated CDH and individualized prediction of neonatal outcome.

Loss of smooth muscle myosin heavy chain results in the bladder and stomach developing lesion during foetal development in mice.

Smooth muscle myosin heavy chain (SM-MHC) is exclusively expresses in smooth muscle, which takes part in smooth muscle cell contraction. Here, we used an insertional mutation mouse whose heavy polypeptide 11 (Myh11) gene has been disrupted and no SM-MHC protein has been detected. Compared to the wild-type and SM-MHC+/- mice, the SM-MHC-/- neonates had large round bellies, thin-walled giant bladders, and large stomachs with huge gas bubbles. Most of it died within 10 h and the rest within 20 h after birth. Further analysis of the developing foetuses from 16.5 days postcoitum (dpc) stage to newborn showed no significant (P<0.05) difference in the ratio of Mendelian inheritance and average body weight among SM-MHC+/+ , SM-MHC+/- and SM-MHC-/- mice, whereas the abnormal exterior appearance was observed in each SM-MHC-/- bladders from 16.5 dpc. Histological analysis showed no difference in stomach tissues but evidently thin-walled smooth muscle layer and a giant cavity in bladders of SM-MHC-/- foetuses at various stages from 15.5 dpc to newborn. The results indicated that the defect of SM-MHC lead to the bladder developing lesions initially at 15.5 dpc stage in mouse and also implied that the SM-MHC loss might result in the gas bubbles in stomach. The study should facilitate further detailed analyses of the potential role of SM-MHC in bladder and stomach development.

Multiple roles of epithelial heparan sulfate in stomach morphogenesis.

Heparan sulfate proteoglycans (HSPGs) have been shown to regulate various developmental processes. However, the function of heparan sulfate (HS) during the development of mammalian stomach has not been characterized yet. Here, we investigate the role of epithelial HS in embryonic stomach by examining mice deficient in the glycosyltransferase gene Ext1 We show that HS exhibits a specific and dynamic expression pattern in mouse embryonic stomach. Depletion of the epithelial HS leads to stomach hypoplasia, with phenotypic differences in the gastric mucosa between the forestomach and hindstomach. In the posterior stomach, HS depletion disrupts glandular stomach patterning and cytodifferentiation via attenuation of Fgf signaling activity. Inhibition of Fgf signaling in vitro recapitulates the patterning defect. Ligand and carbohydrate engagement assay (LACE) reveals a diminished assembly of Fgf10 and Fgfr2b in the mutant. In the anterior stomach, loss of epithelial HS leads to stratification and differentiation defects of the multilayered squamous epithelium, along with reduced Hh and Bmp signaling activity. Our data demonstrate that epithelial HS plays multiple roles in regulating mammalian stomach morphogenesis in a regional-specific manner.

Morphology of alpaca (Vicugna pacos) embryos in the first third of pregnancy.

The breeding of South American camelids is the main economic activity of the high Andean region of South America and it, is potentially, the most profitable resource in of the Puna environmental conditions of the Puna. The duration of the gestation in alpaca is 339.7 ± 12 days. The objective of the present work was to macroscopically and microscopically describe the ontogenic development of the splanchnic cavities of the alpaca and to determine the gestational time in which the post-cranial ossification centers are observed in the embryos/fetuses of this species, from day 21 to 107 of gestation. The documentation of normal ontogenic development, which is vacant for this period, is of the utmost importance to understand the consequences of the alterations at the different gestational times, as well as for the estimation of the gestational age in the case of abortions. Forty-seven alpaca specimens of both sexes, at different times of their gestational development, collected during slaughter at local slaughterhouses of the Department of Huancavelica, Peru, were evaluated. Specimens were assigned to seven groups according to their morphological characteristics. The embryogenesis in the alpaca was characterized by a series of changes comparable to those occurring in other mammals with similar gestational periods. Despite these similarities, species differences were found in some organs as stomach, which are observed too in adult individuals.

Computed tomography study of the fetal development of the dairy cow stomach complex.

In the fetal development of animals, critical physiological and anatomical events influence the long-term health and performance of the offspring. To identify the critical growth phases of the fetal bovine stomach, we used computed tomography imaging on 30 German Holstein fetuses to examine the fetal bovine stomach in situ. Computed tomography allows the study of diverse parameters such as the volume of the stomach chambers in situ without the need for sophisticated filling preparation techniques. The absolute volume, relative volume, and monthly volume increase of each stomach chamber were determined. Computed tomography was a reliable method for in situ examination of the fetal bovine stomach complex from the third month of gestation onward. It was able to detect an abnormal position of the abomasum in 2 fetuses. The crown-rump length of the fetuses studied ranged from 9.5 to 89 cm (from 2.2 to 8.3 mo of gestation). Over this timeline, the changes in the relative volumes of the ruminoreticulum and abomasum were inversely related. Until mo 5 of gestation, the relative volume of the ruminoreticulum increased steadily, whereas that of the abomasum decreased. Thereafter, the relative volume of the ruminoreticulum became gradually smaller, and that of the abomasum became larger; by mo 8, the abomasum was larger than the ruminoreticulum. All stomach chambers had large increases in volume over the gestation period and we observed differences in development patterns and volume changes of the individual stomach chambers over this period. The largest monthly volume increase of the stomach complex was between mo 4 and 5 of gestation. In this period, the volume of the ruminoreticulum increased 43.8 times, that of the omasum 38.9 times, and that of the abomasum 30.03 times. Between mo 5 and 6 of gestation, the abomasum had another growth spurt, with a monthly volume increase of 10.4 times. These 2 time points in the gestation period may be critical phases of fetal development that should be considered in the management of pregnant cattle.

Stomach curvature is generated by left-right asymmetric gut morphogenesis.

Left-right (LR) asymmetry is a fundamental feature of internal anatomy, yet the emergence of morphological asymmetry remains one of the least understood phases of organogenesis. Asymmetric rotation of the intestine is directed by forces outside the gut, but the morphogenetic events that generate anatomical asymmetry in other regions of the digestive tract remain unknown. Here, we show in mouse and Xenopus that the mechanisms that drive the curvature of the stomach are intrinsic to the gut tube itself. The left wall of the primitive stomach expands more than the right wall, as the left epithelium becomes more polarized and undergoes radial rearrangement. These asymmetries exist across several species, and are dependent on LR patterning genes, including Foxj1, Nodal and Pitx2 Our findings have implications for how LR patterning manifests distinct types of morphological asymmetries in different contexts.