Chirality-Induced Spin Polarization over Macroscopic Distances in Chiral Disilicide Crystals.

A spin-polarized state is examined under charge current at room temperature without magnetic fields in chiral disilicide crystals NbSi_{2} and TaSi_{2}. We found that a long-range spin transport occurs over ten micrometers in these inorganic crystals. A distribution of crystalline grains of different handedness is obtained via location-sensitive electrical transport measurements. The sum rule holds in the conversion coefficient in the current-voltage characteristics. A diamagnetic nature of the crystals supports that the spin polarization is not due to localized electron spins but due to itinerant electron spins. A large difference in the strength of antisymmetric spin-orbit interaction associated with 4d electrons in Nb and 5d ones in Ta is oppositely correlated with that of the spin polarization. A robust protection of the spin polarization occurs over long distances in chiral crystals.

Chirality-Induced Spin-Polarized State of a Chiral Crystal CrNb_{3}S_{6}.

Chirality-induced spin transport phenomena are investigated at room temperature without magnetic fields in a monoaxial chiral dichalcogenide CrNb_{3}S_{6}. We found that spin polarization occurs in these chiral bulk crystals under a charge current flowing along the principal c axis. Such phenomena are detected as an inverse spin Hall signal which is induced on the detection electrode that absorbs polarized spin from the chiral crystal. The inverse response is observed when applying the charge current into the detection electrode. The signal sign reverses in the device with the opposite chirality. Furthermore, the spin signals are found over micrometer length scales in a nonlocal configuration. Such a robust generation and protection of the spin-polarized state is discussed based on a one-dimensional model with an antisymmetric spin-orbit coupling.

Elevated Na+/H+ exchanger-1 expression enhances the metastatic collective migration of head and neck squamous cell carcinoma cells.

Cancer cells can migrate as collectives during invasion and/or metastasis; however, the precise molecular mechanisms of this form of migration are less clear compared with single cell migration following epithelial-mesenchymal transition. Elevated Na+/H+ exchanger1 (NHE1) expression has been suggested to have malignant roles in a number of cancer cell lines and in vivo tumor models. Furthermore, a metastatic human head and neck squamous cell carcinoma (HNSCC) cell line (SASL1m) that was isolated based on its increased metastatic potential also exhibited higher NHE1 expression than its parental line SAS. Time-lapse video recordings indicated that both cell lines migrate as collectives, although with different features, e.g., SASL1m was much more active and changed the direction of migration more frequently than SAS cells, whereas locomotive activities were comparable. SASL1m cells also exhibited higher invasive activity than SAS in Matrigel invasion assays. shRNA-mediated NHE1 knockdown in SASL1m led to reduced locomotive and invasive activities, suggesting a critical role for NHE1 in the collective migration of SASL1m cells. SASL1m cells also exhibited a higher metastatic rate than SAS cells in a mouse lymph node metastasis model, while NHE1 knockdown suppressed in vivo SASL1m metastasis. Finally, elevated NHE1 expression was observed in human HNSCC tissue, and Cariporide, a specific NHE1 inhibitor, reduced the invasive activity of SASL1m cells, implying NHE1 could be a target for anti-invasion/metastasis therapy.

A detailed comparison of mouse and human cardiac development.

BACKGROUND: Mouse mutants are used to model human congenital cardiovascular disease. Few studies exist comparing normal cardiovascular development in mice vs. humans. We carried out a systematic comparative analysis of mouse and human fetal cardiovascular development. METHODS: Episcopic fluorescence image capture (EFIC) was performed on 66 wild-type mouse embryos from embryonic day (E) 9.5 to birth; 2-dimensional and 3-dimensional datasets were compared with EFIC and magnetic resonance images from a study of 52 human fetuses (Carnegie stage 13-23). RESULTS: Time course of atrial, ventricular, and outflow septation were outlined and followed a similar sequence in both species. Bilateral venae cavae and prominent atrial appendages were seen in the mouse fetus; in human fetuses, atrial appendages were small, and a single right superior vena cava was present. In contrast to humans with separate pulmonary vein orifices, a pulmonary venous confluence with one orifice enters the left atrium in mice. CONCLUSION: The cardiac developmental sequences observed in mouse and human fetuses are comparable, with minor differences in atrial and venous morphology. These comparisons of mouse and human cardiac development strongly support that mouse morphogenesis is a good model for human development.

The regulation of endogenous retinoic acid level through CYP26B1 is required for elevation of palatal shelves.

BACKGROUND: In previous studies, we investigated the effects of excess retinoic acid (RA) during palatogenesis by RA administration to pregnant mice. In the present study, we deleted Cyp26b1, one of the RA-degrading enzymes, to further study the effects of excess RA in the normal developing palate and to understand how endogenous levels of RA are regulated. RESULTS: Excess RA, due to the absence of Cyp26b1, targets cells in the bend region of the palatal shelves and inhibits their horizontal elevation, leading to cleft palate. An organ culture of Cyp26b1-/- palatal shelves after tongue removal did not rescue the impaired elevation of the palatal shelves. The expression of Fgf10, Bmp2, and Tbx1, important molecules in palatal development, was down-regulated. Cell proliferation was decreased in the bend region of palatal shelves. Tongue muscles were hypoplastic and/or missing in Cyp26b1-/- mice. CONCLUSIONS: We demonstrated that CYP26B1 is essential during palatogenesis. Excess RA due to the lack of Cyp26b1 suppresses the expression of key regulators of palate development in the bend region, resulting in a failure in the horizontal elevation of the palatal shelves. The regulation of RA signaling through CYP26B1 is also necessary for the development of tongue musculature and for tongue depression.

Cerebral edema associated with diabetic ketoacidosis: Two case reports.

Background: Diabetic ketoacidosis (DKA) is associated with a high mortality rate, especially if cerebral edema develops during the disease course. It is rarer and more severe in adults than in children. We present cases of two patients with cerebral edema-related DKA. Case presentation: The first patient was a 38-year-old man with diabetes mellitus who presented with DKA-related disturbed consciousness. Although glycemic correction was performed slowly, he showed pupil dilation 11 h later. He underwent emergency ventricular drainage, but died of cerebral herniation. The second patient was a 25-year-old woman who presented with impaired consciousness secondary to DKA. Head computed tomography showed subarachnoid hemorrhage and cerebral edema. No related intraoperative findings were observed; it was concluded that the first computed tomography scan revealed pseudo-subarachnoid hemorrhage. Conclusion: Diabetic ketoacidosis-related cerebral edema develops despite treatment according to guidelines and is difficult to predict. Therefore, adult patients should be treated cautiously during DKA management.

Dysregulation of the PDGFRA gene causes inflow tract anomalies including TAPVR: integrating evidence from human genetics and model organisms.

Total anomalous pulmonary venous return (TAPVR) is a congenital heart defect inherited via complex genetic and/or environmental factors. We report detailed mapping in extended TAPVR kindreds and mutation analysis in TAPVR patients that implicate the PDGFRA gene in the development of TAPVR. Gene expression studies in mouse and chick embryos for both the Pdgfra receptor and its ligand Pdgf-a show temporal and spatial patterns consistent with a role in pulmonary vein (PV) development. We used an in ovo function blocking assay in chick and a conditional knockout approach in mouse to knock down Pdgfra expression in the developing venous pole during the period of PV formation. We observed that loss of PDGFRA function in both organisms causes TAPVR with low penetrance (approximately 7%) reminiscent of that observed in our human TAPVR kindreds. Intermediate inflow tract anomalies occurred in a higher percentage of embryos (approximately 30%), suggesting that TAPVR occurs at one end of a spectrum of defects. We show that the anomalous pulmonary venous connection seen in chick and mouse is highly similar to TAPVR discovered in an abnormal early stage embryo from the Kyoto human embryo collection. Whereas the embryology of the normal venous pole and PV is becoming understood, little is known about the embryogenesis or molecular pathogenesis of TAPVR. These models of TAPVR provide important insight into the pathogenesis of PV defects. Taken together, these data from human genetics and animal models support a role for PDGF-signaling in normal PV development, and in the pathogenesis of TAPVR.

Imaging of the human embryo with magnetic resonance imaging microscopy and high-resolution transvaginal 3-dimensional sonography: human embryology in the 21st century.

OBJECTIVE: This article illustrates early human development, demonstrated by magnetic resonance (MR) microscopy and computer graphics on human embryo specimens, and advanced 3-dimensional (3D) sonography in clinical obstetrics. STUDY DESIGN: Fixed human embryo specimens were imaged by MR microscopy coupled with computer graphics technology. Transvaginal 3D sonography was used to examine embryos in ongoing gestations and compare embryological findings. RESULTS: Advances in MR microscopy allowed detailed visualization of embryo specimens. Computational techniques allowed reconstruction of tomographic images to render them as 3D structures. High-resolution transvaginal 3D sonography produced images that demonstrated the neural tube from week 6; brain anatomy and vasculature from week 8; and craniofacial morphology and other structures from week 11. CONCLUSION: MR microscopy is a novel technique that enables nondestructive, high-resolution imaging of embryo specimens. On the other hand, 3D sonoembryology allows detailed anatomical visualization in vivo and is the basis for the assessment of anomalies as well as human development.

Developmental atlas of the early first trimester human embryo.

Rapid advances in medical imaging are facilitating the clinical assessment of first-trimester human embryos at increasingly earlier stages. To obtain data on early human development, we used magnetic resonance (MR) imaging and episcopic fluorescence capture (EFIC) to acquire digital images of human embryos spanning the time of dynamic tissue remodeling and organogenesis (Carnegie stages 13 to 23). These imaging data sets are readily resectioned digitally in arbitrary planes, suitable for rapid high-resolution three-dimensional (3D) observation. Using these imaging datasets, a web-accessible digital Human Embryo Atlas (http://apps.devbio.pitt.edu/humanatlas/) was created containing serial 2D images of human embryos in three standard histological planes: sagittal, frontal, and transverse. In addition, annotations and 3D reconstructions were generated for visualizing different anatomical structures. Overall, this Human Embryo Atlas is a unique resource that provides morphologic data of human developmental anatomy that can accelerate basic research investigations into developmental mechanisms that underlie human congenital anomalies.

A life-table analysis of the intrauterine fate of malformed human embryos and fetuses.

BACKGROUND: Various malformations are frequently encountered in spontaneously aborted embryos and fetuses. Thus, spontaneous abortion appears to be a screening device for abnormal conceptuses ("teratothanasia"). However, the prevalence rate of abnormal conceptuses at each gestational stage is unknown and the true picture of prenatal natural selection remains to be elucidated. METHODS: An in utero life-table of normal and malformed human conceptuses was constructed utilizing the data for human embryos and fetuses procured after therapeutic abortion and kept in the Kyoto Collection of Human Embryos (N = 21,798). RESULTS: The prevalence of external major malformations was estimated to be 9.6% at the start of the fifth week after fertilization and drop to 9.2, 8.5, and 7.5% during the following weeks. The malformation rate decreased to 5.3% by the end of the embryonic period (the eighth week), 2.8% by the 13th week and 1% at term. The prenatal mortality rate of externally malformed conceptuses between the fifth week of gestation and term was 92.8%, whereas the corresponding rate for externally normal embryos was 24.9%. The prenatal mortality rates of embryos with neural tube defects and holoprosencephaly were 96.0 and 99.7%, respectively. CONCLUSIONS: Abnormal development occurs frequently early in development and many of the malformed embryos/fetuses die in utero to end in spontaneous abortion. Natural prenatal screening of abnormal conceptuses most likely contributes to reducing the birth of malformed infants.

Comparison of direct anterior approach and posterior approach total hip arthroplasty: More than 5-year follow-up.

PURPOSE: In this study we compare the surgical outcome of DAA and PA more than 5-year follow-up evaluation. MATERIALS AND METHODS: This is a retrospective cohort single-surgeon study of consecutive primary THAs using the DAA or PA. RESULTS: There was no significant difference in HHS and JHEQ score. Posterior dislocation occurred in 4 cases in PA group (9.5%, p = 0.038) while there was no dislocation in DAA group. CONCLUSION: Both DAA and PA yield good results at the final follow-up in terms of function, quality of life, and survivorship. However dislocation was significantly higher in PA group.

25th anniversary of the Berlin workshop on developmental toxicology: DevTox database update, challenges in risk assessment of developmental neurotoxicity and alternative methodologies in bone development and growth.

25 years after the first Berlin Workshop on Developmental Toxicity this 10th Berlin Workshop aimed to bring together international experts from authorities, academia and industry to consider scientific, methodologic and regulatory aspects in risk assessment of developmental toxicity and to debate alternative strategies in testing developmental effects in the future. Proposals for improvement of the categorization of developmental effects were discussed as well as the update of the DevTox database as valuable tool for harmonization. The development of adverse outcome pathways relevant to developmental neurotoxicity (DNT) was debated as a fundamental improvement to guide the screening and testing for DNT using alternatives to animal methods. A further focus was the implementation of an in vitro mechanism-based battery, which can support various regulatory applications associated with the assessment of chemicals and mixtures. More interdisciplinary and translation research should be initiated to accelerate the development of new technologies to test developmental toxicity. Technologies in the pipeline are (i) high throughput imaging techniques, (ii) models for DNT screening tests, (iii) use of computer tomography for assessment of thoracolumbar supernumerary ribs in animal models, and (iv) 3D biofabrication of bone development and regeneration tissue models. In addition, increased collaboration with the medical community was suggested to improve the relevance of test results to humans and identify more clinically relevant endpoints. Finally, the participants agreed that this conference facilitated better understanding innovative approaches that can be useful for the identification of developmental health risks due to exposure to chemical substances.

Early pathogenesis of holoprosencephaly.

Holoprosencephaly (HPE) is one of the most common malformations encountered in early human embryos. It is assumed that more than 90% of HPE embryos die in utero and are eliminated by spontaneous abortion. Embryonic HPE displays some characteristic craniofacial phenotypes, which are not necessarily comparable to those in postnatal HPE cases. In this article, we summarize our studies on HPE in human embryos and discuss the pathogenesis of HPE malformations.

Rudimentary claws and pigmented nail-like structures on the distal tips of the digits of Wnt7a mutant mice: Wnt7A suppresses nail-like structure development in mice.

BACKGROUND: As Wnt7a mutant mice exhibit double ventral structures in the digits of autopods, it has been accepted that dorsal-ventral identity in limb development is regulated by the Wnt7a signal. The most important evidence for this was the presence of surface pads, typical characteristics of ventral structures, on the dorsal side of digital tips and at the base of digits and their pigmentation. METHODS: The morphologic features of the appendages on the distal tips of digits were inspected in the fore- and hindlimbs of mice having a different Wnt7a mutation. The digital structures were examined macroscopically and histologically. RESULTS: The Wnt7a homozygous mutant mice with defects in postaxial digits had rudimentary claws or claws and pigmented nail-like structures, instead of dorsal pads, on the distal digital tips and hairs on the dorsal surface of the digits of fore- and hindlimbs. Furthermore, pigmented ectopic nail-like structures but not pads were also present on the dorsal surface of the base of digits. Double ventral structures were observed in the bones and tendons, excluding pads in digital areas. CONCLUSIONS: These findings suggest that Wnt7a is not necessarily an exclusive dorsalizing signal to the dorsal ectoderm of the digital areas of autopods. Rather, the Wnt7a signal may participate in suppression of the development of pigmented nail-like structures in normal limb development. This means that even rodents, a species lower than primates in the evolution from claws to nails, have molecular potential to develop cutaneous appendages similar to nails at their location.

Methylnitrosourea induces neural progenitor cell apoptosis and microcephaly in mouse embryos.

BACKGROUND: Prenatal exposure to methylnitrosourea (MNU), an alkylating agent, induces microcephaly in mice. However, its pathogenetic mechanism has not been clarified, especially that in the development of the cerebral cortex. METHODS: ICR mice were treated with MNU at 10 mg/kg intraperitoneally on day 13.5 or 15.5 of gestation, and the embryos were observed histologically 24 hr after treatment with MNU or at term. To clarify the pathogenesis of microcephaly and histological changes, especially apoptosis, neurogenesis, and neural migration/positioning, we performed histological analysis employing a cell-specific labeling experiment using thymidine-like substances (BrdU, CldU, and IdU) and markers of neurons/neural stem cells. RESULTS: Histological abnormalities of the dorsal telencephalon, and the excessive cell death of proliferative neural progenitor/stem cells were noted in the MNU-treated embryos. The highest frequencies of cell death occurred at 36 hr after MNU treatment, and little or no neurogenesis was observed in the ventricular zone of the dorsal telencephalon. Abnormality of the radial migration was caused by the reduction of radial fibers in the radial glias. Birth-date analysis revealed the abnormal positioning of neurons and aberrant lamination of the cerebral cortex. CONCLUSIONS: Our data suggest that prenatal exposure to MNU induces the excessive cell death of neural precursor/stem cells, and the defective development of the cerebral cortex, resulting in microcephalic abnormalities.

Mechanism of skull suture maintenance and interdigitation.

Skull sutures serve as growth centers whose function involves multiple molecular pathways. During periods of brain growth the sutures remain thin and straight, later developing complex fractal interdigitations that provide interlocking strength. The nature of the relationship between the molecular interactions and suture pattern formation is not understood. Here we show that by classifying the molecules involved into two groups, stabilizing factors and substrate molecules, complex molecular networks can be modeled by a simple two-species reaction-diffusion model that recapitulates all the known behavior of suture pattern formation. This model reproduces the maintenance of thin sutural tissue at early stages, the later modification of the straight suture to form osseous interdigitations, and the formation of fractal structures. Predictions from the model are in good agreement with experimental observations, indicating that the model captures the essential nature of the interdigitation process.

Variability in human embryonic development and its implications for the susceptibility to environmental teratogenesis.

Considerable variability is observed in the size and developmental stage among human embryos at a given gestational age, suggesting that prenatal development does not proceed at the same speed in every embryo. Such variability in embryonic development seems to occur in many (probably all) animal species, and is probably a normal "biologic" phenomenon to some extent. In the case of humans, some other factors (e.g., maternal memory bias, difficulty in assessing the timing of ovulation and fertilization) make it more difficult to assess the developmental stage of embryos in utero. Such facts related to human embryonic development should be taken into account when the teratogenic risk of a human embryo is considered.

Terminology of developmental abnormalities in common laboratory mammals (Version 2).

This update (Version 2) of the Terminology of Developmental Abnormalities in Common Laboratory Mammals (Version 1) by Wise et al. (1997) incorporates improvements and enhancements to both content and organization of the terminology, to enable greater flexibility in its application, while maintaining a consistent approach to the description of findings. The revisions are the result of an international collaboration among interested organizations, advised by individual experts and the outcomes of several workshops. The terminology remains organized into tables under the broad categories of external, visceral, and skeletal observations, following the manner in which data are typically collected and recorded in developmental toxicity studies. This arrangement of the tables, as well as other information provided in appendices, is intended to facilitate the process of specimen evaluation at the laboratory bench level. Only the commonly used laboratory mammals (i.e., rats, mice, rabbits) are addressed in the current terminology tables. The inclusion of other species that are used in developmental toxicity testing, such as primates, is considered outside the scope of the present update. Similarly, categorization of findings as, for example, "malformation" or "variation" remains unaddressed, in accordance with the overall principle that the focus of this document is descriptive terminology and not diagnosis/interpretation. The skeletal terms have been augmented to accommodate cartilage findings.

Isolated levocardia: prenatal diagnosis and management.

Isolated levocardia (IL) is a rare condition of situs anomaly in which there is a normal left-sided heart (levocardia) with dextro position of the abdominal viscera. IL has been reported in children and adults with complex cardiac defects, whereas there are only few published reports regarding the prenatal diagnosis of IL. We report two prenatal cases of IL diagnosed by ultrasonography and magnetic resonance imaging (MRI). In both cases, fetal cardiac function remained within the normal range throughout pregnancy, and no treatment for the heart was required after birth. For the dextro position of abdominal viscera, one case was followed without any surgical procedure, but the other case required prophylactic operation due to malrotation of the small intestine. Although the prognosis of IL largely depends on the severity of associated cardiac anomaly, future bowel obstruction caused by intestinal malrotation may also be life-threatening. In this respect, prenatal diagnosis of IL is important, even when there is no associated cardiac structural anomaly. If IL is suspected in routine fetal ultrasonography, MRI may be recommended to obtain more detailed information on the anatomy of abdominal viscerae, and careful observation for bowel problems is required, especially after oral nutrition is started.

Expression dynamics of the LIM-homeobox genes, Lhx1 and Lhx9, in the diencephalon during chick development.

The diencephalon is the caudal part of the developing forebrain, which corresponds to prosomeres 1 to 3. The mature diencephalon is functionally and anatomically divided into well-defined nuclei. Previous researches have shown that LIM-homeobox genes are important transcription factors during diencephalon regionalization in mice. Here we examined expression patterns of several chick orthologs of LIM-homeobox genes. Lhx1 and Lhx9 were expressed in the diencephalon from early stages and their expression in the diencephalon became restricted to prosomeres 1 and 2 in distinct fashions. Then we also studied the regulatory effects of possible upstream signals by in ovo electroporation. Lhx1 was found to be up-regulated by Shh signaling. Whereas Lhx9 was up-regulated by Wnt3a and Fgf15, it was down-regulated by Shh. Our data suggest that the LIM-homeobox genes, Lhx1 and Lhx9, regulated by ventral and/or dorsal signals, may play important roles in controlling regionalization of the diencephalon during chick development.