近年来,各种新的教育理念和模式被引入到医学教学改革中,特别是信息与网络通信技术快速发展,逐渐渗透融入到医学教育中,医学教育信息化程度得以迅速提高,促进了医学教育资源建设[1-2].微课就是顺应信息技术高速发展的时代背景而产生的新型教学模式,并且已经成为我国教育信息化资源建设和教学改革的研究热点[3].而对分课堂是顺应中国高等教育的国情提出的一种较新的大学教学模式[4].医学遗传学是交叉学科,学习难度大,大部分遗传病较为罕见,且向低年级医学生开课,传统课堂教学效果不佳,如何推进医学遗传学教学改革,提高医学遗传学的教学效果,是教师所面临的一个重要问题[5-6].

Hyperphosphorylation of tau and imbalanced expression of 3R-tau and 4R-tau as a result of dysregulation of tau exon 10 splicing are believed to be pivotal to the pathogenesis of tau pathology, but the molecular mechanism leading to the pathologic tau formation in Alzheimer’s disease (AD) brain is not fully understood. In the present study, we found that casein kinase 1ε (CK1ε) was increased significantly in AD brains. Overexpression of CK1ε in cultured cells led to increased tau phosphorylation at many sites. Moreover, we found that CK1ε suppressed tau exon 10 inclusion. Levels of CK1ε were positively correlated to tau phosphorylation, 3R-tau expression and tau pathology, and negatively correlated to 4R-tau in AD brains. Overexpression of CK1ε in the mouse hippocampus increased tau phosphorylation and impaired spontaneous alternation behavior. These data suggest that CK1ε is involved in the regulation of tau phosphorylation, the alternative splicing of tau exon 10, and cognitive performance. Up-regulation of CK1ε might contribute to tau pathology by hyperphosphorylating tau and by dysregulating the alternative splicing of tau exon 10 in AD.

Anthropoid primates arose during the Eocene approximately 55 million years ago (mya), and extant anthropoids share a most recent common ancestor ∼40mya. Paleontology has been very successful at describing the morphological phenotypes of extinct anthropoids. Less well understood is the molecular biology of these extinct species as well as the phenotypic consequences of evolutionary variation in their genomes. Here we resurrect the most recent common ancestral anthropoid estrogen receptor β gene (ESR2) and demonstrate that the function of this ancestral estrogen receptor has been maintained during human descent but was altered during early New World monkey (NWM) evolution by becoming a more potent transcriptional activator. We tested hypotheses of adaptive evolution in the protein coding sequences of ESR2, and determined that ESR2 evolved via episodic positive selection on the NWM stem lineage. We separately co-transfected ESR2 constructs for human, NWM, and the anthropoid ancestor along with reporter gene vectors and performed hormone binding dose response experiments that measure transactivation activity. We found the transactivation potentials of the ancestral and human sequences to be significantly lower (p<0.0001 in each comparison) than that of the NWM when treated with estradiol, the most prevalent estrogen. We conclude the difference in fold activation is due to positive selection in the NWM ERβ ligand binding domain. Our study validates inferential methods for detecting adaptive evolution that predict functional consequences of nucleotide substitutions and points a way toward examining the functional consequences of positive Darwinian selection.

BACKGROUND:Human chorionic gonadotropin (hCG) can play a crucial role in angiogenesis. In the present study, we focused on hCG to gain insight into its potential effects on vasculogenic mimicry (VM) in ovarian cancer cells.METHODS:Ovarian cancer OVCAR-3 cells were incubated with different concentrations of recombinant hCG in 3-dimensional cultures. VM was identified by morphological observations and vascular endothelial cell marker detection in OVCAR-3 cells. Expression of hCG, hypoxia-inducible factor-1α (HIF-1α), and the endothelial cell markers CD31, VEGF, and factor VIII were detected by reverse transcription polymerase chain reaction and western blotting. The effect of hCG on endothelial cell-marker expression in ovarian cancer cells was further explored using small interfering RNA (siRNA) and plasmid-based approaches.RESULTS:Incubation of OVCAR-3 cells with recombinant hCG induced vessel-like network formation, which was accompanied by significant elevation of vascular marker expression. Attenuation of hCG expression by siRNA in OVCAR-3 cells suppressed the expression of endothelial cell markers and HIF-1α by tumour cells. Overexpression of hCG in OVCAR-3 cells resulted in increased expression of endothelial cell markers and HIF-1α.CONCLUSIONS:HCG was crucial for changing the phenotype of OVCAR-3 cells to endothelial-like cells. The effect of hCG induction on VM in ovarian cancer cells is potentially associated with HIF-1α.

临床上遗传性罕见病存在高误诊、治疗不规范、预防不得力等问题。本文从医学遗传学课程中加强罕见病教学角度，提出精选教学内容，采用多元化教学，参与临床实践等措施，就如何提高医学生罕见病的认知水平进行了初步探讨。

Alternative splicing of tau exon 10 generates tau with three or four microtubule-binding repeats (3R-tau or 4R-tau). The ratio of 3R-tau to 4R-tau is approximately 1:1 in the adult normal human brain. Disturbances in the ratio result in neurodegenerative tauopathies. Splicing factor SC35 acts on a SC35-like element located at the 5′ end of tau exon 10 and promotes tau exon 10 inclusion. Here, we report that protein kinase (PKA) was able to interact and phosphorylate SC35. Activation or overexpression of PKA catalytic subunits promoted SC35-mediated tau exon 10 inclusion. Four PKA catalytic subunits, α1, α2, β1, and β2, all enhanced SC35-promoted tau exon 10 inclusion. SC35 has four putative PKA phosphorylation sites, Ser121, Ser128, Ser130, and Ser171. Pseudophosphorylation (SC354E) and blockage (SC354A) of phosphorylation of SC35 at these four sites increased and decreased, respectively, SC35’s ability to promote tau exon 10 inclusion. Moreover, PKA catalytic subunits no longer further enhanced tau exon 10 inclusion when these four were mutated to either alanine or glutamate. These results suggest that PKA interacts with and phosphorylates SC35 and enhances SC35-promoted tau exon 10 inclusion. In Alzheimer’s brain, down-regulation of the PKA pathway could lead to dysregulation of tau exon 10, contributing to tau pathogenesis.

Microtubule-associated protein tau is abnormally hyperphosphorylated and deposited as intracellular neurofibrillary tangles (NFTs) in Alzheimer disease (AD) brain and related tauopathies. The altered tau is believed to be pivotal to the pathogenesis of AD, but the molecular mechanism leading to the abnormal hyperphosphorylation of this protein is not fully understood. Casein kinase 1 e (CK1ε) belongs to CK1 family of ubiquitous serine/threonine-specific protein kinases. By phosphorylating many different substrates, such as cellular enzymes, transcriptional proteins, cytoskeletal and non-cytoskeletal proteins, viral oncogenes and receptors, it regulates diverse cellular processes, including circadian rhythms, cellular signaling, vesicular trafficking, cell division, DNA repair pathways. In the present study, we determined the role of CK1 e on tau pathogenesis in A D. The levels of CK1ε protein and mRNA in AD and control human brain tissues were determined by Western blots and quantitative real-time PCR, respectively. The levels of tau and phosphorylated tau were detected by immuno-dot blots. The relationship between CK1ε and tau phosphorylation was analyzed by the Pearson correlation analysis. We found that in AD brain, the level of CK1ε at either protein or mRNA was increased significantly. CK1 e was mainly expressed in neurons. Overexpression CK1ε in HEK-293FT cells or primary cultured neurons led to increased tau phosphorylation at many sites. In addition to phosphorylate tau, CK1 e also regulated the alternative splicing of tau exon 10. Over-expression of CK1 e suppressed tau exon 10 inclusion, while knock down CK1 e promoted tau exon 10 inclusion. CK1 e level was positively correlated to tau phosphorylation in human brains. These data suggest that CK1 e is involved in the regulation of tau phosphorylation and the alternative splicing of tau exon 10. Up-regulation of CK1 e could be involved in tau pathology via phosphorylating tau and dysregulating the alternative splicing of tau exon 10 in AD and related tauopathies.

Transactive response DNA-binding protein of 43 kDa (TDP-43) is an RNA and DNA binding protein and involved in transcriptional repression, RNA splicing and RNA metabolism. This protein is the major component of neuronal inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions, now referred to as FTLD-TDP. In addition, TDP-43 pathology has now been detected in a number of other neurodegenerative diseases, many associated with tau pathology, including Guam Parkinson dementia complex and Alzheimer's disease (AD). In AD brain, neuronal microtubule-associated protein tau is hyperphosphorylated and aggregated into neurofibrillary tangles, a hall marker of this disease and related tauopathies. The alternative splicing of tau exon 10 generates tau isoforms with three or four microtubule-binding repeats (3R-tau or 4R-tau). In normal adult human brain, approximately equal levels of 3R- and 4R-tau are expressed. Alteration in 3R-tau/4R-tau ratio is sufficient to trigger tauopathies. In the present study, we investigated the regulation of TDP-43 on alternative splicing of tau exon 10. We over-expressed or knocked down TDP-43 expression, and determined the effects of TDP-43 and mutations related to FTLD-TDP or ALS or tau exon 10 splicing by reverse transcription PCR (RT-PCR). We found that TDP-43 regulated tau exon splicing. Overexpression of TDP-43 promoted tau exon 10 inclusion and knock down TDP-43 suppressed tau exon 10 inclusion. FTLD-TDP or ALS related mutations promoted tau exon 10 inclusion more efficiently. TDP-43 is a phosphor-protein and phosphorylated by casein kinase 1 (CK1). CK1delta and CK1epsilon modulated TDP-43-regulated tau exon 10 splicing. 1) TDP-43 regulates the alternative splicing of tau exon 10; 2) TDP-43 promotes tau exon 10 inclusion; 3) CK1delta and CK1epsilon phosphorylates TDP-43 and modulates its function in tau exon 10 splicing.

Plant Ash1 SET proteins are involved in H3K36 methylation, and play a key role in plant reproductive development. Genes encoding Ash1 SET proteins constitute a multigene family in which the copy number varies among plant species and functional divergence appears to have occurred repeatedly. To investigate the evolutionary history and functional differentiation of the Ash1 SET gene family, we made a comprehensive evolutionary analysis of this gene family from eleven major representatives of green plants. A novel deep sister relationship grouping previously resolved II-1 and II-2 orthologous groups was identified. The absence of AWS domain in the group II-2 suggests that the independent losses of AWS domain have occurred during evolution. A diversity of gene structures in plant Ash1 SET gene family have been presented since the divergence of Physcomitrella patens (moss) from the other land plants. A small proportion of codons in SET domain regions were detected to be under positive selection along the branches ancestral to land plant and angiosperms, which may have allowed changes of substrate specificity among different evolutionary groups while maintaining the primary function of SET domains. Our predictive subcellular localization and comparative anatomical meta-expression analyses can assort with the structural divergences of Ash1 SET proteins.

Objective:To study transcription factor NIN and its paralogous proteins in Lotus japonicus for their structural divergence and functional differentiation.Method:NIN paralogous proteins were obtained from Lotus japonicus genome.Bioinformatic approaches were used for investigating phylogeny,physicochemical property,functional site identification and homology modeling.Result:A total of five NIN paralogous proteins were obtained,and among them,two are newly recognized members,which belong to two different clusters;the proline content in LjNLP3 increased 33% than the second LjNLP1,indicating the possible characteristic of drought resistance;functional site analysis shows the discrepancy in five paralogous proteins,indicating that functional differentiations could have occurred by post-translational modifications;three-dimensional structural comparison between LjNIN and LjNLP1 reveals that a stretch of β-pleated sheet in LjNLP1 is displaced by a stretch of α-helix in LjNIN,which probably become the basis of Nin being recruited as nodule inception genes.Conclusion:A preliminary relationships between structural divergence and functional differentiation of Lotus japonicus NIN paralogous proteins were established,which lay the foundations for future experimental study.

Plant Trx SET proteins are involved in H3K4 methylation and play a key role in plant floral development. Genes encoding Trx SET proteins constitute a multigene family in which the copy number varies among plant species and functional divergence appears to have occurred repeatedly. To investigate the evolutionary history of the Trx SET gene family, we made a comprehensive evolutionary analysis on this gene family from 13 major representatives of green plants. A novel clustering (here named as cpTrx clade), which included the III-1, III-2, and III-4 orthologous groups, previously resolved was identified. Our analysis showed that plant Trx proteins possessed a variety of domain organizations and gene structures among paralogs. Additional domains such as PHD, PWWP, and FYR were early integrated into primordial SET-PostSET domain organization of cpTrx clade. We suggested that the PostSET domain was lost in some members of III-4 orthologous group during the evolution of land plants. At least four classes of gene structures had been formed at the early evolutionary stage of land plants. Three intronless orphan Trx SET genes from the Physcomitrella patens (moss) were identified, and supposedly, their parental genes have been eliminated from the genome. The structural differences among evolutionary groups of plant Trx SET genes with different functions were described, contributing to the design of further experimental studies.

The aim of this study was to reconstruct the phylogenetic relationships of Anthropoidea.The coding region of the progesterone receptor gene of fourteen species belonging to fourteen genera of Anthropoidea were amplified and sequenced.Phylogenetic trees based on the progesterone receptor genes' coding region sequences were reconstructed using neighbor joining(NJ),maximum parsimony(MP)and maximum likelihood(ML)methods.All phylogenetic reconstructions yielded trees with very similar topologies with high bootstrap values except the topologies of families in Platyrrhini.The results indicated that there were two principle clades in Anthropoidea:the Catarrhini and Platyrrhini.Catarrhini consisted of Hominoidea and Cercopithecidae.The phylogenies within Cercopithecidae and Hominoidea were recovered with very high bootstrap values,which agree with the widely accepted taxonomic view of Cercopithecidae and Hominoidea.The results also suggested that humans were most closely related to chimpanzees and present evidence for a sister relationship between humans and chimpanzees.Platyrrhini consisted of three principle families:Atelidae,Cebidae and Pitheciidae.However,the phylogenetic relationships among Atelidae,Cebidae and Pitheciidae were not well resolved in our analyses.

OBJECTIVES:Vasculogenic mimicry (VM) is induced by hypoxia in 3-dimensional culture of ovarian cancer cells. By using this 3D model system, we explored the expression of human chorionic gonadotropin (hCG) and its effects on VM formation in ovarian cancer cell line OVCAR-3 both under normoxic and hypoxic conditions. METHODS:Vasculogenic mimicry was identified by morphological observation and detection of vascular cell marker expressed by OVCAR-3. Potential formation of tumor channels was observed by light microscopy and scanning electron microscopy. Expression of vascular cell marker CD31, vascular endothelial growth factor, and Factor VIII were detected by flow cytometry, immunochemistry, and Western blot. Expression of hCG was investigated by enzyme-linked immunosorbent assay, chemiluminescence immunoassay, real-time polymerase chain reaction (PCR), and Western blot. Expression of hypoxia-inducible factor-1α (HIF-1α) was detected by real-time PCR, Western blot, and blocked by small interference RNA. Incubation of OVCAR-3 with recombinant hCG was used to evaluate its effect on VM formation. The specificity of the effect of hCG was assessed by inhibition with the neutralizing anti-hCG antibody. RESULTS:OVCAR-3 cells formed vessel-like network structures and expressed vascular marker significantly under hypoxia in 3D. The expression level of hCG under hypoxia was significantly higher than that under normoxia. Attenuating hypoxia-inducible factor (HIF)-1α expression via small interference RNA resulted in a significantly decreased hCG expression in OVCAR-3, which indicated that the effect of hypoxia on hCG expression was mediated through HIF-1α. Treatment of OVCAR-3 with 5000 mU/mL hCG resulted in the presence of tumor cell-lined vasculature and significant elevation in vascular marker expression, even under normoxia. Expression level of vascular marker and HIF-1α in OVCAR-3 increased in response to hCG treatment in a dose-dependent manner. The effect of hCG was inhibited by the neutralizing anti-hCG antibody. CONCLUSIONS:Human chorionic gonadotropin has the potential to induce VM in OVCAR-3. Human chorionic gonadotropin might have synergistic hypoxia-induced effect on vascular marker and HIF-1α expression.

Little has been known about Tlr13 (Toll-like receptor 13), a novel member of the Toll-like receptor family. To elucidate the molecular basis of murine Tlr13 gene expression, the activity of the Tlr13 gene promoter was characterized. Reporter gene analysis and electrophoretic mobility shift assays demonstrated that Tlr13 gene transcription was regulated through three cis-acting elements that interacted with the Ets2, Sp1, and PU.1 transcription factors. Furthermore, our work suggests that these transcription factors may cooperate, culminating in maximal transcription of the Tlr13 gene. In contrast, NF-kappa B appeared to act as an inhibitor of Tlr13 transcription. Overexpression of Ets2 caused a strong increase in the transcriptional activity of the Tlr13 promoter; however, overexpression of NF-kappa B p65 dramatically inhibited it. Additionally, interferon-beta is capable of acting Tlr13 transcription, but the activated signaling of lipopolysaccharide/TLR4 and peptidoglycan/TLR2 strongly inhibited the Tlr13 gene promoter. Thus, these findings reveal the mechanism of Tlr13 gene regulation, thereby providing insight into the function of Tlr13 in the immune response to pathogen.

Case Reports| August 20 2009 Molecular Analysis of a Novel Case of Congenital Atransferrinemia Subject Area: Hematology , Oncology Caoyi Chen; Caoyi Chen aNantong University, Nantong, China; Search for other works by this author on: This Site PubMed Google Scholar Shu Wen; Shu Wen bBaylor College of Medicine, Houston, Tex., USA Search for other works by this author on: This Site PubMed Google Scholar Xiangling Tan Xiangling Tan aNantong University, Nantong, China; Search for other works by this author on: This Site PubMed Google Scholar Acta Haematol (2009) 122 (1): 27–28. https://doi.org/10.1159/000235614 Article history Received: April 20 2009 Accepted: June 14 2009 Published Online: August 20 2009 Content Tools Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Caoyi Chen, Shu Wen, Xiangling Tan; Molecular Analysis of a Novel Case of Congenital Atransferrinemia. Acta Haematol 1 October 2009; 122 (1): 27–28. https://doi.org/10.1159/000235614 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsActa Haematologica Search Advanced Search Article PDF first page preview Close Modal This content is only available via PDF. © 2008 S. Karger AG, Basel2009Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. You do not currently have access to this content.

More and more colleges have recognized the importance of bilingual teaching in improvement students' capability to integrate the specialized knowledge with the foreign language. Bilingual teaching courses have been designed to enhance the innovation of high education and improve the culture quality of students. Genetics is one of the most important courses for undergraduate students majored in the region of life sciences. However, in the case of genetics, the advisable model to carry out bilingual teaching and the matter of great concern are ambiguous and need evidence accumulated by more teaching experiments. The classic papers in genetics are valuable resources to the bilingual teaching of genetics. This paper analyzed the role of classic papers in the bilingual teaching of genetics and discussed the methods for improving the bilingual teaching of genetics.

The gene encoding the progesterone receptor (PGR) acts as a transcription factor, and participates in the regulation of reproductive processes including menstruation, implantation, pregnancy maintenance, parturition, mammary development, and lactation. Unlike other mammals, primates do not exhibit progesterone withdrawal at the time of parturition. Because progesterone-mediated reproductive features vary among mammals, PGR is an attractive candidate gene for studies of adaptive evolution. Thus, we sequenced the progesterone receptor coding regions in a diverse range of species including apes, Old World monkeys, New World monkeys, prosimian primates, and other mammals. Adaptive evolution occurred on the human and chimpanzee lineages as evidenced by statistically significant increases in nonsynonymous substitution rates compared to synonymous substitution rates. Positive selection was rarely observed in other lineages. In humans, amino acid replacements occurred mostly in a region of the gene that has been shown to have an inhibitory function (IF) on the ability of the progesterone receptor to act as a transcription factor. Moreover, many of the nonsynonymous substitutions in primates occurred in the N-terminus. This suggests that cofactor interaction surfaces might have been altered, resulting in altered progesterone-regulated gene transcriptional effects. Further evidence that the changes conferred an adaptive advantage comes from SNP analysis indicating only one of the IF changes is polymorphic in humans. In chimpanzees, amino acid changes occurred in both the inhibitory and transactivation domains. Positive selection provides the basis for the hypothesis that changes in structure and function of the progesterone receptor during evolution contribute to the diversity of primate reproductive biology, especially in parturition.

The placenta is essential for the success of therian mammalian reproduction. Intense selective pressure has shaped changes in placental anatomy and function during mammalian cladogenesis. Here we challenge the view that the hemochorial placenta is a derived feature in haplorhine primates. Using phylogenetic and statistical analyses of molecular and morphological data, we demonstrate that the ancestral eutherian mammalian placenta had the distinctive features of ( i ) hemochorial placental interface, ( ii ) a discoid shape, and ( iii ) a labyrinthine maternofetal interdigitation. These results reveal that the first eutherians had a deeply invasive placenta and imply that the major role of the placenta in sustaining pregnancy and promoting gestational development existed throughout the eutherian lineage that descended to humans from the last common ancestor of placental mammals. The ancestral state reconstructions demonstrate both clade-specific patterns of placentation and specific cases of convergent evolution within individual eutherian clades. Determining the mammalian pattern of change in placental morphology is important for understanding the evolutionary pressures faced by these lineages. The effects of selection pressures on the efficiency of placentation may stem from changes in nutritional demand, gestational length, number of embryos per pregnancy, uterine shape, and maternal body constitution. The influence of these factors on placental development needs further investigation.