scholarly journals Ancestry of the AUTS2 family–A novel group of polycomb-complex proteins involved in human neurological disease

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0232101
Author(s):  
Robert A. Sellers ◽  
David L. Robertson ◽  
May Tassabehji

Autism susceptibility candidate 2 (AUTS2) is a neurodevelopmental regulator associated with an autosomal dominant intellectual disability syndrome, AUTS2 syndrome, and is implicated as an important gene in human-specific evolution. AUTS2 exists as part of a tripartite gene family, the AUTS2 family, which includes two relatively undefined proteins, Fibrosin (FBRS) and Fibrosin-like protein 1 (FBRSL1). Evolutionary ancestors of AUTS2 have not been formally identified outside of the Animalia clade. A Drosophila melanogaster protein, Tay bridge, with a role in neurodevelopment, has been shown to display limited similarity to the C-terminal of AUTS2, suggesting that evolutionary ancestors of the AUTS2 family may exist within other Protostome lineages. Here we present an evolutionary analysis of the AUTS2 family, which highlights ancestral homologs of AUTS2 in multiple Protostome species, implicates AUTS2 as the closest human relative to the progenitor of the AUTS2 family, and demonstrates that Tay bridge is a divergent ortholog of the ancestral AUTS2 progenitor gene. We also define regions of high relative sequence identity, with potential functional significance, shared by the extended AUTS2 protein family. Using structural predictions coupled with sequence conservation and human variant data from 15,708 individuals, a putative domain structure for AUTS2 was produced that can be used to aid interpretation of the consequences of nucleotide variation on protein structure and function in human disease. To assess the role of AUTS2 in human-specific evolution, we recalculated allele frequencies at previously identified human derived sites using large population genome data, and show a high prevalence of ancestral alleles, suggesting that AUTS2 may not be a rapidly evolving gene, as previously thought.

2018 ◽  
Vol 10 (466) ◽  
pp. eaau7137 ◽  
Author(s):  
Julia Luther ◽  
Timur Alexander Yorgan ◽  
Tim Rolvien ◽  
Lorenz Ulsamer ◽  
Till Koehne ◽  
...  

WNT1mutations in humans are associated with a new form of osteogenesis imperfecta and with early-onset osteoporosis, suggesting a key role of WNT1 in bone mass regulation. However, the general mode of action and the therapeutic potential of Wnt1 in clinically relevant situations such as aging remain to be established. Here, we report the high prevalence of heterozygousWNT1mutations in patients with early-onset osteoporosis. We show that inactivation of Wnt1 in osteoblasts causes severe osteoporosis and spontaneous bone fractures in mice. In contrast, conditional Wnt1 expression in osteoblasts promoted rapid bone mass increase in developing young, adult, and aged mice by rapidly increasing osteoblast numbers and function. Contrary to current mechanistic models, loss of Lrp5, the co-receptor thought to transmit extracellular WNT signals during bone mass regulation, did not reduce the bone-anabolic effect of Wnt1, providing direct evidence that Wnt1 function does not require the LRP5 co-receptor. The identification of Wnt1 as a regulator of bone formation and remodeling provides the basis for development of Wnt1-targeting drugs for the treatment of osteoporosis.


2020 ◽  
Author(s):  
Zhaozhong Zhu ◽  
Huiting Chen ◽  
Yang Cao ◽  
Taijiao Jiang ◽  
Yuanqiang Zou ◽  
...  

AbstractAfrican swine fever virus (ASFV) is a large and complex double-stranded DNA virus that poses serious threats to the pig industry. It is well-accepted that the multigene family (MGF) proteins are extensively distributed in ASFVs and are generally classified into five families, including MGF-100, MGF-110, MGF-300, MGF-360 and MGF-505. Most MGF proteins, however, have not been well characterized and classified within each family. To bridge this gap, this study first classified the MGF proteins into 35 groups based on protein sequence homology. A web server for classifying the MGF proteins was then established and available for free at http://www.computationalbiology.cn/MGF/home.html. Results showed that the genetic diversity of the MGF groups varied widely, mainly due to the occurrence of indels. In addition, the MGF proteins were predicted to have large structural and functional diversity, and the MGF proteins of the same MGF family tended to have similar structure, location and function. Evolutionary analysis revealed the dynamic changes of the MGF proteins in the ASFV genomes, and more than half of MGF groups were presented in all ASFV genomes, which indicated the important role of MGF proteins in ASFVs. Overall, it is expected that the work would not only provide a detailed classification for MGF proteins, but also facilitate further research on MGF proteins.


Author(s):  
Grace C.H. Yang

The size and organization of collagen fibrils in the extracellular matrix is an important determinant of tissue structure and function. The synthesis and deposition of collagen involves multiple steps which begin within the cell and continue in the extracellular space. High-voltage electron microscopic studies of the chick embryo cornea and tendon suggested that the extracellular space is compartmentalized by the fibroblasts for the regulation of collagen fibril, bundle, and tissue specific macroaggregate formation. The purpose of this study is to gather direct evidence regarding the association of the fibroblast cell surface with newly formed collagen fibrils, and to define the role of the fibroblast in the control and the precise positioning of collagen fibrils, bundles, and macroaggregates during chick tendon development.


Author(s):  
Edna S. Kaneshiro

It is currently believed that ciliary beating results from microtubule sliding which is restricted in regions to cause bending. Cilia beat can be modified to bring about changes in beat frequency, cessation of beat and reversal in beat direction. In ciliated protozoans these modifications which determine swimming behavior have been shown to be related to intracellular (intraciliary) Ca2+ concentrations. The Ca2+ levels are in turn governed by the surface ciliary membrane which exhibits increased Ca2+ conductance (permeability) in response to depolarization. Mutants with altered behaviors have been isolated. Pawn mutants fail to exhibit reversal of the effective stroke of ciliary beat and therefore cannot swim backward. They lack the increased inward Ca2+ current in response to depolarizing stimuli. Both normal and pawn Paramecium made leaky to Ca2+ by Triton extrac¬tion of the surface membrane exhibit backward swimming only in reactivating solutions containing greater than IO-6 M Ca2+ Thus in pawns the ciliary reversal mechanism itself is left operational and only the control mechanism at the membrane is affected. The topographic location of voltage-dependent Ca2+ channels has been identified as a component of the ciliary mem¬brane since the inward Ca2+ conductance response is eliminated by deciliation and the return of the response occurs during cilia regeneration. Since the ciliary membrane has been impli¬cated in the control of Ca2+ levels in the cilium and therefore is the site of at least one kind of control of microtubule sliding, we have focused our attention on understanding the structure and function of the membrane.


2019 ◽  
Vol 47 (5) ◽  
pp. 1393-1404 ◽  
Author(s):  
Thomas Brand

Abstract The Popeye domain-containing gene family encodes a novel class of cAMP effector proteins in striated muscle tissue. In this short review, we first introduce the protein family and discuss their structure and function with an emphasis on their role in cyclic AMP signalling. Another focus of this review is the recently discovered role of POPDC genes as striated muscle disease genes, which have been associated with cardiac arrhythmia and muscular dystrophy. The pathological phenotypes observed in patients will be compared with phenotypes present in null and knockin mutations in zebrafish and mouse. A number of protein–protein interaction partners have been discovered and the potential role of POPDC proteins to control the subcellular localization and function of these interacting proteins will be discussed. Finally, we outline several areas, where research is urgently needed.


1999 ◽  
Vol 81 (06) ◽  
pp. 951-956 ◽  
Author(s):  
J. Corral ◽  
R. González-Conejero ◽  
J. Rivera ◽  
F. Ortuño ◽  
P. Aparicio ◽  
...  

SummaryThe variability of the platelet GP Ia/IIa density has been associated with the 807 C/T polymorphism (Phe 224) of the GP Ia gene in American Caucasian population. We have investigated the genotype and allelic frequencies of this polymorphism in Spanish Caucasians. The T allele was found in 35% of the 284 blood donors analyzed. We confirmed in 159 healthy subjects a significant association between the 807 C/T polymorphism and the platelet GP Ia density. The T allele correlated with high number of GP Ia molecules on platelet surface. In addition, we observed a similar association of this polymorphism with the expression of this protein in other blood cell types. The platelet responsiveness to collagen was determined by “in vitro” analysis of the platelet activation and aggregation response. We found no significant differences in these functional platelet parameters according to the 807 C/T genotype. Finally, results from 3 case/control studies involving 302 consecutive patients (101 with coronary heart disease, 104 with cerebrovascular disease and 97 with deep venous thrombosis) determined that the 807 C/T polymorphism of the GP Ia gene does not represent a risk factor for arterial or venous thrombosis.


2010 ◽  
Vol 30 (03) ◽  
pp. 150-155 ◽  
Author(s):  
J. W. Wang ◽  
J. Eikenboom

SummaryVon Willebrand factor (VWF) is a pivotal haemostatic protein mediating platelet adhesion to injured endothelium and carrying coagulation factor VIII (FVIII) in the circulation to protect it from premature clearance. Apart from the roles in haemostasis, VWF drives the formation of the endothelial cell specific Weibel-Palade bodies (WPBs), which serve as a regulated storage of VWF and other thrombotic and inflammatory factors. Defects in VWF could lead to the bleeding disorder von Willebrand disease (VWD).Extensive studies have shown that several mutations identified in VWD patients cause an intracellular retention of VWF. However, the effects of such mutations on the formation and function of its storage organelle are largely unknown. This review gives an overview on the role of VWF in WPB biogenesis and summarizes the limited data on the WPBs formed by VWD-causing mutant VWF.


2020 ◽  
Vol 4 (3) ◽  
pp. 167-178
Author(s):  
Zurayna Sari

ABSTRAKPelabuhan berperan sebagai fasilitas penunjang pusat pertumbuhan regional dalam proses pembangunan ekonomi wilayah. Pelabuhan Bebas Sabang diarahkan sebagai pusat pertumbuhan ekonomi regional dan diharapkan dapat meningkatkan perekonomian Kawasan Sabang. Permasalahan yang dihadapi Pelabuhan Bebas Sabang adalah belum optimalnya peran dan fungsi Pelabuhan Bebas Sabang dalam menunjang perekonomian wilayah. Penelitian ini bertujuan untuk mengetahui peran Pelabuhan Bebas Sabang dalam mendorong perkembangan perekonomian Kawasan Sabang. Lingkup materi yang dibahas mencakup peran-peran Pelabuhan Bebas Sabang, menentukan potensi dan masalah serta upaya-upaya peningkatan peran Pelabuhan Bebas Sabang. Metode analisis yang dilakukan adalah analisis deskriptif dengan pendekatan analisis data kualitatif dan kuantitatif. Alat analisis yang digunakan adalah analisis SWOT IFAS-EFAS. Hasil analisis menunjukkan dalam kurun waktu 4 (empat) tahun terakhir dari tahun 2010-2013, Pelabuhan Bebas Sabang belum optimal dalam menjalankan perannya, sehingga membutuhkan strategi pengembangan dengan pendekatan Agressive Maintenance Strategy (strategi perbaikan agresif), yaitu strategi konsolidasi internal dengan memperbaiki faktor-faktor kelemahan untuk memaksimalkan pemanfaatan peluang.Kata kunci: Pengelolaan, SWOT IFAS-EFAS, WilayahABSTRACTPort was supporting facility of regional growth center in the process of regional economic development. Sabang free port was directed as the center of regional economic growth and expected to raise the economy of sabang. Problems faced by sabang free port was yet optimal role and function in supporting the economy of the region. This study aimed to determine the role of sabang free port in supporting the economic development of sabang. The covered material scope included roles of sabang free port, determining the potentials and problems and efforts of increasing the role of sabang free port. The method of analysis was descriptive analysis with qualitative and quantitative approach. The analytical tool used was the swot ifas-efas analysis. The analysis results showed in the period of 4 (four) years from 2010 until 2013, sabang free port was not optimal in carrying out its role yet, so it requires development strategies with agressive maintenance strategy approach, which is internal consolidation strategy by improving vulnerability factors to maximize the utilization of opportunities.Keywords:, Management, Regional, SWOT IFAS-EFAS


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