Permanent damage to hair cells(HCs)is the leading cause of sensory deafness.Supporting cells(SCs)are essential in the restoration of hearing in mammals because they can proliferate and differentiate to HCs.MDS1 and EV...Permanent damage to hair cells(HCs)is the leading cause of sensory deafness.Supporting cells(SCs)are essential in the restoration of hearing in mammals because they can proliferate and differentiate to HCs.MDS1 and EVI1 complex locus(MECOM)is vital in early development and cell differentiation and regulates the TGF-βsignaling pathway to adapt to pathophysiological events,such as hematopoietic proliferation,differentiation and cells death.In addition,MECOM plays an essential role in neurogenesis and craniofacial development.However,the role of MECOM in the development of cochlea and its way to regulate related signaling are not fully understood.To address this problem,this study examined the expression of MECOM during the development of cochlea and observed a significant increase of MECOM at the key point of auditory epithelial morphogenesis,indicating that MECOM may have a vital function in the formation of cochlea and regeneration of HCs.Meanwhile,we tried to explore the possible effect and potential mechanism of MECOM in SC proliferation and HC regeneration.Findings from this study indicate that overexpression of MECOM markedly increases the proliferation of SCs in the inner ear,and the expression of Smad3 and Cdkn2b related to TGF signaling is significantly down-regulated,corresponding to the overexpression of MECOM.Collectively,these data may provide an explanation of the vital function of MECOM in SC proliferation and trans-differentiation into HCs,as well as its regulation.The interaction between MECOM,Wnt,Notch and the TGF-βsignaling may provide a feasible approach to induce the regeneration of HCs.展开更多
After socio-political breakthrough in 1989 foreign companies entered Polish media market. Firstly, investors appeared in the press sector, later on in the electronic media. One of the first groups presented in Poland ...After socio-political breakthrough in 1989 foreign companies entered Polish media market. Firstly, investors appeared in the press sector, later on in the electronic media. One of the first groups presented in Poland was Orkla Media. The Norwegians launched a brand new regional daily. After subsequent failure they changed the pattern of business activity. When in 2006 Mecom bought out Orkla＇s shares, a new era began. The British fund was mainly interested in making their assets more profitable. The biggest shareholder of the regional press sector, however, is still Verlagsgruppe Passau （VGP）. The German group appeared in 1993, in disguise of a Swiss company and next year took over eight regional dailies. In due course, VGP bought out a couple of more regional titles and became the leader of this sector of the market. Although the Germans were competing against the Norwegians and the Brits, they showed a different style of managing their assets. The author attempts to describe different patterns of business strategy in the press sector in Poland, examining each investor＇s behavior and the results of their efforts. This can lead to conclusions about the past activities as well as to predictions about the future of the market.展开更多
Myelodysplasia syndrome 1 (MDS1) and Ecotropic viral integration site 1 (EVI1) complex (MECOM) locus encode multiple isoforms of the EVI1 protein that are essential for normal vertebrate development and when inappropr...Myelodysplasia syndrome 1 (MDS1) and Ecotropic viral integration site 1 (EVI1) complex (MECOM) locus encode multiple isoforms of the EVI1 protein that are essential for normal vertebrate development and when inappropriately expressed play a significant role in malignancy and in particular leukaemias. However, the function of individual EVI1 isoforms is not fully understood. Recently, EVI1 or PRDM3, which is structurally closely related to the brown adipose tissue determining factor PRDM16, was shown to be required for differentiation of adipocytes. In this study, we show that 3T3-L1 preadipocytes sustain expression of all Evi1 isoforms examined, including Mds1-Evi1, Evi1FL, Evi1Δ324, Evi1FL + 9 and Evi1Δ105 throughout the adipogenesis differentiation programme. We also show that differentiation markers are enhanced by enforced expression of either Evi1, Evi1FL + 9 or Evi1Δ105 isoforms. Interestingly 3T3-L1 differentiation markers are also moderately enhanced by enforced expression of Evi1Δ324, which lacks part of the N-ter-minal zinc finger domain (ZF1), demonstrating a biological activity for this particular isoform. Enforced expression of an Evi1 mutant lacking C-terminal binding protein (CtBP) co-repressor protein binding activity fails to stimulate 3T3-L1 differentiation markers and may have dominant negative activity, causing partial inhibition of this developmental programme. These studies show that multiple EVI1 isoforms are expressed in adipocytes and can stimulate adipogenic markers in a manner that is partially independent of the ZF1 DNA binding domain but fully dependent upon interaction with co-repressor CtBP proteins.展开更多
目的探讨MECOM基因变异致先天性无巨核细胞血小板减少症的临床表现、遗传学特征及预后。方法分析贵阳市妇幼保健院收治的1例基因诊断为先天性无巨核细胞血小板减少症的新生儿临床特征、基因变异类型和治疗情况。以“先天性无巨核细胞血...目的探讨MECOM基因变异致先天性无巨核细胞血小板减少症的临床表现、遗传学特征及预后。方法分析贵阳市妇幼保健院收治的1例基因诊断为先天性无巨核细胞血小板减少症的新生儿临床特征、基因变异类型和治疗情况。以“先天性无巨核细胞血小板减少症”“MECOM基因”“MDS1 and EVI1融合基因”“新生儿”“早产儿”“婴儿”“congenital amegakaryocytic thrombocytopenia”“MECOM gene”“MDS1 and EVI1 complex locus gene”“newborn”“preterm”“infant”等为关键词,分别对中华医学期刊全文数据库、中国知网、万方数据库、PubMed、Web of Science、Embase、Cochrane Library自建库至2024年8月31日收录的文献进行检索,总结国内外报道的MECOM基因变异导致先天性无巨核细胞血小板减少症患儿的临床特征、治疗情况和基因类型。结果本例患儿生后23 d,主要表现为发育迟缓、持续依赖呼吸机支持、骨髓巨核细胞极少见、血小板减少、红系增生减低、左心房增大、房间隔缺损、左心收缩功能降低、双手第5指仅2个指节、右足第5趾背于第4趾上。全外显子组测序提示MECOM基因第7外显子存在c.1345G>T(p.E449X)无义变异,为新发变异,父母为野生型。生后46 d家属放弃治疗,1个月后死于感染。文献检索到2月龄内诊断MECOM基因变异致先天性无巨核细胞血小板减少症的文献19篇,包含本例共42例。患儿在新生儿期均存在血液学异常(42/42),包括全血细胞减少(26/42),血小板严重减少(21/42),严重贫血(11/42);骨骼异常(25/42)包括尺桡骨融合(11/42)和其他骨骼异常,如指(趾)骨异常;此外还有心脏病、B细胞异常、肾脏异常、耳聋、特殊面容、发育迟缓及严重感染。新生儿期死亡8例。进行造血干细胞移植25例,其中4例死于移植后并发症。未移植的9例中,1例随访4个月仍表现为持续性贫血和严重血小板减少症;其他8例在新生儿期对症治疗后,血小板减少由严重变为轻-中度。42例MECOM基因变异患儿中共计37个变异,主要集中在第11至12外显子之间区域(47.6%,20/42),c.2248G>A(p.R750W)位点变异患儿占比最高,为11.9%(5/42)。结论先天性无巨核细胞血小板减少症患儿在新生儿期主要表现为全血细胞减少、血小板减少、无巨核细胞等血液学异常,同时可能累及骨骼异常,严重者死亡。此类患儿应考虑MECOM基因变异的可能,尽快行遗传学检查,明确病因,进行造血干细胞移植治疗。展开更多
基金was supported by the Chinese National Natural Science Foundation of China(grant number 81371089)the Research Project of Wannan Medical College(grant number WK202122).
文摘Permanent damage to hair cells(HCs)is the leading cause of sensory deafness.Supporting cells(SCs)are essential in the restoration of hearing in mammals because they can proliferate and differentiate to HCs.MDS1 and EVI1 complex locus(MECOM)is vital in early development and cell differentiation and regulates the TGF-βsignaling pathway to adapt to pathophysiological events,such as hematopoietic proliferation,differentiation and cells death.In addition,MECOM plays an essential role in neurogenesis and craniofacial development.However,the role of MECOM in the development of cochlea and its way to regulate related signaling are not fully understood.To address this problem,this study examined the expression of MECOM during the development of cochlea and observed a significant increase of MECOM at the key point of auditory epithelial morphogenesis,indicating that MECOM may have a vital function in the formation of cochlea and regeneration of HCs.Meanwhile,we tried to explore the possible effect and potential mechanism of MECOM in SC proliferation and HC regeneration.Findings from this study indicate that overexpression of MECOM markedly increases the proliferation of SCs in the inner ear,and the expression of Smad3 and Cdkn2b related to TGF signaling is significantly down-regulated,corresponding to the overexpression of MECOM.Collectively,these data may provide an explanation of the vital function of MECOM in SC proliferation and trans-differentiation into HCs,as well as its regulation.The interaction between MECOM,Wnt,Notch and the TGF-βsignaling may provide a feasible approach to induce the regeneration of HCs.
文摘After socio-political breakthrough in 1989 foreign companies entered Polish media market. Firstly, investors appeared in the press sector, later on in the electronic media. One of the first groups presented in Poland was Orkla Media. The Norwegians launched a brand new regional daily. After subsequent failure they changed the pattern of business activity. When in 2006 Mecom bought out Orkla＇s shares, a new era began. The British fund was mainly interested in making their assets more profitable. The biggest shareholder of the regional press sector, however, is still Verlagsgruppe Passau （VGP）. The German group appeared in 1993, in disguise of a Swiss company and next year took over eight regional dailies. In due course, VGP bought out a couple of more regional titles and became the leader of this sector of the market. Although the Germans were competing against the Norwegians and the Brits, they showed a different style of managing their assets. The author attempts to describe different patterns of business strategy in the press sector in Poland, examining each investor＇s behavior and the results of their efforts. This can lead to conclusions about the past activities as well as to predictions about the future of the market.
文摘Myelodysplasia syndrome 1 (MDS1) and Ecotropic viral integration site 1 (EVI1) complex (MECOM) locus encode multiple isoforms of the EVI1 protein that are essential for normal vertebrate development and when inappropriately expressed play a significant role in malignancy and in particular leukaemias. However, the function of individual EVI1 isoforms is not fully understood. Recently, EVI1 or PRDM3, which is structurally closely related to the brown adipose tissue determining factor PRDM16, was shown to be required for differentiation of adipocytes. In this study, we show that 3T3-L1 preadipocytes sustain expression of all Evi1 isoforms examined, including Mds1-Evi1, Evi1FL, Evi1Δ324, Evi1FL + 9 and Evi1Δ105 throughout the adipogenesis differentiation programme. We also show that differentiation markers are enhanced by enforced expression of either Evi1, Evi1FL + 9 or Evi1Δ105 isoforms. Interestingly 3T3-L1 differentiation markers are also moderately enhanced by enforced expression of Evi1Δ324, which lacks part of the N-ter-minal zinc finger domain (ZF1), demonstrating a biological activity for this particular isoform. Enforced expression of an Evi1 mutant lacking C-terminal binding protein (CtBP) co-repressor protein binding activity fails to stimulate 3T3-L1 differentiation markers and may have dominant negative activity, causing partial inhibition of this developmental programme. These studies show that multiple EVI1 isoforms are expressed in adipocytes and can stimulate adipogenic markers in a manner that is partially independent of the ZF1 DNA binding domain but fully dependent upon interaction with co-repressor CtBP proteins.
文摘目的探讨MECOM基因变异致先天性无巨核细胞血小板减少症的临床表现、遗传学特征及预后。方法分析贵阳市妇幼保健院收治的1例基因诊断为先天性无巨核细胞血小板减少症的新生儿临床特征、基因变异类型和治疗情况。以“先天性无巨核细胞血小板减少症”“MECOM基因”“MDS1 and EVI1融合基因”“新生儿”“早产儿”“婴儿”“congenital amegakaryocytic thrombocytopenia”“MECOM gene”“MDS1 and EVI1 complex locus gene”“newborn”“preterm”“infant”等为关键词,分别对中华医学期刊全文数据库、中国知网、万方数据库、PubMed、Web of Science、Embase、Cochrane Library自建库至2024年8月31日收录的文献进行检索,总结国内外报道的MECOM基因变异导致先天性无巨核细胞血小板减少症患儿的临床特征、治疗情况和基因类型。结果本例患儿生后23 d,主要表现为发育迟缓、持续依赖呼吸机支持、骨髓巨核细胞极少见、血小板减少、红系增生减低、左心房增大、房间隔缺损、左心收缩功能降低、双手第5指仅2个指节、右足第5趾背于第4趾上。全外显子组测序提示MECOM基因第7外显子存在c.1345G>T(p.E449X)无义变异,为新发变异,父母为野生型。生后46 d家属放弃治疗,1个月后死于感染。文献检索到2月龄内诊断MECOM基因变异致先天性无巨核细胞血小板减少症的文献19篇,包含本例共42例。患儿在新生儿期均存在血液学异常(42/42),包括全血细胞减少(26/42),血小板严重减少(21/42),严重贫血(11/42);骨骼异常(25/42)包括尺桡骨融合(11/42)和其他骨骼异常,如指(趾)骨异常;此外还有心脏病、B细胞异常、肾脏异常、耳聋、特殊面容、发育迟缓及严重感染。新生儿期死亡8例。进行造血干细胞移植25例,其中4例死于移植后并发症。未移植的9例中,1例随访4个月仍表现为持续性贫血和严重血小板减少症;其他8例在新生儿期对症治疗后,血小板减少由严重变为轻-中度。42例MECOM基因变异患儿中共计37个变异,主要集中在第11至12外显子之间区域(47.6%,20/42),c.2248G>A(p.R750W)位点变异患儿占比最高,为11.9%(5/42)。结论先天性无巨核细胞血小板减少症患儿在新生儿期主要表现为全血细胞减少、血小板减少、无巨核细胞等血液学异常,同时可能累及骨骼异常,严重者死亡。此类患儿应考虑MECOM基因变异的可能,尽快行遗传学检查,明确病因,进行造血干细胞移植治疗。
