Cyclin O controls entry into the cell-cycle variant required for multiciliated cell differentiation.

Multiciliated cells (MCCs) ensure fluid circulation in various organs. Their differentiation is marked by the amplification of cilia-nucleating centrioles, driven by a genuine cell-cycle variant, which is characterized by wave-like expression of canonical and non-canonical cyclins such as Cyclin O (CCNO). Patients with CCNO mutations exhibit a subtype of primary ciliary dyskinesia called reduced generation of motile cilia (RGMC).

GEMC1 and MCIDAS interactions with SWI/SNF complexes regulate the multiciliated cell-specific transcriptional program.

Multiciliated cells (MCCs) project dozens to hundreds of motile cilia from their apical surface to promote the movement of fluids or gametes in the mammalian brain, airway or reproductive organs. Differentiation of MCCs requires the sequential action of the Geminin family transcriptional activators, GEMC1 and MCIDAS, that both interact with E2F4/5-DP1. How these factors activate transcription and the extent to which they play redundant functions remains poorly understood.

miR-24-3p regulates CDX2 during intestinalization of cardiac-type epithelium in a human model of Barrett's esophagus.

Background: Cardiac-type epithelium has been proposed as the precursor of intestinal metaplasia in the development of Barrett's esophagus. Dysregulation of microRNAs (miRNAs) and their effects on CDX2 expression may contribute to intestinalization of cardiac-type epithelium. The aim of this study was to examine the possible effect of specific miRNAs on the regulation of CDX2 in a human model of Barrett's esophagus.

Targeted metabolomics in formalin-fixed paraffin-embedded tissue specimens: Liquid chromatography-tandem mass spectrometry determination of acidic metabolites in cancer research.

Formalin-fixed paraffin-embedded (FFPE) tissues play an irreplaceable role in cancer research. Although extensive research has been conducted for the detection of DNA, RNA and proteins in FFPE samples, literature dealing with the FFPE determination of small molecules is scarce. In this study, we aimed to explore the potential of targeted metabolomics in FFPE specimens.

Defects in efferent duct multiciliogenesis underlie male infertility in GEMC1-, MCIDAS- or CCNO-deficient mice.

GEMC1 and MCIDAS are geminin family proteins that transcriptionally activate E2F4/5-target genes during multiciliogenesis, including and Male mice that lacked , or were found to be infertile, but the origin of this defect has remained unclear. Here, we show that all three genes are necessary for the generation of functional multiciliated cells in the efferent ducts that are required for spermatozoa to enter the epididymis. In mice that are mutant for , or , we observed a similar spectrum of phenotypes, including thinning of the seminiferous tubule epithelia, dilation of the rete testes, sperm agglutinations in the efferent ducts and lack of spermatozoa in the epididymis (azoospermia).

Constitutive Cyclin O deficiency results in penetrant hydrocephalus, impaired growth and infertility.

Cyclin O (encoded by ) is a member of the cyclin family with regulatory functions in ciliogenesis and apoptosis. Homozygous mutations have been identified in human patients with Reduced Generation of Multiple Motile Cilia (RGMC) and conditional inactivation of in the mouse recapitulates some of the pathologies associated with the human disease. These include defects in the development of motile cilia and hydrocephalus.

Defective Cyclin B1 Induction in Trastuzumab-emtansine (T-DM1) Acquired Resistance in HER2-positive Breast Cancer.

Trastuzumab-emtansine (T-DM1) is a standard treatment in advanced HER2-positive breast cancer. However, resistance inevitably occurs. We aimed to identify mechanisms of acquired T-DM1 resistance.

GEMC1 is a critical regulator of multiciliated cell differentiation.

The generation of multiciliated cells (MCCs) is required for the proper function of many tissues, including the respiratory tract, brain, and germline. Defects in MCC development have been demonstrated to cause a subclass of mucociliary clearance disorders termed reduced generation of multiple motile cilia (RGMC). To date, only two genes, Multicilin (MCIDAS) and cyclin O (CCNO) have been identified in this disorder in humans.

Fibrinogen nitrotyrosination after ischemic stroke impairs thrombolysis and promotes neuronal death.

Ischemic stroke is an acute vascular event that compromises neuronal viability, and identification of the pathophysiological mechanisms is critical for its correct management. Ischemia produces increased nitric oxide synthesis to recover blood flow but also induces a free radical burst. Nitric oxide and superoxide anion react to generate peroxynitrite that nitrates tyrosines.

Methylglyoxal produced by amyloid-β peptide-induced nitrotyrosination of triosephosphate isomerase triggers neuronal death in Alzheimer's disease.

Amyloid-β peptide (Aβ) aggregates induce nitro-oxidative stress, contributing to the characteristic neurodegeneration found in Alzheimer's disease (AD). One of the most strongly nitrotyrosinated proteins in AD is the triosephosphate isomerase (TPI) enzyme which regulates glycolytic flow, and its efficiency decreased when it is nitrotyrosinated. The main aims of this study were to analyze the impact of TPI nitrotyrosination on cell viability and to identify the mechanism behind this effect.

Highly crosslinked polyethylene does not reduce the wear in total knee arthroplasty: in vivo study of particles in synovial fluid.

The aim was to assess if the reduction in polyethylene wear with highly crosslinked polyethylene suggested by studies with knee simulators is confirmed in patients with a knee arthroplasty. The use of a conventional or a highly crosslinked polyethylene was randomly assigned intraoperatively. Twelve months after surgery a knee arthrocentesis was performed and the synovial fluid of 17 patients in each group was studied analysing the number, size and shape of the polyethylene particles by scanning electron microscope.

Combined loss of p21(waf1/cip1) and p27(kip1) enhances tumorigenesis in mice.

The cell cycle inhibitors p21(Waf1/Cip1) and p27(Kip1) are frequently downregulated in many human cancers, and correlate with a worse prognosis. We show here that combined deficiency in p21 and p27 proteins in mice is linked to more aggressive spontaneous tumorigenesis, resulting in a decreased lifespan. The most common tumors developed in p21p27 double-null mice were endocrine, with a higher incidence of pituitary adenomas, pheochromocytomas and thyroid adenomas.

Measurement of changes in Cdk2 and cyclin o-associated kinase activity in apoptosis.

Many cell cycle regulatory proteins have been shown to be able to regulate cell death. Activation of Cdk2 has been shown to be necessary for apoptosis of quiescent cells such as thymocytes, neurons, and endothelial cells. This activation is stimulus-specific because it occurs in glucocorticoid and DNA damage but not in CD95-induced apoptosis in thymocytes.

Role of Bcl-2 family members on apoptosis: what we have learned from knock-out mice.

B-cell lymphoma-2 (Bcl-2) family members have been demonstrated to play a crucial role in the regulation of apoptosis as mediators in between the apical stimuli sensing steps and the executory mechanisms of apoptosis. Deregulation of their role may subvert the homeostasis of a given tissue and collaborate in the genesis of a myriad of diseases characterised by exacerbated or insufficient apoptosis, including diseases such as neurodegenerative diseases or cancer. Structural studies have defined homology regions shared by the members of the family that are responsible of the network of interactions established amongst the members of the family.

Mcl-1 interacts with truncated Bid and inhibits its induction of cytochrome c release and its role in receptor-mediated apoptosis.

Engagement of death receptors such as tumor necrosis factor-R1 and Fas brings about the cleavage of cytosolic Bid to truncated Bid (tBid), which translocates to mitochondria to activate Bax/Bak, resulting in the release of cytochrome c. The mechanism underlying the activation, however, is not fully understood. Here, we have identified the anti-apoptotic Bcl-2 family member Mcl-1 as a potent tBid-binding partner.

Cdk2 activation acts upstream of the mitochondrion during glucocorticoid induced thymocyte apoptosis.

Thymocytes undergo apoptosis during negative selection in vivo and following treatment with glucocorticoids or DNA-damaging drugs in vitro. The post-mitochondrial biochemical steps leading to apoptosis induced by these stimuli are well characterized, however, much less is known about the pathways connecting receptor triggering, apical caspase activation and induction of mitochondrial dysfunction. These stimuli specifically activate the kinase Cdk2 and this step is obligatory for these forms of thymocyte apoptosis.

Measurement of changes in apoptosis and cell cycle regulatory kinase Cdk2.

Many cell cycle regulatory proteins have been shown to be able to regulate cell death. Activation of Cdk2 has been shown to be necessary for the apoptosis of quiescent cells such as thymocytes, neurons, and endothelial cells. This activation is stimulus-specific because it occurs in glucocorticoid and DNA damage-induced but not in CD95-induced apoptosis in thymocytes.

Vitamin E but not 17beta-estradiol protects against vascular toxicity induced by beta-amyloid wild type and the Dutch amyloid variant.

Amyloid beta-peptide (Abeta) fibril deposition on cerebral vessels produces cerebral amyloid angiopathy that appears in the majority of Alzheimer's disease patients. An early onset of a cerebral amyloid angiopathy variant called hereditary cerebral hemorrhage with amyloidosis of the Dutch type is caused by a point mutation in Abeta yielding Abeta(Glu22-->Gln). The present study addresses the effect of amyloid fibrils from both wild-type and mutated Abeta on vascular cells, as well as the putative protective role of antioxidants on amyloid angiopathy.