598 research outputs found
Congenital heart defects in CHARGE: The molecular role of CHD7 and effects on cardiac phenotype and clinical outcomes
CHARGE syndrome is characterized by a pattern of congenital anomalies (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth, Genital abnormalities, and Ear abnormalities). De novo mutations of chromodomain helicase DNA binding protein 7 (CHD7) are the primary cause of CHARGE syndrome. The clinical phenotype is highly variable including a wide spectrum of congenital heart defects. Here, we review the range of congenital heart defects and the molecular effects of CHD7 on cardiovascular development that lead to an overārepresentation of atrioventricular septal, conotruncal, and aortic arch defects in CHARGE syndrome. Further, we review the overlap of cardiovascular and noncardiovascular comorbidities present in CHARGE and their impact on the periāoperative morbidity and mortality in individuals with CHARGE syndrome.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154391/1/ajmgc31761_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154391/2/ajmgc31761.pd
Het Nieuwe Telen bij chrysant: Verkenning van energiebesparingsopties voor de chrysantenteelt
Het Nieuwe Telen (HNT) is een verzamelnaam voor verschillende methoden om energie te besparen in de glastuinbouw. In dit rapport is onderzocht welke methoden voor de chrysantenteelt interessant zijn. Er is gebruik gemaakt van een expertpanel en de rekenmodellen Kaspro en QMS
Biostimulatoren, middelen en ziekteonderdrukking van Pythium in chrysant : indicatoren voor ziekteonderdrukking in de bodem
Bodem gebonden ziekten en plagen veroorzaken schade in de teelt van chrysant onder glas. Op dit moment gebruiken telers grondstomen en chemische middelen. Grondstomen is duur, werkt kort en doodt antagonisten in de bodem. Chemische middelen zijn beperkt toegelaten, terwijl de bestaande toelatingen onder druk staan. Binnen dit onderzoek werd gezocht naar alternatieven voor chemische gewasbescherming tegen Pythium ultimum
Parental experiences of rapid exome sequencing in cases with major ultrasound anomalies during pregnancy
BACKGROUND: Adding rapid Exome Sequencing (rES) to conventional genetic tests improves the diagnostic yield of pregnancies showing ultrasound abnormalities but also carries a higher chance of unsolicited findings. We evaluated how rES, including pre- and post-test counseling, was experienced by parents investigating its impact on decision-making and experienced levels of anxiety. METHODS: A mixed-methods approach was adopted. Participating couples (n=46) were asked to fill in two surveys (pre-test and post-test counseling) and 11 couples were approached for an additional interview. RESULTS: All couples accepted the rES test-offer with the most important reason for testing emphasizing their hope of finding an underlying diagnosis that would aid decision-making. The actual impact on decision-making was low, however, since most parents decided to terminate the pregnancy based on the major and multiple fetal ultrasound anomalies and did not wait for their rES results. Anxiety was elevated for most participants and decreased over time. CONCLUSION: Major congenital anomalies detected on ultrasound seem to have more impact on prenatal parental decision-making and anxiety then the offer and results of rES. However, the impact of rES on reproductive decision-making and experienced anxiety requires further investigation, especially in pregnancies where less (severe) fetal anomalies are detected on ultrasound. This article is protected by copyright. All rights reserved
Differential Runx3, Eomes, and T-bet expression subdivides MS-associated CD4<sup>+</sup> T cells with brain-homing capacity
Multiple sclerosis (MS) is a common and devastating chronic inflammatory disease of the CNS. CD4 + T cells are assumed to be the first to cross the bloodācentral nervous system (CNS) barrier and trigger local inflammation. Here, we explored how pathogenicity-associated effector programs define CD4 + T cell subsets with brain-homing ability in MS. Runx3- and Eomes-, but not T-bet-expressing CD4 + memory cells were diminished in the blood of MS patients. This decline reversed following natalizumab treatment and was supported by a Runx3 +Eomes +T-bet ā enrichment in cerebrospinal fluid samples of treatment-naĆÆve MS patients. This transcription factor profile was associated with high granzyme K (GZMK) and CCR5 levels and was most prominent in Th17.1 cells (CCR6 +CXCR3 +CCR4 ā/dim). Previously published CD28 ā CD4 T cells were characterized by a Runx3 +Eomes āT-bet + phenotype that coincided with intermediate CCR5 and a higher granzyme B (GZMB) and perforin expression, indicating the presence of two separate subsets. Under steady-state conditions, granzyme K high Th17.1 cells spontaneously passed the bloodābrain barrier in vitro. This was only found for other subsets including CD28 ā cells when using inflamed barriers. Altogether, CD4 + T cells contain small fractions with separate pathogenic features, of which Th17.1 seems to breach the bloodābrain barrier as a possible early event in MS.</p
Differential Runx3, Eomes, and T-bet expression subdivides MS-associated CD4<sup>+</sup> T cells with brain-homing capacity
Multiple sclerosis (MS) is a common and devastating chronic inflammatory disease of the CNS. CD4 + T cells are assumed to be the first to cross the bloodācentral nervous system (CNS) barrier and trigger local inflammation. Here, we explored how pathogenicity-associated effector programs define CD4 + T cell subsets with brain-homing ability in MS. Runx3- and Eomes-, but not T-bet-expressing CD4 + memory cells were diminished in the blood of MS patients. This decline reversed following natalizumab treatment and was supported by a Runx3 +Eomes +T-bet ā enrichment in cerebrospinal fluid samples of treatment-naĆÆve MS patients. This transcription factor profile was associated with high granzyme K (GZMK) and CCR5 levels and was most prominent in Th17.1 cells (CCR6 +CXCR3 +CCR4 ā/dim). Previously published CD28 ā CD4 T cells were characterized by a Runx3 +Eomes āT-bet + phenotype that coincided with intermediate CCR5 and a higher granzyme B (GZMB) and perforin expression, indicating the presence of two separate subsets. Under steady-state conditions, granzyme K high Th17.1 cells spontaneously passed the bloodābrain barrier in vitro. This was only found for other subsets including CD28 ā cells when using inflamed barriers. Altogether, CD4 + T cells contain small fractions with separate pathogenic features, of which Th17.1 seems to breach the bloodābrain barrier as a possible early event in MS.</p
Assembly of the membrane domain of ATP synthase in human mitochondria.
The ATP synthase in human mitochondria is a membrane-bound assembly of 29 proteins of 18 kinds. All but two membrane components are encoded in nuclear genes, synthesized on cytoplasmic ribosomes, and imported into the matrix of the organelle, where they are assembled into the complex with ATP6 and ATP8, the products of overlapping genes in mitochondrial DNA. Disruption of individual human genes for the nuclear-encoded subunits in the membrane portion of the enzyme leads to the formation of intermediate vestigial ATPase complexes that provide a description of the pathway of assembly of the membrane domain. The key intermediate complex consists of the F1-c8 complex inhibited by the ATPase inhibitor protein IF1 and attached to the peripheral stalk, with subunits e, f, and g associated with the membrane domain of the peripheral stalk. This intermediate provides the template for insertion of ATP6 and ATP8, which are synthesized on mitochondrial ribosomes. Their association with the complex is stabilized by addition of the 6.8 proteolipid, and the complex is coupled to ATP synthesis at this point. A structure of the dimeric yeast Fo membrane domain is consistent with this model of assembly. The human 6.8 proteolipid (yeast j subunit) locks ATP6 and ATP8 into the membrane assembly, and the monomeric complexes then dimerize via interactions between ATP6 subunits and between 6.8 proteolipids (j subunits). The dimers are linked together back-to-face by DAPIT (diabetes-associated protein in insulin-sensitive tissue; yeast subunit k), forming long oligomers along the edges of the cristae
A prospective study on rapid exome sequencing as a diagnostic test for multiple congenital anomalies on fetal ultrasound
Objective: Conventional genetic tests (quantitative fluorescent-PCR [QF-PCR] and single nucleotide polymorphism-array) only diagnose ~40% of fetuses showing ultrasound abnormalities. Rapid exome sequencing (rES) may improve this diagnostic yield, but includes challenges such as uncertainties in fetal phenotyping, variant interpretation, incidental unsolicited findings, and rapid turnaround times. In this study, we implemented rES in prenatal care to increase diagnostic yield. Methods: We prospectively studied 55 fetuses. Inclusion criteria were: (a) two or more independent major fetal anomalies, (b) hydrops fetalis or bilateral renal cysts alone, or (c) one major fetal anomaly and a first-degree relative with the same anomaly. In addition to conventional genetic tests, we performed trio rES analysis using a custom virtual gene panel of ~3850 Online Mendelian Inheritance in Man (OMIM) genes. Results: We established a genetic rES-based diagnosis in 8 out of 23 fetuses (35%) without QF-PCR or array abnormalities. Diagnoses included MIRAGE (SAMD9), Zellweger (PEX1), Walker-Warburg (POMGNT1), Noonan (PTNP11), Kabuki (KMT2D), and CHARGE (CHD7) syndrome and two cases of Osteogenesis Imperfecta type 2 (COL1A1). In six cases, rES diagnosis aided perinatal management. The median turnaround time was 14 (range 8-20) days. Conclusion: Implementing rES as a routine test in the prenatal setting is challenging but technically feasible, with a promising diagnostic yield and significant clinical relevance
Boolean Dynamics with Random Couplings
This paper reviews a class of generic dissipative dynamical systems called
N-K models. In these models, the dynamics of N elements, defined as Boolean
variables, develop step by step, clocked by a discrete time variable. Each of
the N Boolean elements at a given time is given a value which depends upon K
elements in the previous time step.
We review the work of many authors on the behavior of the models, looking
particularly at the structure and lengths of their cycles, the sizes of their
basins of attraction, and the flow of information through the systems. In the
limit of infinite N, there is a phase transition between a chaotic and an
ordered phase, with a critical phase in between.
We argue that the behavior of this system depends significantly on the
topology of the network connections. If the elements are placed upon a lattice
with dimension d, the system shows correlations related to the standard
percolation or directed percolation phase transition on such a lattice. On the
other hand, a very different behavior is seen in the Kauffman net in which all
spins are equally likely to be coupled to a given spin. In this situation,
coupling loops are mostly suppressed, and the behavior of the system is much
more like that of a mean field theory.
We also describe possible applications of the models to, for example, genetic
networks, cell differentiation, evolution, democracy in social systems and
neural networks.Comment: 69 pages, 16 figures, Submitted to Springer Applied Mathematical
Sciences Serie
Therapy with un-engineered naĆÆve rat umbilical cord matrix stem cells markedly inhibits growth of murine lung adenocarcinoma
<p>Abstract</p> <p>Background</p> <p>Lung cancer remains the leading cause of cancer-related mortality despite continuous efforts to find effective treatments. Data from the American Cancer Society indicate that while the overall incidence of lung cancer is declining, it continues to rise in women. Stem cell-based therapy has been an emerging strategy to treat various diseases. The purpose of this paper is to determine the efficacy of an intrinsic anti-cancer effect of rat umbilical cord matrix stem cells (UCMSCs) on lung cancer.</p> <p>Methods</p> <p>A mouse syngeneic lung carcinoma model was used to test the basic ability of UCMSCs to control the growth of lung cancer. Lung tumors were experimentally induced by tail vein administration of Lewis lung carcinoma (LLC) cells derived from the lung of C57BL/6 mouse. Rat UCMSCs were then administered intratracheally five days later or intravenously on days 5 and 7. The tumor burdens were determined by measuring lung weight three weeks after the treatment.</p> <p>Results</p> <p>Co-culture of rat UCMSCs with LLC significantly attenuated the proliferation of LLC cells as monitored by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), a tetrazole cell proliferation assay, thymidine uptake, and direct cell counts. <it>In vitro </it>colony assays with rat UCMSCs as feeder layers markedly reduced LLC colony size and number. Co-culture of rat UCMSCs with LLCs causes G0/G1 arrest of cancer cells. This is evident in the decrease of cyclin A and CDK2 expression. The <it>in vivo </it>studies showed that rat UCMSC treatment significantly decreased tumor weight and the total tumor mass. Histological study revealed that intratracheally or systemically administered rat UCMSCs homed to tumor areas and survived for at least 3 weeks without any evidence of differentiation or adverse effects.</p> <p>Conclusions</p> <p>These results indicate that rat UCMSCs alone remarkably attenuate the growth of lung carcinoma cells <it>in vitro </it>and in a mouse syngeneic lung carcinoma graft model and could be used for targeted cytotherapy for lung cancer.</p
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