Arp2/3 gene deletions result in embryonic lethality in the mouse.2 The genetic defects in the regulatory proteins for cytoskeletal rearrangements cause different syndromes, mostly dominated by blood ...and immune phenotypes.3 The activities of nucleation-promoting factors for actin polymerization are mostly regulated by signal-transduction pathways, one of which involves the activation by the Rho-family guanosine triphosphatases CDC42 and RAC2, and the Wiskott-Aldrich Syndrome protein (WASP) family as the intermediary Arp2/3 activator that can control actin assembly downstream of these small guanosine triphosphatases.4,5 Here we describe the first human genetic defect in a component of the Arp2/3 complex itself. The immunoglobulin spectrum shows increased IgA and IgE (Table E1). Because of the early leukocytosis and initial bleeding tendency, we excluded leukocyte adhesion defects, including LAD-III.6 The most eminent in vitro findings consisted of the neutrophil defect in motility and directed movement (chemotaxis) due to an F-actin polymerization defect (Fig 1, F and G); a result supported by confocal analysis (see Fig E1, A, in this article's Online Repository at www.jacionline.org), adhesion was unimpaired (data not shown). The complex nature of the mutation in this family might be the consequence of a double strand break repaired by nonhomologous end joining, or by a microhomology-mediated end-joining mechanism.8,9 Proteomics analysis demonstrated the presence of the Arp2/3 complex in normal neutrophils, T cells, and platelets to consist of ARPC1B, ARPC2, ARPC3, ARPC4, ARPC5, and ARPC5L, but there was an absence of ARPC1A. Because ARPC1B was ARPC1B-deficient patientWBCs, White blood cells. Symptoms Patient Knock-out mouse Growth Small...
Afforestation is considered a cost‐effective and readily available climate change mitigation option. In recent studies afforestation is presented as a major solution to limit climate change. However, ...estimates of afforestation potential vary widely. Moreover, the risks in global mitigation policy and the negative trade‐offs with food security are often not considered. Here we present a new approach to assess the economic potential of afforestation with the IMAGE 3.0 integrated assessment model framework. In addition, we discuss the role of afforestation in mitigation pathways and the effects of afforestation on the food system under increasingly ambitious climate targets. We show that afforestation has a mitigation potential of 4.9 GtCO2/year at 200 US$/tCO2 in 2050 leading to large‐scale application in an SSP2 scenario aiming for 2°C (410 GtCO2 cumulative up to 2100). Afforestation reduces the overall costs of mitigation policy. However, it may lead to lower mitigation ambition and lock‐in situations in other sectors. Moreover, it bears risks to implementation and permanence as the negative emissions are increasingly located in regions with high investment risks and weak governance, for example in Sub‐Saharan Africa. Afforestation also requires large amounts of land (up to 1,100 Mha) leading to large reductions in agricultural land. The increased competition for land could lead to higher food prices and an increased population at risk of hunger. Our results confirm that afforestation has substantial potential for mitigation. At the same time, we highlight that major risks and trade‐offs are involved. Pathways aiming to limit climate change to 2°C or even 1.5°C need to minimize these risks and trade‐offs in order to achieve mitigation sustainably.
Afforestation is often presented as a key climate change mitigation option, but potential risks and trade‐offs are generally disregarded. In this study we show afforestation has large potential for mitigation, which could reduce overall costs. However, we also show there could be major risks regarding implementation and permanence as well as large trade‐offs with food security. Pathways aiming to limit climate change to 2°C or even 1.5°C need to minimize these risks and trade‐offs in order to achieve mitigation sustainably.
The human neuroblastoma cell line, SH-SY5Y, is a commonly used cell line in studies related to neurotoxicity, oxidative stress, and neurodegenerative diseases. Although this cell line is often used ...as a cellular model for Parkinson's disease, the relevance of this cellular model in the context of Parkinson's disease (PD) and other neurodegenerative diseases has not yet been systematically evaluated.
We have used a systems genomics approach to characterize the SH-SY5Y cell line using whole-genome sequencing to determine the genetic content of the cell line and used transcriptomics and proteomics data to determine molecular correlations. Further, we integrated genomic variants using a network analysis approach to evaluate the suitability of the SH-SY5Y cell line for perturbation experiments in the context of neurodegenerative diseases, including PD.
The systems genomics approach showed consistency across different biological levels (DNA, RNA and protein concentrations). Most of the genes belonging to the major Parkinson's disease pathways and modules were intact in the SH-SY5Y genome. Specifically, each analysed gene related to PD has at least one intact copy in SH-SY5Y. The disease-specific network analysis approach ranked the genetic integrity of SH-SY5Y as higher for PD than for Alzheimer's disease but lower than for Huntington's disease and Amyotrophic Lateral Sclerosis for loss of function perturbation experiments.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Systems vaccinology approaches have been used successfully to define early signatures of the vaccine-induced immune response. However, the possibility that transcriptomics can also identify a ...correlate or surrogate for vaccine inflammation has not been fully explored. We have compared four licensed vaccines with known safety profiles, as well as three agonists of Toll-like receptors (TLRs) with known inflammatory potential, to elucidate the transcriptomic profile of an acceptable response to vaccination versus that of an inflammatory reaction. In mice, we looked at the transcriptomic changes in muscle at the injection site, the lymph node that drained the muscle, and the peripheral blood mononuclear cells (PBMCs)isolated from the circulating blood from 4 hr after injection and over the next week. A detailed examination and comparative analysis of these transcriptomes revealed a set of novel biomarkers that are reflective of inflammation after vaccination. These biomarkers are readily measurable in the peripheral blood, providing useful surrogates of inflammation, and provide a way to select candidates with acceptable safety profiles.
Background and Purpose
Kv11.1 (hERG) channel blockade is an adverse effect of many drugs and lead compounds, associated with lethal cardiac arrhythmias. LUF7244 is a negative allosteric ...modulator/activator of Kv11.1 channels that inhibits early afterdepolarizations in vitro. We tested LUF7244 for antiarrhythmic efficacy and potential proarrhythmia in a dog model.
Experimental Approach
LUF7244 was tested in vitro for (a) increasing human IKv11.1 and canine IKr and (b) decreasing dofetilide‐induced action potential lengthening and early afterdepolarizations in cardiomyocytes derived from human induced pluripotent stem cells and canine isolated ventricular cardiomyocytes. In vivo, LUF7244 was given intravenously to anaesthetized dogs in sinus rhythm or with chronic atrioventricular block.
Key Results
LUF7244 (0.5–10 μM) concentration dependently increased IKv11.1 by inhibiting inactivation. In vitro, LUF7244 (10 μM) had no effects on IKIR2.1, INav1.5, ICa‐L, and IKs, doubled IKr, shortened human and canine action potential duration by approximately 50%, and inhibited dofetilide‐induced early afterdepolarizations. LUF7244 (2.5 mg·kg−1·15 min−1) in dogs with sinus rhythm was not proarrhythmic and shortened, non‐significantly, repolarization parameters (QTc: −6.8%). In dogs with chronic atrioventricular block, LUF7244 prevented dofetilide‐induced torsades de pointes arrhythmias in 5/7 animals without normalization of the QTc. Peak LUF7244 plasma levels were 1.75 ± 0.80 during sinus rhythm and 2.34 ± 1.57 μM after chronic atrioventricular block.
Conclusions and Implications
LUF7244 counteracted dofetilide‐induced early afterdepolarizations in vitro and torsades de pointes in vivo. Allosteric modulators/activators of Kv11.1 channels might neutralize adverse cardiac effects of existing drugs and newly developed compounds that display QTc lengthening.
Predictors for postpartum PGP were somatisation and >8hours of sleep or rest in pregnancy. A protective factor was 3 to 4days of bed rest after delivery.
The objective of this study was to examine ...which factors during pregnancy and postpartum predict pelvic girdle pain (PGP) at 12weeks postpartum among working women. A total of 548 Dutch pregnant employees were recruited in 15 companies, mainly health care, child care, and supermarkets. The definition of PGP was any pain felt in the pelvic girdle region at 12weeks postpartum. Participants received questionnaires at 30weeks of pregnancy and at 6 and 12weeks postpartum with demographic, work-related, pregnancy-related, fatigue, psychosocial, PGP-related and delivery-related questions. Univariate and multiple logistic regression analyses were performed. Almost half of the women experienced pain in their pelvic girdle at 12weeks postpartum. However, the level of pain and the degree of disability due to postpartum PGP was low. Pregnancy-related predictors for PGP at 12weeks were history of low back pain, higher somatisation, more than 8hours of sleep or rest per day, and uncomfortable postures at work. The pregnancy and postpartum-related predictors were: more disability at 6weeks, having PGP at 6weeks, higher mean pain at 6weeks, higher somatisation during pregnancy and at 6weeks postpartum, higher birth weight of the baby, uncomfortable postures at work and number of days of bed rest. Based on these results, it is concluded that extra attention should be given to women who experience PGP during pregnancy to prevent serious PGP during late pregnancy and postpartum. More research is needed to confirm the roles of hours of sleep, somatisation, and bed rest in relation to PGP.
We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) on the basis of multidimensional and comprehensive characterization, including mtDNA and ...whole-genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared with other kidney cancers with more proximal origins. Combined mtDNA and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting alternative roles for mtDNA mutations in cancers relying on oxidative phosphorylation. Genomic rearrangements lead to recurrent structural breakpoints within TERT promoter region, which correlates with highly elevated TERT expression and manifestation of kataegis, representing a mechanism of TERT upregulation in cancer distinct from previously observed amplifications and point mutations.
•Comprehensive molecular analysis is performed on 66 kidney chromophobe cases•Global molecular patterns provide clues as to this cancer’s cell of origin•mtDNA sequencing reveals loss-of-function mutations in NADH dehydrogenase subunits•Genomic structural rearrangements involving TERT promoter region are assessed
Davis et al. describe the landscape of somatic genomic alterations of chromophobe renal cell carcinomas, showing that changes in mitochondrial function are an inherent component of the disease biology and identifying genomic rearrangement as a mechanism for elevated TERT expression.
Karyotype is an independent indicator of prognosis in acute myeloid leukemia (AML) that is widely applied to risk-adapted therapy. Because AML is rare in children, the true prognostic significance of ...individual chromosomal abnormalities in this age group remains unclear.
This cytogenetic study of 729 childhood patients classified them into 22 subgroups and evaluated their incidence and risk.
Rearrangements of 11q23 were the most frequent abnormality found in approximately 16% of patients, with 50% of these in infants. The outcome for all patients with 11q23 abnormalities was intermediate; no difference was observed for those with t(9;11)(p21-22;q23). The core binding factor leukemias with the translocations t(8;21)(q22;q22) and inv(16)(p13q22) occurred at incidences of 14% and 7%, respectively, predominantly in older children, and their prognosis was favorable. An adverse outcome was observed in patients with monosomy 7, abnormalities of 5q, and t(6;9)(p23;q34). Abnormalities of 3q and complex karyotypes, in the absence of favorable-risk features, have been associated with an adverse outcome in adults, but the results were not significant in this childhood series. However, the presence of 12p abnormalities predicted a poor outcome.
Because the spectrum of chromosomal changes and their risk association seem to differ between children and adults with AML, biologic differences are emerging, which will contribute to the redefinition of risk stratification for different age groups in the future.
Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a ...cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits.
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