Autosomal reciprocal translocations in newborn children and their relatives

Summary In an incidence study of chromosome abnormalities among 5049 consecutive liveborn children at a Danish maternity hospital we found 43 with major chromosome abnormalities; 7 had a balanced reciprocal autosomal translocation. Segregation rate in the families of the 6 cases, who were inherited, showed no significant deviation from unity between carriers of balanced translocations and individuals with normal chromosome constitution. The sex distribution of carriers and those with normal chromosome constitution was normal, and segregation and distribution between carriers and non-carriers was independent of whether the carrier was a male or a female.No relatives with the unbalanced form of the translocations were found in the 6 families studied, but there was a significant increase of stillborns and children, who died during the first week of life, among carriers of the translocation compared with near relatives with a normal chromosome constitution as well as with all children born in the hospital, where they were found, and in the Danish population. The frequency of abortions was higher among the carriers than among the individuals with normal karyotypes. When the figures of stillborn children, children who died during the first week of life as well as spontaneous abortions were added to those who lived, we found that the average number of pregnancies per family was the same in carriers as in their relatives with normal chromosomes. Children with presumptive unbalanced form of translocations thus seem to have ended up as abortions, stillborns or children, who died during their first week of life.None of the probands or their relatives with reciprocal translocations had physical or mental abnormalities which could be associated with the translocation. There was no obvious difference in the physical and mental appearance or health between carriers and relatives with normal chromosome constitutions. Reciprocal autosomal translocations do not seem to have any deleterious effect on mental or physical development.

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Zusammenfassung In einer Untersuchung über Chromosomenanomalien bei 5049 auslesefrei gewonnenen Neugeborenen einer dänischen Entbindungsklinik wurden 43 mit gröberen Anomalien der Chromosomen gefunden; 7 hatten eine balancierte autosomale reziproke Translokation. Eine Untersuchung der Aufspaltung zwischen Trägern balancierter Translokationen und Personen mit normalem Karyotyp zeigte in den 6 Familien, in denen die Translokation ererbt war, keine signifikante Abweichung von der Gleichverteilung. Auch das Geschlechtsverhältnis zwischen Überträgern und Normalen weicht nicht von der Erwartung ab. Die Überträgereigenschaft war vom Geschlecht unabhängig. In den 6 untersuchten Familien fanden sich keine Verwandten mit der unbalancierten Form der Translokation; jedoch war die Zahl der Totgeburten sowie der Kinder, die in der 1. Lebenswoche starben, signifikant erhöht bei den Trägern der Translokation im Vergleich mit nahen Verwandten mit normalem Karyotyp sowie mit den im gleichen Hospital geborenen Kindern und der dänischen Gesamtbevölkerung. Bei den Überträgern war auch die Abortrate höher als bei Personen mit normalem Karyotyp. Wenn man die Zahl der Totgeburten, der Todesfälle der 1. Lebenswoche sowie der spontanen Aborte zu den lebenden hinzuzählt, so erwies sich die durchschnittliche Zahl der Schwangerschaften/Familie in den Überträgerfamilien als gleich hoch wie bei den Verwandten mit normalem Karyotyp. Es sieht also so aus, als ob Früchte mit unbalancierten Translokationen als Aborte, Totgeburten und Todesfälle in der 1. Lebenswoche geendet wären.Keiner der Probanden oder ihrer Verwandten mit reziproker Translokation hatte physische oder geistige Anomalien, die auf die Translokation zurückgeführt werden konnten, und es fand sich kein physischer, geistiger oder geburtsbedingter Unterschied zwischen Überträgern und Verwandten mit normalen Chromosomen. Demnach haben autosomale reziproke Translokationen offenbar keinen schädlichen Effekt auf die geistige oder körperliche Entwicklung.

     

Generation of Viable Plant-Vertebrate Chimeras

The extreme dependence on external oxygen supply observed in animals causes major clinical problems and several diseases are related to low oxygen tension in tissues. The vast majority of the animals do not produce oxygen but a few exceptions have shown that photosynthetic capacity is physiologically compatible with animal life. Such symbiotic photosynthetic relationships are restricted to a few aquatic invertebrates. In this work we aimed to explore if we could create a chimerical organism by incorporating photosynthetic eukaryotic cells into a vertebrate animal model. Here, the microalgae Chlamydomonas reinhardtii was injected into zebrafish eggs and the interaction and viability of both organisms were studied. Results show that microalgae were distributed into different tissues, forming a fish-alga chimera organism for a prolonged period of time. In addition, microscopic observation of injected algae, in vivo expression of their mRNA and re-growth of the algae ex vivo suggests that they survived to the developmental process, living for several days after injection. Moreover microalgae did not trigger a significant inflammatory response in the fish. This work provides additional evidence to support the possibility that photosynthetic vertebrates can be engineered.     

Prenatal antidepressant exposure associated with CYP2E1 DNA methylation change in neonates

Some but not all neonates are affected by prenatal exposure to serotonin reuptake inhibitor antidepressants (SRI) and maternal mood disturbances. Distinguishing the impact of these 2 exposures is challenging and raises critical questions about whether pharmacological, genetic, or epigenetic factors can explain the spectrum of reported outcomes. Using unbiased DNA methylation array measurements followed by a detailed candidate gene approach, we examined whether prenatal SRI exposure was associated with neonatal DNA methylation changes and whether such changes were associated with differences in birth outcomes. Prenatal SRI exposure was first associated with increased DNA methylation status primarily at CYP2E1(β_Non-exposed = 0.06, β_SRI-exposed = 0.30, FDR = 0); however, this finding could not be distinguished from the potential impact of prenatal maternal depressed mood. Then, using pyrosequencing of CYP2E1 regulatory regions in an expanded cohort, higher DNA methylation status—both the mean across 16 CpG sites (P < 0.01) and at each specific CpG site (P < 0.05)—was associated with exposure to lower 3rd trimester maternal depressed mood symptoms only in the SRI-exposed neonates, indicating a maternal mood x SRI exposure interaction. In addition, higher DNA methylation levels at CpG2 (P = 0.04), CpG9 (P = 0.04) and CpG10 (P = 0.02), in the interrogated CYP2E1 region, were associated with increased birth weight independently of prenatal maternal mood, SRI drug exposure, or gestational age at birth. Prenatal SRI antidepressant exposure and maternal depressed mood were associated with altered neonatal CYP2E1 DNA methylation status, which, in turn, appeared to be associated with birth weight.     

Forced IDO1 expression in dendritic cells restores immunoregulatory signalling in autoimmune diabetes

Indoleamine 2,3‐dioxygenase (IDO1), a tryptophan catabolizing enzyme, is recognized as an authentic regulator of immunity in several physiopathologic conditions. We have recently demonstrated that IDO1 does not merely degrade tryptophan and produce immunoregulatory kynurenines, but it also acts as a signal‐transducing molecule, independently of its enzymic function. IDO1 signalling activity is triggered in plasmacytoid dendritic cells (pDCs) by transforming growth factor‐β (TGF‐β), an event that requires the non‐canonical NF‐κB pathway and induces long‐lasting IDO1 expression and autocrine TGF‐β production in a positive feedback loop, thus sustaining a stably regulatory phenotype in pDCs. IDO1 expression and catalytic function are defective in pDCs from non‐obese diabetic (NOD) mice, a prototypic model of autoimmune diabetes. In the present study, we found that TGF‐β failed to activate IDO1 signalling function as well as up‐regulate IDO1 expression in NOD pDCs. Moreover, TGF‐β‐treated pDCs failed to exert immunosuppressive properties in vivo. Nevertheless, transfection of NOD pDCs with Ido1 prior to TGF‐β treatment resulted in activation of the Ido1 promoter and induction of non‐canonical NF‐κB and TGF‐β, as well as decreased production of the pro‐inflammatory cytokines, interleukin 6 (IL‐6) and tumour necrosis factor‐α (TNF‐α). Overexpression of IDO1 in TGF‐β‐treated NOD pDCs also resulted in pDC ability to suppress the in vivo presentation of a pancreatic β‐cell auto‐antigen. Thus, our data suggest that a correction of IDO1 expression may restore its dual function and thus represent a proper therapeutic manoeuvre in this autoimmune setting.     

How Do Stomata Sense Reductions in Atmospheric Relative Humidity？

Dear Editor, It has been known since the work of Francis Darwin that, in response to a reduction in atmospheric relative humidity （rh）, stomatal aperture decreases. Screening for Arabidopsis mutants compromised in stomatal responses to reduced rh resulted in the identification of two genes, OST1 and ABA2, that are involved in stomatal response to low rh conditions. Interestingly both encode proteins previously known to be involved in ABA signaling （Xie et al., 2006, and references therein）. These findings strongly suggested that, at least in part, the stomatal response to low rh is mediated by ABA and the intracellular ABA signaling pathway. Our most recent data show that low rh-induced stomatal closure can pro- ceed by guard cell autonomous ABA synthesis （Bauer et al., 2013）,     

Structures of B-Lymphotropic Polyomavirus VP1 in Complex with Oligosaccharide Ligands

B-Lymphotropic Polyomavirus (LPyV) serves as a paradigm of virus receptor binding and tropism, and is the closest relative of the recently discovered Human Polyomavirus 9 (HPyV9). LPyV infection depends on sialic acid on host cells, but the molecular interactions underlying LPyV-receptor binding were unknown. We find by glycan array screening that LPyV specifically recognizes a linear carbohydrate motif that contains α2,3-linked sialic acid. High-resolution crystal structures of the LPyV capsid protein VP1 alone and in complex with the trisaccharide ligands 3′-sialyllactose and 3′-sialyl-N-acetyl-lactosamine (3SL and 3SLN, respectively) show essentially identical interactions. Most contacts are contributed by the sialic acid moiety, which is almost entirely buried in a narrow, preformed cleft at the outer surface of the capsid. The recessed nature of the binding site on VP1 and the nature of the observed glycan interactions differ from those of related polyomaviruses and most other sialic acid-binding viruses, which bind sialic acid in shallow, more exposed grooves. Despite their different modes for recognition, the sialic acid binding sites of LPyV and SV40 are half-conserved, hinting at an evolutionary strategy for diversification of binding sites. Our analysis provides a structural basis for the observed specificity of LPyV for linear glycan motifs terminating in α2,3-linked sialic acid, and links the different tropisms of known LPyV strains to the receptor binding site. It also serves as a useful template for understanding the ligand-binding properties and serological crossreactivity of HPyV9.     

Leptin and resistin induce increased procoagulability in diabetes mellitus

Background

Patients with diabetes mellitus (DM) suffer from an increased risk of cardiovascular events caused by thrombotic conditions. Adipose tissue might play a crucial role in this pathogenesis by synthesis of procoagulant mediators. This study was performed to elucidate the role of the adipocytokines leptin and resistin in the development of hypercoagulability and hypofibrinolysis under diabetic conditions.

Methods

Sixty two patients with or without DM were included in our study to measure leptin, resistin and tissue factor (TF) plasma concentrations. Moreover, flow chamber experiments were performed to assess factor Xa and plasmin activity on the surface of HUVECs. Western blot and real-time PCR were performed to determine mRNA and protein expression of main factors of the coagulation and fibrinolytic system.

Results

Patients with diabetes showed increased levels of leptin and resistin (leptin: 25.69 ± 13.9 vs. 15.98 ± 17.5 ng/mL, p < 0.05; resistin: 2.61 ± 0.6 vs. 1.19 ± 0.7 ng/mL, p < 0.05), which were positively correlated with TF. In vitro, leptin and resistin induced increased factor Xa activity (leptin: 4.29 ± 0.57-fold, p < 0.05; resistin 4.19 ± 0.7-fold, p < 0.05 vs. control) on HUVECs as also reflected by elevated TF mRNA and protein expression. Moreover, stimulatory (plasminogen activator inhibitor 1) and inhibitory (tissue plasminogen activator) mediators of the fibrinolytic cascade were induced by leptin and resistin, leading to a balanced plasmin activity regulation.

Conclusions

Leptin and resistin lead to a procoagulant state in HUVECs by inducing TF expression. This mechanism might be one explanation for the prothrombotic state observed under diabetic conditions.