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Interestingly, the TNF-α signaling pathway was also flagged by other genetic findings in our study (Supplementary Fig. 48). For example, ADAM17 (also known as TNF-α-converting enzyme) is of pivotal importance in the activation of TNF-α signaling32. For TNIP1, its gene product (TNF-α-induced protein 3-interacting protein 1) is involved in the inhibition of the TNF-α signaling pathway and nuclear factor κB activation/translocation33. Additional signal related to TNF-α is the one found at SPPL2A (one of the 33 confirmed loci). The protein encoded by SPPL2A is involved in noncanonical shedding of TNF-α34, and PGRN has been described as a TNF receptor ligand and an antagonist of TNF-α signaling35. Several lines of evidence had linked the inhibition of TNF-α signaling with reduction of both Aβ and tau pathologies in vivo36,37. Although a potential inflammatory connection has been suggested for TNF-α through the activation of NLRP3 inflammasome38, the TNF-α signaling pathway is also involved in many other brain physiological functions (e.g., synaptic plasticity in neurons) and pathophysiological processes (e.g., synapse loss) in the brain39. Furthermore, the involvement of the TNF-α signaling pathway and the LUBAC might be important in cell types other than microglia in AD. It is important to note that six of our prioritized (tier 1) genes (ICA1L, EGFR, RITA1, MYO15A, LIME1 and APP) are expressed at a low level in microglia (
Matthew Espinosa: More Than Me download pdf
We computed a gene prioritization score for each candidate gene as the weighted sum of the evidence identified in the seven domains. We specified a weight for each type of evidence, as detailed in Supplementary Table 19. For the molecular QTL-GWAS integration domains, we gave more weight to replicated hits (i.e., evidence in several datasets) than to single hits. We also gave more weight to hits observed in brain (the bulk brain and microglia datasets) than to hits observed in other tissues/cell types (LCLs, monocytes, macrophages and blood). To avoid score inflation, several specific rules were applied: (1) for the results of sQTL- and mQTL-based analyses, multiple splice junctions or CpGs annotated for the same genes were aggregated prior to weighting due to correlated data; (2) if we observed a fine-mapped eTWAS association for a gene, its other significant (but not fine-mapped) eTWAS associations were not considered; (3) for genes having several significant CpGs (prior to aggregation) in MetaMeth analyses, the associated CpGs with a low (
We recommend women with renal transplants wait until their kidney function is stable on medications that are safe in pregnancy before conceiving, which is usually more than one year after transplantation (1D).
Cohort studies [98,99,100] and meta-analysis [101, 102] show that women with CKD have an increased risk of antenatal complications including pre-eclampsia, preterm delivery, fetal growth restriction compared to women without CKD, although a successful pregnancy is feasible for most women. A meta-analysis that compared 2682 pregnancies in women with CKD with 26,149 pregnancies in healthy controls showed that weighted averages of adverse maternal events in women with CKD and healthy controls were 11.5 and 2% respectively, with a two-fold increase in adverse neonatal outcomes (premature births, fetal growth restriction, small for gestational age, neonatal mortality, stillbirths, and low birth weight) in women with CKD . The likelihood of adverse outcomes are predominantly dependent on baseline excretory renal function, hypertension, proteinuria and, to a lesser extent, aetiology of renal disease [98, 99, 103, 104]. However, as adverse outcomes are more common even in women with preserved excretory renal function (pre-pregnancy CKD stages 1 and 2) than the general obstetric population, counselling should be offered to all women with CKD . A questionnaire study in the UK found that over 90% of women with CKD attending pre-pregnancy counselling found consultations informative and helpful in making a decision on pursuing pregnancy .
Prior to falling pregnant I attended the pre-pregnancy appointment. At this appointment I met the renal transplant doctor who specialised in pregnant transplant patients, a high-risk obstetrician and a specialist in pregnant women with complex medical conditions. At this appointment, which lasted approximately one hour, my medical history was taken and my medication was reviewed. I was then informed of all the potential risks associated with falling pregnant and I was taken off all the medication that could be harmful to my unborn baby and these medications were changed to medication safe to use in pregnancy. I remember walking out of the appointment feeling more comfortable, and confident that I would be provided with appropriate care during my pregnancy, and even though I may encounter more problems than the average pregnant woman, I would have the support and medical care required. Some of the main pieces of information I remember very clearly are that I would be at higher risk for having a premature baby and I would be high-risk for pre-eclampsia, but I was happily surprised to hear that research suggests there would no effects on the baby secondary to me taking immunosuppressive medication in pregnancy. I never expected to be able to have children with a renal transplant.
My interpretation of these recommendations is probably more strict than that of most endocrinologists or gynecologists. Lab-specific reference ranges better identify women with gestational thyroid dysfunction than reference ranges defined by another methodology [7, 10]. Calculating lab-specific references ranges is not difficult and every hospital in which prenatal care is provided would be able to perform a good study at very low costs (i.e. less than a few thousand euro/GBP), particularly when collaborating with the clinical chemistry department. Adequate reference ranges can be obtained by selecting at least 400 pregnant women with a singleton pregnancy, free of pre-existing thyroid disease, that do not use thyroid interfering medication, that did not undergo IVF treatment and are TPOAb negative . Therefore, I believe that if a center does not have lab-specific reference ranges readily available, physicians should not automatically move to step 2 or 3 of the guideline recommendations, but try to obtain lab-specific reference ranges. Calculating such reference ranges will instantly improve the quality of clinically diagnosing thyroid dysfunction in pregnancy. When specific expertise is missing, groups involved in the field of thyroid and pregnancy (including our group) would be more than willing to share their experience.
Complex II in plants [63, 64] and trypanosomatids  has been reported to contain additional lineage-specific subunits, one of which (an ortholog of plant Sdh5) we identified here (Table 2). Together with the recent identification of homologs of plant Sdh5, Sdh6, and Sdh7 outside of land plants , this result suggests that CII in LECA may have been more complex than its four-subunit bacterial counterpart, implying that the additional subunits represent a retained ancestral eukaryotic trait, rather than resulting from lineage-specific additions as is generally assumed. This observation would imply that the four-subunit CII in opisthokonts resulted from loss of subunits originally present in LECA CII (essentially a reversion to the primitive bacterial composition). This scenario has been argued in the case of CI, which in opisthokonts specifically lacks γ-type carbonic anhydrase subunits that are otherwise widely distributed among other eukaryotes .
Including the SSU rRNA DMT discussed earlier, we have identified more than 20 enzymes involved in post-transcriptional modification of Andalucia mitochondrial rRNA and tRNA. In addition to a variety of methyltransferases and pseudouridine synthases, these enzymes include several activities involved in formation of hypermodified residues located in the anticodon loop in tRNA (e.g., mnm5U, m6t6A, i6A). We identified orthologs of seven human genes (GTPBP, MTO1, NSUN3, TRIT1, TRMT5, TRMU, TRNT) encoding mitochondrial rRNA or tRNA modification enzymes that are linked to mitochondrial energy generation disorders .
Design of the structural genome annotation pipeline employed here was based on the one outlined by , with a major difference in the order of operations and minor differences in the gene prediction software used. Rather than performing various steps of gene modeling in parallel, the repeat discovery step was performed first. Further, Spaln  rather than GeneWise plus tBLASTn was used for protein sequence similarity searches in a local version of the UniProtKB and Protozoan RefSeq data sets (downloaded November 8, 2017) against the genome. The ab initio predictors employed were Augustus , Snap , Genemark , and CodingQuarry . For the functional gene annotation, we followed the procedure outlined in . Expert mitoproteome curations were applied to the respective gene models in the current version of the genome annotation (see below).
This second figure illustrates a larger community with more people involved in co-authorships. Hence, we see more complex structures that show a more extensive community. There are more triads (54) than dyads (48) and many network cliques of four (23) and five (15) co-authors. The main component is considerably larger than the REDES journal, which has 60 nodes. There are more men (light blue) than women (dark blue), and there are also more authors with institutional affiliations from the Global North.