Mapping domains of early life determinants of future multimorbidity across three UK longitudinal cohort studies.

Many studies use a reductionist approach to isolate the influence of one factor in childhood on multimorbidity rather than consider the combined effect of wider determinants. We explored how potential multiple early life determinants of multimorbidity can be characterised across three UK cohort studies. We used the National Child Development Study (NCDS), the 1970 British Cohort Study (BCS70), and the Aberdeen Children of the 1950s Study (ACONF) to identified early life variables that fit into 12 conceptualised domains of early life determinants of multimorbidity. Variables were assigned into 12 domains; principal component analysis reduced the dimensionality of the data and structured variables into subgroups. The data audit identified 7 domains in ACONF, 10 domains in NCDS and 12 domains in BCS70. Dominant components included maternal fertility histories within the prenatal, antenatal and birth domain, long-term illnesses within the child health domain, educational ability within the child education and health literacy domain, ethnicity within the demography domain, parental health behaviours within the transgenerational domain, housing within the socioeconomic domain and parental-child interactions within the parental-family domain. We demonstrated that if multiple large scale longitudinal studies are used, there is enough data available for researchers to consider conceptualising early life risk factors of multimorbidity across groups or domains. Such conceptualisation can help challenge the existing understanding of disease aetiology and develop new ideas for prevention of multimorbidity.

Association between dietary patterns and renal function in a cross-sectional study using baseline data from the ELSA-Brasil cohort.

Previous analyses of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) identified four main dietary patterns (DP). The aim of this study was to explore the association between the previously defined DP and renal function (RF). A cross-sectional study using the ELSA-Brasil baseline data was carried out. DP ("traditional", "fruits and vegetables", "bakery", and "low sugar/low fat), metabolic syndrome (MS) using the Joint Interim Statement criteria, microalbuminuria (MA), and glomerular filtration rate (eGFR) through the CKD-EPI equation were evaluated. Abnormal RF was defined as eGFR<60 mL·min-1·(1.73 m2)-1 and MA≥3.0 mg/dL. Factors associated with RF were determined and mediation analysis was performed to investigate the association between DP, MS, and RF. A total of 15,105 participants were recruited, with a mean age of 52±9 years; 8,134 participants (54%) were females. The mediation analysis identified indirect associations between "bakery" and "fruits and vegetables", and both were associated with decreased eGFR and albuminuria in both genders, compared with "traditional" and "low sugar/low fat" patterns in the general population. There was a direct association of the "bakery" pattern with MA in men (OR: 1.17, 95%CI: 1.92-1.48). The "fruits and vegetables" pattern also showed a direct association with reduced eGFR in women (OR: 1.65, 95%CI: 1.28-2.12), although there was no significance after adjustment. The "fruits and vegetables" and "bakery" DPs were associated with renal dysfunction. The only independent, direct association was between "bakery" DP and MA in men, raising concerns about DP and renal damage in men.

Association between dietary patterns and renal function in a cross-sectional study using baseline data from the ELSA-Brasil cohort

Previous analyses of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) identified four main dietary patterns (DP). The aim of this study was to explore the association between the previously defined DP and renal function (RF). A cross-sectional study using the ELSA-Brasil baseline data was carried out. DP ("traditional", "fruits and vegetables", "bakery", and "low sugar/low fat), metabolic syndrome (MS) using the Joint Interim Statement criteria, microalbuminuria (MA), and glomerular filtration rate (eGFR) through the CKD-EPI equation were evaluated. Abnormal RF was defined as eGFR<60 mL·min-1·(1.73 m2)-1 and MA≥3.0 mg/dL. Factors associated with RF were determined and mediation analysis was performed to investigate the association between DP, MS, and RF. A total of 15,105 participants were recruited, with a mean age of 52±9 years; 8,134 participants (54%) were females. The mediation analysis identified indirect associations between "bakery" and "fruits and vegetables", and both were associated with decreased eGFR and albuminuria in both genders, compared with "traditional" and "low sugar/low fat" patterns in the general population. There was a direct association of the "bakery" pattern with MA in men (OR: 1.17, 95%CI: 1.92-1.48). The "fruits and vegetables" pattern also showed a direct association with reduced eGFR in women (OR: 1.65, 95%CI: 1.28-2.12), although there was no significance after adjustment. The "fruits and vegetables" and "bakery" DPs were associated with renal dysfunction. The only independent, direct association was between "bakery" DP and MA in men, raising concerns about DP and renal damage in men.

Small- and wide-angle X-ray scattering (SWAXS) for quantification of aspirin content in a binary powder mixture.

This article presents a novel application of small and wide angle X-ray scattering (SWAXS) in the assessment of aspirin and lactose content in a binary pharmaceutical powder formulation. It is shown that the content correlates with the intensity of the SAXS signal and the intensity of polymorph fingerprints in the WAXS spectra that are collected from the same samples. Because the polymorph WAXS fingerprints and the SAXS signal are two independent characteristics of the same sample, simultaneous SWAXS analysis provides the basis for a dual independent assessment of the same contents.

The RNA binding protein YB-1 binds A/C-rich exon enhancers and stimulates splicing of the CD44 alternative exon v4.

Exon enhancers are accessory pre-mRNA splicing signals that stimulate exon splicing. One class of proteins, the serine-arginine-rich (SR) proteins, have been demonstrated to bind enhancers and activate splicing. Here we report that A/C-rich exon enhancers (ACE elements) are recognized by the human YB-1 protein, a non-SR protein. Sequence-specific binding of YB-1 was observed both to an ACE derived from an in vivo iterative selection protocol and to ACE elements in an alternative exon (v4) from the human CD44 gene. The ACE element that was the predominant YB-1 binding site in CD44 exon v4 was required for maximal in vivo splicing and in vitro spliceosome assembly. Expression of wild-type YB-1 increased inclusion of exon v4, whereas a truncated form of YB-1 did not. Stimulation of exon v4 inclusion by wild-type YB-1 required the ACE necessary for YB-1 binding in vitro, suggesting that YB-1 stimulated exon inclusion in vivo by binding to an exonic ACE element. These observations identify a protein in addition to SR proteins that participates in the recognition of exon enhancers.

Stimulation of translation and cytoplasmic polyadenylation by the Xenopus c-mycI 3'-untranslated region.

Expression of messenger RNA (mRNA) in both embryonic and adult cells may be profoundly influenced by untranslated sequences in the 3'-end. Elements in the 3'-untranslated regions (UTRs) of messengers are known to influence messenger stability, polyadenylation, and translation. We have examined the effects of the 3'-UTR of Xenopus laevis c-mycI (either alone or in combination with the 5'-first exon) on the expression of a chloramphenicol acetyltransferase (CAT) reporter in Xenopus embryos. The Xenopus c-mycI 3'-UTR enhanced messenger translation independent of the 5'-UTR. RNase H analysis indicated that the Xenopus c-mycI 3'-UTR can promote the cytoplasmic polyadenylation of CAT mRNA in embryos. The result suggests that the post-fertilization enhancement of translation caused by the c-mycI 3'-UTR may be a consequence of cytoplasmic polyadenylation. A uridine (U)-rich sequence in the Xenopus c-mycI 3'-UTR that may be responsible for polyadenylation is similar to an element that destabilizes mammalian c-myc transcripts. We discuss the possibility that U-rich sequences may play a dual role by destabilizing growth-related transcripts in adult cells and stimulating their polyadenylation during development, and we propose that a switch in the role of such sequences in adult cells could lead to stabilization of these messengers, increased translation, and abnormal growth control.

5'-3' interactions in regulation of translation in Xenopus early embryos.

We have investigated the effects of 3' noncoding elements in enhancing translation of messengers having translation-inhibiting 5' untranslated regions (UTRs). The translation of transcripts bearing the 5' UTRs of either human c-myc or a synthetic hairpin structure upstream of a chloramphenicol acetyltransferase (CAT) reporter sequence is greatly attenuated in early embryos of Xenopus laevis. Translation of transcripts bearing the human c-myc-5' UTR was markedly stimulated by the presence of 3' poly(A). Transcripts bearing the 5' hairpin element were insensitive to the presence of poly(A), but they were extremely sensitive to the composition of the 3' UTR. A GC-rich distal sequence repressed translation, whereas a proximal GGAAU sequence promoted translation of these transcripts. Our results support the concept that long-range interactions between the 5' and 3' ends of transcripts are important in regulating translation in Xenopus embryos.

Effects of c-myc first exons and 5' synthetic hairpins on RNA translation in oocytes and early embryos of Xenopus laevis.

Mammalian c-myc transcripts have long G/C-rich 5' untranslated regions (UTRs) that may fold into secondary structural elements that may impede translation. We have examined the effects of different c-myc first exons, which produce most of the 5' UTR of c-myc transcripts, on translation in Xenopus oocytes and embryos, by placing these structures upstream of a chloramphenicol acetyltransferase (CAT) reporter. Our results demonstrate that the human c-myc first exon inhibits reporter translation in both oocytes and embryos. Unlike their mammalian counterparts, Xenopus c-mycI first exons initiated at either promoter 1 or promoter 2 do not impede translation. We conclude that translation inhibition reported in a previous investigation (Lazarus, 1992. Oncogene, 7:1037) utilizing Xenopus c-mycI 5' non-coding elements was due to the inclusion of nonrelevant non-transcribed sequences. Previous investigators have reported that inhibition of translation in Xenopus oocytes by 5' secondary structure is alleviated after fertilization (Lazarus et al., 1988. Oncogene 3:517; Fu et al., 1991, Science 251:807). We repeated the experiments of Fu et al., examining the effects on translation by a highly stable synthetic hairpin. The hairpin severely [correction of severly] restricted translation in both oocytes and embryos, indicating that highly stable 5' secondary structure is equally inhibitory in oocytes and embryos.