Recent evidence suggests a role for phosphatidylinositol (PI) 3‐kinase in various inflammatory responses. In this study, the consequences of LPS‐induced PI 3‐kinase activation on cytokine and chemokine expression and the intracellular mechanisms of inflammatory activation were examined in mouse macrophages. LPS stimulation induced a complex formation between PI 3‐kinase and myeloid differentiation factor 88 (MyD88), which was followed by an induction of IL‐1β, tumor necrosis factor‐α (TNF‐α) and macrophage inflammatory protein (MIP)‐2. The induction of IL‐1β, but not of MIP‐2 or TNF‐α, was blocked by the PI 3‐kinase inhibitors LY294002 and wortmannin. The nuclear factor‐κB (NF‐κB) inhibitor pyrrolidinedithiocarbamate (PDTC) blocked the induction of IL‐1β and TNF‐α, but had no effect on MIP‐2 expression. Inhibition of PI 3‐kinase decreased the LPS‐induced transcriptional activity of NF‐κB, but it had no effect on the nuclear DNA binding activity of NF‐κB. These findings suggest that, while NF‐κB nuclear localization and DNA binding are necessary, they are not sufficient for transcriptional activation of the IL‐1β gene in the absence of PI 3‐kinase activity. Taken together, our results demonstrate that activation of Toll‐like receptor (TLR)‐4 results in PI 3‐kinase‐MyD88 complex formation, and that PI 3‐kinase activity selectively leads to cytokine induction downstream of TLR4.

Spontaneous preterm birth (SPTB) is the leading cause of neonatal death and morbidity worldwide. Both maternal and fetal genetic factors likely contribute to SPTB. We performed a genome-wide association study (GWAS) on a population of Finnish origin that included 247 infants with SPTB (gestational age [GA] < 36 weeks) and 419 term controls (GA 38–41 weeks). The strongest signal came within the gene encoding slit guidance ligand 2 (SLIT2; rs116461311, minor allele frequency 0.05, p = 1.6×10⁻⁶). Pathway analysis revealed the top-ranking pathway was axon guidance, which includes SLIT2. In 172 very preterm-born infants (GA <32 weeks), rs116461311 was clearly overrepresented (odds ratio 4.06, p = 1.55×10⁻⁷). SLIT2 variants were associated with SPTB in another European population that comprised 260 very preterm infants and 9,630 controls. To gain functional insight, we used immunohistochemistry to visualize SLIT2 and its receptor ROBO1 in placentas from spontaneous preterm and term births. Both SLIT2 and ROBO1 were located in villous and decidual trophoblasts of embryonic origin. Based on qRT-PCR, the mRNA levels of SLIT2 and ROBO1 were higher in the basal plate of SPTB placentas compared to those from term or elective preterm deliveries. In addition, in spontaneous term and preterm births, placental SLIT2 expression was correlated with variations in fetal growth. Knockdown of ROBO1 in trophoblast-derived HTR8/SVneo cells by siRNA indicated that it regulate expression of several pregnancy-specific beta-1-glycoprotein (PSG) genes and genes involved in inflammation. Our results show that the fetal SLIT2 variant and both SLIT2 and ROBO1 expression in placenta and trophoblast cells may be correlated with susceptibility to SPTB. SLIT2-ROBO1 signaling was linked with regulation of genes involved in inflammation, PSG genes, decidualization and fetal growth. We propose that this receptor-ligand couple is a component of the signaling network that promotes SPTB. Worldwide, more than 10% of babies are born prematurely without effective means of prevention. Premature birth is associated with mortality and lifelong comorbidities. Aggregation of spontaneous preterm birth in certain families suggests that there are underlying genetic factors that predispose to preterm birth. Both maternal and fetal genomes likely affect susceptibility. We set out to identify fetal genetic variants that predispose infants to premature birth in a population of Finnish origin. Our results from a genome-wide association study indicate that a variant of slit guidance ligand 2 (SLIT2) is associated with the risk of spontaneous preterm birth. Furthermore, SLIT2 and its receptor roundabout guidance receptor 1 (ROBO1) are expressed in placental cells, and their mRNA levels are higher in placentas from spontaneous preterm deliveries compared to term controls. Based on gene knockdown experiments in cultured placental tissue–derived cells, ROBO1 regulates expression of pregnancy-specific beta-1-glycoprotein (PSG) genes and genes involved in inflammation. Thus, our results indicate that the fetal SLIT2 variant and expression of both SLIT2 and ROBO1 in placental cells are correlated with susceptibility to spontaneous preterm birth. We propose that this receptor–ligand pair is a component of the signaling network that promotes spontaneous preterm birth.

Defects in genes mediating thyroid hormone biosynthesis result in dyshormonogenic congenital hypothyroidism (CH). Here, we report homozygous truncating mutations in SLC26A7 in 6 unrelated families with goitrous CH and show that goitrous hypothyroidism also occurs in Slc26a7 -null mice. In both species, the gene is expressed predominantly in the thyroid gland, and loss of function is associated with impaired availability of iodine for thyroid hormone synthesis, partially corrected in mice by iodine supplementation. SLC26A7 is a member of the same transporter family as SLC26A4 (pendrin), an anion exchanger with affinity for iodide and chloride (among others), whose gene mutations cause congenital deafness and dyshormonogenic goiter. However, in contrast to pendrin, SLC26A7 does not mediate cellular iodide efflux and hearing in affected individuals is normal. We delineate a hitherto unrecognized role for SLC26A7 in thyroid hormone biosynthesis, for which the mechanism remains unclear.

What is the association between childhood and adolescent BMI and reproductive capacity in women? Adolescent girls with obesity had an increased risk of infertility and childlessness in adulthood independently of their marital status or the presence of polycystic ovary syndrome (PCOS). Girls with obesity (BMI (kg/m²) $>$95th percentile) more often exhibit menstrual irregularities and infertility problems as compared to those with normal weight, and premenarcheal girls with obesity have an increased risk of childlessness and infertility in adulthood. Follow-up studies on the relation between childhood and adolescence growth patterns and fertility or parity throughout the reproductive life span are limited. A prospective, population-based cohort study (the Northern Finland birth cohort 1966) was performed with 5889 women born in 1966 and followed from birth to age 50 years. Postal questionnaires at ages 31 and 46 years addressed questions on reproductive capacity evaluated by decreased fecundability, need for infertility assessment and treatment by 46 years of age. Childlessness and number of children by age 50 years were recovered from registers. Women who did not report ever having attempted to achieve pregnancy (n = 1507) were excluded. The final study population included 4382 women who attempted to achieve pregnancy before age 46 years. Data on BMI were collected by trained personnel at all stages. We assessed association with both prospectively measured BMI at various time points and with early adiposity phenotypes derived from linear mixed models including the timing and the BMI at adiposity peak (AP) and adiposity rebound (AR). Self-reported infertility assessments and treatments were assessed at ages 31 and 46 years. Data on deliveries were collected from the national birth register. Decreased fecundability was defined at age 31 years as time to achieve pregnancy over 12 months. Logistic regression analyses were conducted with adjustments for marital status, education level and smoking at age 31 years. Women with PCOS were excluded from stratification-based sensitivity analyses. Obesity at a specific age group was defined by having at least one BMI value above the 95th percentile during the related period. BMI at the age of AR (5–7 years) was not associated with fertility outcomes after adjustments, but girls with AR <5.1 years had a higher risk of remaining childless compared to girls with AR over 5.1 years (adjusted odds ratio (OR): 1.45 (1.10–1.92)). At ages 7–10 and 11–15 years, obesity was associated with decreased fecundability (adjusted OR 2.05 (1.26–3.35) and 2.04 (1.21–3.44), respectively) and a lower number of children. At age 11–15 years, both overweight and obesity were associated with a higher risk of childlessness (adjusted OR 1.56 (1.06–2.27), 1.77 (1.02–3.07), respectively), even after excluding women with PCOS. Underweight at age 11–15 years was associated with an increased risk for infertility treatment (adjusted OR 1.55 (1.02–2.36)) and a tendency for an increased risk for infertility assessment (adjusted OR 1.43 (0.97–2.10)) after excluding women with PCOS. Despite a high participation rate throughout the follow-up, some growth data for children over the different age groups were missing. Infertility outcomes were self-reported. A potential over-diagnosis of obesity may have reduced the significance of the association between childhood obesity and fertility outcomes, and the diagnosis of PCOS was self-reported. This study supports previous results showing that girls with obesity in late childhood and in adolescence displayed reduced fertility and an increased risk of remaining childless in adulthood, independently of marital history and PCOS in adulthood. These findings corroborate the body of evidence for a causal relation between early adiposity and the reproductive functions in women. We recommend reinforcing the prevention of obesity in school-age girls to reduce the risk of impaired reproductive functions. NFBC1966 received financial support from University of Oulu Grant no. 65354, Oulu University Hospital Grant no. 2/97, 8/97, Ministry of Health and Social Affairs Grant no. 23/251/97, 160/97, 190/97, National Institute for Health and Welfare, Helsinki Grant no. 54121, Regional Institute of Occupational Health, Oulu, Finland Grant no. 50621, 54231. The Finnish Medical Foundation, the North Ostrobothnia Regional Fund, the Academy of Finland (project grants 315921, 104781, 120315, 129269, 1114194, 24300796), Center of Excellence in Complex Disease Genetics and SALVE, the Sigrid Juselius Foundation, Biocenter Oulu, University Hospital Oulu and University of Oulu (75617), Jalmari ja Rauha Ahokkaan säätiö, The Finnish Medical Foundation, Medical Research Center Oulu, National Institute for Health Research (UK). M. R. J., S. S. and R. N. received funding by the Academy of Finland (#268336) and the European Union’s Horizon 2020 research and innovation program (under Grant agreement no. 633595 for the DynaHEALTH action and GA 733206 for LifeCycle). The funders had no role in study design, in the collection, analysis and interpretation of the data, in the writing of the article and in the decision to submit it for publication. The authors have no conflict of interest to disclose. N/A.

Little is known of the cognitive functions, employment, and social status in adult survivors of childhood brain tumor (BT). We aimed to determine the long-term neurocognitive profile of radiotherapy-treated adult survivors of childhood BT and the relationship between cognitive functions and employment and social status. Neurocognitive profiles of survivors were assessed in a Finnish national cohort of 71 radiotherapy-treated survivors of childhood BT (median follow-up time: 21 years [range: 5-33 years]) using a cross-sectional design. Neurocognitive outcomes were compared to control (n = 45) and normative values. Tumor- and treatment-related data were collected from the patient files. Information on employment and social status was gathered. Survivors’ (median age: 27 years [range: 16-43 years]) median verbal and performance intelligence quotient (IQ) was 90 (range: 49-121) and 87 (range: 43-119), respectively. The cognitive domains with the greatest impairment were executive functions (median z score, −3.5 SD [range: −25.0 to 1.3 SD]), and processing speed and attention (median z score, −2.5 SD [range: −24.9 to 0.5 SD]). Executive functions were associated with employment, educational level, living independently, having an intimate relationship, and having a driving license. Processing speed and attention were related to educational level, living independently, having an intimate relationship, and having a driving license. Performance IQ was associated with educational level and employment status. Working memory was associated with educational level and living independently. Radiotherapy-treated adult survivors of childhood BT experience significant neurocognitive impairment, which is associated with difficulties related to employment and social status.