Palmitic acid induces inflammation in placental trophoblasts and impairs their migration toward smooth muscle cells through plasminogen activator inhibitor-1

A critical component of early human placental development includes migration of extravillous trophoblasts (EVTs) into the decidua. EVTs migrate toward and displace vascular smooth muscle cells (SMCs) surrounding several uterine structures, including spiral arteries. Shallow trophoblast invasion features in several pregnancy complications including preeclampsia. Maternal obesity is a risk factor for placental dysfunction, suggesting that factors within an obese environment may impair early placental development. Herein, we tested the hypothesis that palmitic acid, a saturated fatty acid circulating at high levels in obese women, induces an inflammatory response in EVTs that hinders their capacity to migrate toward SMCs. We found that SMCs and SMC-conditioned media stimulated migration and invasion of an EVT-like cell line, HTR8/SVneo. Palmitic acid impaired EVT migration and invasion toward SMCs, and induced expression of several vasoactive and inflammatory mediators in EVTs, including endothelin, interleukin (IL)-6, IL-8 and PAI1. PAI1 was increased in plasma of women with early-onset preeclampsia, and PAI1-deficient EVTs were protected from the anti-migratory effects of palmitic acid. Using first trimester placental explants, palmitic acid exposure decreased EVT invasion through Matrigel. Our findings reveal that palmitic acid induces an inflammatory response in EVTs and attenuates their migration through a mechanism involving PAI1. High levels of palmitic acid in pathophysiological situations like obesity may impair early placental development and predispose to placental dysfunction

Microfluidic chromatography for early stage evaluation of biopharmaceutical binding and separation conditions

Optimization of separation conditions for biopharmaceuticals requires evaluation of a large number of process variables. To miniaturize this evaluation a microfluidic column (1.5 mu L volume and 1cm height) was fabricated and packed with a typical process scale resin. The device was assessed by comparison to a protein separation at conventional laboratory scale. This was based upon measurement of the quality of packing and generation of breakthrough and elution curves. Dynamic binding capacities from the microfluidic column compared well with the laboratory scale. Microfluidic scale gradient elution separations also equated to the laboratory column three orders of magnitude larger in scale

A life course approach to the relationship between fetal growth and hypothalamic-pituitary-adrenal axis function

CONTEXT: Human and animal studies suggest that hypothalamic-pituitary-adrenal axis (HPA-A) function may be programmed in utero; however, these findings are inconsistent. Given the powerful metabolic actions of cortisol, it is important to clarify the influence of early life on adult HPA-A function. OBJECTIVE: To determine the relationship between fetal growth and HPA-A stress response to a psychosocial stressor in young adults. DESIGN: Multigenerational, prospective cohort study (the Raine Study) conducted between 1989 and 1991. SETTING: King Edward Memorial Hospital, Perth, Western Australia, Australia. PARTICIPANTS: A total of 917 participants aged 18 years from Gen2 of the Raine Study. MAIN OUTCOME MEASURES: Measures of hypothalamic-pituitary-adrenal axis function before and after exposure to the Trier Social Stress Test. RESULTS: In fully adjusted models, an inverse linear relationship was observed between birthweight and plasma measures of (1) baseline cortisol (β = -0.90%, 95% CI: -1.73 to -0.07; P = 0.03); (2) peak cortisol (β = -0.78%, 95% CI -1.51 to -0.06; P = 0.03); (3) area under the curve with respect to ground (β = -0.89%, 95% CI -1.60 to -0.18; P = 0.01); and (4) adrenal sensitivity (β = -1.02, 95% CI: -1.85 to -0.18; P = 0.02). Similar results were demonstrated for percent optimal birthweight. No consistent quadratic relationships were identified. No associations were found between measures of fetal adiposity and HPA-A function at age 18 years, or fetal growth and HPA-A response pattern. Removal of anticipatory responders from the models substantially attenuated the observed relationships. CONCLUSION: We observed an inverse linear relationship between fetal growth and HPA-A function at age 18 years. This differs from the inverse parabolic relationship (inverted U curve) reported in adults of advanced age. Altered adrenal sensitivity may underlie this relationship

Dual energy X-ray absorptiometry compared with anthropometry in relation to cardio-metabolic risk factors in a young adult population: Is the ‘Gold Standard’ tarnished?

Background and Aims: Assessment of adiposity using dual energy x-ray absorptiometry (DXA) has been considered more advantageous in comparison to anthropometryfor predicting cardio-metabolic risk in the older population, by virtue of its ability to distinguish total and regional fat. Nonetheless, there is increasing uncertainty regarding the relative superiority of DXA and little comparative data exist in young adults. This study aimed to identify which measure of adiposity determined by either DXA or anthropometry is optimal within a range of cardio-metabolic risk factors in young adults. Methods and Results: 1138 adults aged 20 years were assessed by DXA and standard anthropometry from the Western Australian Pregnancy Cohort (Raine) Study. Cross-sectional linear regression analyses were performed. Waist to height ratio was superior to any DXA measure with HDL-C. BMI was the superior model in relation to blood pressure than any DXA measure. Midriff fat mass (DXA) and waist circumference were comparable in relation to glucose. For all the other cardio-metabolic variables, anthropometricand DXA measures were comparable. DXA midriff fat mass compared with BMI or waist hip ratio was the superior measure for triglycerides, insulin and HOMA-IR. Conclusion: Although midriff fat mass (measured by DXA) was the superior measure with insulin sensitivity and triglycerides, the anthropometricmeasures were better or equal with various DXA measures for majority of the cardio-metabolic risk factors. Our findings suggest, clinical anthropometry is generally as useful as DXA in the evaluation of the individual cardio-metabolic risk factors in young adults

Visual attentional load influences plasticity in the human motor cortex

Neural plasticity plays a critical role in learning, memory, and recovery from injury to the nervous system. Although much is known about the physical and physiological determinants of plasticity, little is known about the influence of cognitive factors. In this study, we investigated whether selective attention plays a role in modifying changes in neural excitability reflecting long-term potentiation (LTP)like plasticity. We induced LTP-like effects in the hand area of the human motor cortex using transcranial magnetic stimulation (TMS). During the induction of plasticity, participants engaged in a visual detection task with either low or high attentional demands. Changes in neural excitability were assessed by measuring motor-evoked potentials in a small hand muscle before and after the TMS procedures. In separate experiments plasticity was induced either by paired associative stimulation (PAS) or intermittent theta-burst stimulation (iTBS). Because these procedures induce different forms of LTP-like effects, they allowed us to investigate the generality of any attentional influence on plasticity. In both experiments reliable changes in motor cortex excitability were evident under low-load conditions, but this effect was eliminated under high-attentional load. In a third experiment we investigated whether the attentional task was associated with ongoing changes in the excitability of motor cortex, but found no difference in evoked potentials across the levels of attentional load. Our findings indicate that in addition to their role in modifying sensory processing, mechanisms of attention can also be a potent modulator of cortical plasticity

Retention and loss of RNA interference pathways in trypanosomatid protozoans

RNA interference (RNAi) pathways are widespread in metaozoans but the genes required show variable occurrence or activity in eukaryotic microbes, including many pathogens. While some Leishmania lack RNAi activity and Argonaute or Dicer genes, we show that Leishmania braziliensis and other species within the Leishmania subgenus Viannia elaborate active RNAi machinery. Strong attenuation of expression from a variety of reporter and endogenous genes was seen. As expected, RNAi knockdowns of the sole Argonaute gene implicated this protein in RNAi. The potential for functional genetics was established by testing RNAi knockdown lines lacking the paraflagellar rod, a key component of the parasite flagellum. This sets the stage for the systematic manipulation of gene expression through RNAi in these predominantly diploid asexual organisms, and may also allow selective RNAi-based chemotherapy. Functional evolutionary surveys of RNAi genes established that RNAi activity was lost after the separation of the Leishmania subgenus Viannia from the remaining Leishmania species, a divergence associated with profound changes in the parasite infectious cycle and virulence. The genus Leishmania therefore offers an accessible system for testing hypothesis about forces that may select for the loss of RNAi during evolution, such as invasion by viruses, changes in genome plasticity mediated by transposable elements and gene amplification (including those mediating drug resistance), and/or alterations in parasite virulence

Failure of Decidualization and Maternal Immune Tolerance Underlies Uterovascular Resistance in Intra Uterine Growth Restriction

Failure of uterine vascular transformation is associated with pregnancy complications including Intra Uterine Growth Restriction (IUGR). The decidua and its immune cell populations play a key role in the earliest stages of this process. Here we investigate the hypothesis that abnormal decidualization and failure of maternal immune tolerance in the second trimester may underlie the uteroplacental pathology of IUGR. Placental bed biopsies were obtained from women undergoing elective caesarian delivery of a healthy term pregnancy, an IUGR pregnancy or a pregnancy complicated by both IUGR and preeclampsia. Decidual tissues were also collected from second trimester terminations from women with either normal or high uterine artery Doppler pulsatile index (PI). Immunohistochemical image analysis and flow cytometry were used to quantify vascular remodeling, decidual leukocytes and decidual status in cases vs. controls. Biopsies from pregnancies complicated by severe IUGR with a high uterine artery pulsatile index (PI) displayed a lack of: myometrial vascular transformation, interstitial, and endovascular extravillous trophoblast (EVT) invasion, and a lower number of maternal leukocytes. Apoptotic mural EVT were observed in association with mature dendritic cells and T cells in the IUGR samples. Second trimester pregnancies with high uterine artery PI displayed a higher incidence of small for gestational age fetuses; a skewed decidual immunology with higher numbers of; CD8 T cells, mature CD83 dendritic cells and lymphatic vessels that were packed with decidual leukocytes. The decidual stromal cells (DSCs) failed to differentiate into the large secretory DSC in these cases, remaining small and cuboidal and expressing lower levels of the nuclear progesterone receptor isoform B, and DSC markers Insulin Growth Factor Binding protein-1 (IGFBP-1) and CD10 as compared to controls. This study shows that defective progesterone mediated decidualization and a hostile maternal immune response against the invading endovascular EVT contribute to the failure of uterovascular remodeling in IUGR pregnancies

Cross-sectional associations between mental health indicators and social vulnerability, with physical activity, sedentary behaviour and sleep in urban African young women

Background Relationships between mental health and multiple health behaviours have not been explored in young South African women experiencing social constraints. The aim of this study was to identify associations between mental health indicators and risk factors with physical activity, sedentary behaviour, and sleep, amongst young women living in Soweto, a predominantly low-income, urban South African setting. Methods For this cross-sectional study, baseline measurements for participants (n = 1719, 18.0–25.9 years old) recruited for the Healthy Life Trajectories Initiative were used including: physical activity, sedentary behaviour (sitting, screen and television time), sleep (duration and quality), depression and anxiety indicators, emotional health, adverse childhood experiences, alcohol-use risk; social vulnerability, self-efficacy, and social support. Results Multiple regression analyses showed that depression (β = 0.161, p < 0.001), anxiety (β = 0.126, p = 0.001), adverse childhood experiences (β = 0.076, p = 0.014), and alcohol-use risk (β = 0.089, p = 0.002) were associated with poor quality sleep. Alcohol-use risk was associated with more screen time (β = 0.105, p < 0.001) and television time (β = 0.075, p < 0.016). Social vulnerability was associated with lower sitting time (β = − 0.187, p < 0001) and screen time (β = − 0.014, p < 0.001). Higher self-efficacy was associated with more moderate- to vigorous-intensity physical activity (β = 0.07, p = 0.036), better-quality sleep (β = − 0.069, p = 0.020) and less television time (β = − 0.079, p = 0.012). Having no family support was associated with more sitting time (β = 0.075, p = 0.022). Binomial logistic regression analyses supported these findings regarding sleep quality, with anxiety and depression risk doubling the risk of poor-quality sleep (OR = 2.425, p < 0.001, OR = 2.036, p = 0.003 respectively). Conclusions These findings contribute to our understanding of how mental health indicators and risk factors can be barriers to health behaviours of young women in Soweto, and that self-efficacy and social support can be protective for certain of these behaviours for these women. Our results highlight the uniqueness of this setting regarding associations between mental health and behaviours associated with non-communicable diseases risk

Genome assemblies across the diverse evolutionary spectrum of Leishmania protozoan parasites

We report the high-quality draft assemblies and gene annotations for 13 species and/or strains of the protozoan parasite gener