Direct interaction of the Fanconi anaemia protein FANCG with BRCA2/FANCD1

Fanconi anaemia (FA) is an autosomal recessive genetic disorder characterized by progressive bone marrow failure, multiple congenital abnormalities, and an increased risk of cancer. FA cells are characterized by chromosomal instability and hypersensitivity to DNA interstrand crosslinking agents. At least eight complementation groups exist (FA-A to G), and the genes for all of these except FA-B have been cloned. Functional linkage between the FA pathway and genes involved in susceptibility to breast cancer has been demonstrated by the interaction of the FANCA and FANCD2 proteins with BRCA1, and the discovery that the FANCD1 gene is identical to BRCA2. Here we have used the yeast two-hybrid system to test for direct interaction between BRCA2 or its effector RAD51 and the FANCA, FANCC and FANCG proteins. We found that FANCG was capable of binding to two separate sites in the BRCA2 protein, located either side of the BRC repeats. Furthermore, FANCG could be co-immunoprecipitated with BRCA2 from human cells, and FANCG co-localized in nuclear foci with both BRCA2 and RAD51 following DNA damage with mitomycin C. These results demonstrate that BRCA2 is directly connected to a pathway that is deficient in interstrand crosslink repair, and that at least one other FA protein is closely associated with the homologous recombination DNA repair machinery.     

Aspirin-Interleukin-3 Interrelationships in Patients With Anti-Phospholipid Syndrome

PROBLEM: Previously we reported on the generation of experimental anti-phospholipid syndrome (APS) in mice. These models were employed to evaluate the efficacy of various novel therapeutic modalities including interleukin-3 (IL-3) and low dose aspirin. The efficacy of the latter was found to be interrelated. Low dose aspirin is capable of inhibiting the activity of the enzyme cyclooxygenase which is responsible for the metabolism of arachidonic acid towards the production of prostaglandins. This shifts the metabolism of arachidonic acid to the other pathway and leads to an overproduction of leukotrienes. The leukotrienes act as stimulators of IL-3 production, a positive cytokine in pregnancy which enhances placental and fetal development. In the current study we evaluated the IL-3 levels in pregnant women with APS and expanded our knowledge on the interrelationships between aspirin, arachidonic acid metabolites and IL-3 in the human system. METHODS: IL-3 levels were recorded in the serum of pregnant women with APS and compared to a control pregnant group. In addition peripheral blood mononuclear cells from healthy subjects were incubated with different concentrations of aspirin or with arachidonic acid metabolites (Leukotriene B4, C4 or PGE₂), and IL-3 production in the culture fluids was evaluated. RESULTS: Serum level of IL-3 in pregnant patients with primary APS, APS secondary to SLE and SLE was lower in comparison to the control group. The in vitro studies revealed that only low dose aspirin (10 mg/μl) stimulated IL-3 production while higher doses of the drug failed to induce the cytokine generation. Leukotriene B4 and C4 were stimulatory whereas PGE₂ acted as inhibitor of IL-3 production. CONCLUSIONS: The serum level of IL-3 is decreased to pregnant women with primary or secondary APS. Low dose aspirin is capable of stimulating EL-3 production in vitro most probably through an elevation of leukotriene production, which may explain its beneficial activity in preventing the manifestations of APS.     

Pediatric Multi-Organ Dysfunction Syndrome: Analysis by an Untargeted “Shotgun” Lipidomic Approach Reveals Low-Abundance Plasma Phospholipids and Dynamic Recovery over 8-Day Period,a Single-Center Observational Study

Lipids are molecules involved in metabolism and inflammation. This study investigates the plasma lipidome for markers of severity and nutritional status in critically ill children. Children with multi-organ dysfunction syndrome (MODS) (n = 24) are analyzed at three time-points and cross-referenced to sedation controls (n = 4) for a total of N = 28. Eight of the patients with MODS, needed veno-arterial extracorporeal membrane oxygenation (VA ECMO) support to survive. Blood plasma lipid profiles are quantified by nano-electrospray (nESI), direct infusion high resolution/accurate mass spectrometry (MS), and tandem mass spectrometry (MS/MS), and compared to nutritional profiles and pediatric logistic organ dysfunction (PELOD) scores. Our results show that PELOD scores were not significantly different between MODS and ECMO cases across time-points (p = 0.66). Lipid profiling provides stratification between sedation controls and all MODS patients for total lysophosphatidylserine (lysoPS) (p-value = 0.004), total phosphatidylserine (PS) (p-value = 0.015), and total ether-linked phosphatidylethanolamine (ether-PE) (p-value = 0.03) after adjusting for sex and age. Nutrition intake over time did not correlate with changes in lipid profiles, as measured by caloric and protein intake. Lipid measurement in the intensive care environment shows dynamic changes over an 8-day pediatric intensive care unit (PICU) course, suggesting novel metabolic indicators for defining critically ill children.     

Time-Restricted Eating for 12 Weeks Does Not Adversely Alter Bone Turnover in Overweight Adults

Weight loss is a major focus of research and public health efforts. Time-restricted eating (TRE) is shown to be effective for weight loss, but the impact on bone is unclear. Short-term TRE studies show no effect on bone mineral density (BMD), but no study has measured bone turnover markers. This secondary analysis examined the effect of 12 weeks of TRE vs. unrestricted eating on bone turnover and BMD. Overweight and obese adults aged 18–65 y (n = 20) were randomized to TRE (ad libitum 8-h eating window) or non-TRE. Serum N-terminal propeptide of type I collagen (P1NP), cross-linked N-telopeptide of type I collagen (NTX), and parathyroid hormone (PTH) levels were measured and dual-energy X-ray absorptiometry (DXA) scans were taken pre- and post-intervention. In both groups, P1NP decreased significantly (p = 0.04) but trended to a greater decrease in the non-TRE group (p = 0.07). The treatment time interaction for bone mineral content (BMC) was significant (p = 0.02), such that BMC increased in the TRE group and decreased in the non-TRE group. Change in P1NP was inversely correlated with change in weight (p = 0.04) overall, but not within each group. These findings suggest that TRE does not adversely affect bone over a moderate timeframe. Further research should examine the long-term effects of TRE on bone.     

The Hunger Games: Homeostatic State-Dependent Fluctuations in Disinhibition Measured with a Novel Gamified Test Battery

Food homeostatic states (hunger and satiety) influence the cognitive systems regulating impulsive responses, but the direction and specific mechanisms involved in this effect remain elusive. We examined how fasting, and satiety, affect cognitive mechanisms underpinning disinhibition using a novel framework and a gamified test-battery. Thirty-four participants completed the test-battery measuring three cognitive facets of disinhibition: attentional control, information gathering and monitoring of feedback, across two experimental sessions: one after overnight fasting and another after a standardised meal. Homeostatic state was assessed using subjective self-reports and biological markers (i.e., blood-derived liver-expressed antimicrobial protein 2 (LEAP-2), insulin and leptin). We found that participants who experienced greater subjective hunger during the satiety session were more impulsive in the information gathering task; results were not confounded by changes in mood or anxiety. Homeostatic state did not significantly influence disinhibition mechanisms linked to attentional control or feedback monitoring. However, we found a significant interaction between homeostatic state and LEAP-2 on attentional control, with higher LEAP-2 associated with faster reaction times in the fasted condition only. Our findings indicate lingering hunger after eating increases impulsive behaviour via reduced information gathering. These findings identify a novel mechanism that may underpin the tendency to overeat and/or engage in broader impulsive behaviours.     

Health Literacy and Associated Outcomes in the Postpartum Period at Grady Memorial Hospital

Maternal and Child Health Journal - Many studies correlate lower health literacy with poorer health outcomes and inferior provider-patient communication. Little is known about how impaired health...     

Ecological Systems Affecting Urban Childbearing Puerto Rican Women in the City of Philadelphia

Maternal and Child Health Journal - The purpose of this study was to explore socio-ecological influences affecting the daily lives of urban, pregnant Puerto Rican women and factors negatively...     

Adverse Childhood Experiences are Associated with Miscarriage in Adulthood: The GROWH Study

Maternal and Child Health Journal - To investigate whether adverse childhood experiences are associated with miscarriage. The Gulf Resilience on Women’s Health Consortium recruited from...     

Pediatric Group Care: A Systematic Review

Maternal and Child Health Journal - To describe characteristics and outcomes of Group Well-Child Care programs and provide recommendations for future research. Informed by Preferred Reporting Items...     

Lactation Patterns in Women with Hypertensive Disorders of Pregnancy: An Analysis of Illinois 2012–2015 Pregnancy Risk Assessment Monitoring System (PRAMS) Data

Maternal and Child Health Journal - Hypertensive disorders of pregnancy have lifelong implications on maternal cardiovascular health. Breastfeeding has a variety of maternal benefits, including...