Prenatal Serum Concentrations of Brominated Flame Retardants and Autism Spectrum Disorder and Intellectual Disability in the Early Markers of Autism Study: A Population-Based Case-Control Study in California.

BackgroundPrior studies suggest neurodevelopmental impacts of polybrominated diphenyl ethers (PBDEs), but few have examined diagnosed developmental disorders.ObjectivesOur aim was to determine whether prenatal exposure to brominated flame retardants (BFRs) is associated with autism spectrum disorder (ASD) or intellectual disability without autism (ID).MethodsWe conducted a population-based case-control study including children with ASD (n=545) and ID (n=181) identified from the California Department of Developmental Services and general population (GP) controls (n=418) from state birth certificates. ASD cases were matched to controls by sex, birth month, and birth year. Concentrations of 10 BFRs were measured in maternal second trimester serum samples stored from routine screening. Logistic regression was used to calculate crude and adjusted odds ratios (AOR) for associations with ASD, and separately for ID, compared with GP controls, by quartiles of analyte concentrations in primary analyses.ResultsGeometric mean concentrations of five of the six congeners with ≥55% of samples above the limit of detection were lower in mothers of children with ASD or ID than in controls. In adjusted analyses, inverse associations with several congeners were found for ASD relative to GP (e.g., quartile 4 vs. 1, BDE-153: AOR=0.56, 95% CI: 0.38, 0.84). When stratified by child sex (including 99 females with ASD, 77 with ID, and 73 with GP), estimates were consistent with overall analyses in boys, but in the opposite direction among girls, particularly for BDE-28 and -47 (AOR=2.58, 95% CI: 0.86, 7.79 and AOR=2.64, 95% CI: 0.97, 7.19, respectively). Similar patterns overall and by sex were observed for ID.ConclusionsContrary to expectation, higher PBDE concentrations were associated with decreased odds of ASD and ID, though not in girls. These findings require confirmation but suggest potential sexual dimorphism in associations with prenatal exposure to BFRs. https://doi.org/10.1289/EHP1079

Syringe Pump

Our team was asked to design a syringe pump that would deliver fluid at a controlled flow rate to cells in a microfluidic device. The design process of our syringe pump proved to be a very dynamic one. The beginning research of both microfluidic devices and existing syringe pumps helped our team get an idea of ways we could implement existing aspects that work into our design. There were many existing devices that resembled the one that we were asked to make closely; however, due to our resources as students, we had to be a bit more creative in figuring out how to afford and assemble each component to the best of our abilities. Developing customer requirements was a huge step in the process of understanding what exactly you as our customer wanted to see delivered in our syringe pump. The main requirements of our pump were that it was able to deliver accurate shear stress values so that they could mimic those found in true physiology, that it was able to deliver an accurate flow rate to the device, that it was easily usable, and that it was compact to both fit in a desired location and have ease of mobility when needed to be moved to or from that location. Next, it was our job as the engineers to turn those requirements into quantitative engineering specifications that our device needed to meet via testing of the device once the prototype was finished. Once we determined what numbers needed to be hit to quantify the requirements set by you, we were able to create a network diagram of tasks in order to organize the design, manufacturing, and testing processes that we had ahead. Our design process then became a series of brainstorming via tools like a conjoint analysis, morphology, and Pugh matrices. We did these exercises in order to compile a multitude of ideas for each component of the pump to determine which combination of these ideas would produce the optimal pump that is attractive to the user and does the best job at meeting the customer specifications. We determined the main functions of our pump were inputting flow rate parameters on the interface, having a power source for the pushing mechanism, the physical pushing mechanism, and lastly the mechanism through which the fluid would be delivered into the tube. Ultimately, through the many exercises as well as iterations due to a multitude of realizations down the road, we settled upon using a stepper motor linear actuator for the pushing mechanism and a screen with buttons for the input from the user, powered by a 24 V DC Power Supply and connected by a needle attachment to the syringe. Next came acquiring the materials and aspects of the pump that were to be purchased from a manufacturer as well as designing the aspects that we were going to manufacture ourselves. The primary component of our design that we purchased was the FUYU stepper motor linear actuator, to which we programmed electrically and designed adapters to fit onto. Our electrical programming revolved around the Arduino UNO and the Sketch coding software. The chassis was our last component to design, and its main purpose was to keep the user safe from any potential harm from the pump and protect the pump from any water or other wear. When we had performed the Hazard Safety Assessment, we determined a lot of the risk involved the user having their hands in the pinch points as well as having the device fall on the user, both of which were mitigated by having a chassis that covered the pinch point and made the device more compact and mobile. Once we had those components designed, we determined how we would both manufacture and assemble the final prototype. These plans were surely dynamic as we changed materials and found new ways to better manufacture each piece. Critical changes included changing the chassis material from acrylic to polycarbonate, and thus changing the manufacturing process from laser jetting to water jetting to using a variety of saws to cut the pieces. Another critical change came after having manufactured the pusher block adapter, as we were sent back to the design process when the adapter did not perform the way we wanted it to. Additionally, the electrical side of our design manufacturing had to be iterated multiple times as we determined what was feasible and still effective for inputting the parameters. Our design changed from a 4 x 4 keypad to two buttons, one increasing the flow rate value and one decreasing the value. Once the prototype had been built, it was time to verify that we had made a device that met the customer specifications. We created protocols for how we would test these specifications and executed each of the four, the most time-consuming ones being the flow rate and shear stress tests. Our testing plans for shear stress included both an analytical COMSOL simulation through the solid model of the microfluidic device as well as physical testing of the velocity of the particles moving via the LabSmith Micro Particle Image Velocimetry microscope. The physical testing was to verify that our analytical model accurately displayed what velocity and thus shear stresses the cells in our microfluidic devices would be experiencing. Next, we tested flow rate via running water through our pump at specified flow rates for a given period of time, measuring the mass acquired on a sensitive scale to back-calculate what flow rate was actually being delivered. Additionally, we used a gauge to measure the displacement of our pusher block over a specified time to first ensure that the correct speed was being programmed to the motor. In terms of surface area testing, we simply used a ruler to measure the dimensions of the bottom of our chassis to verify it would fit in the desired location in the lab. Lastly, our ease of use testing included simply numbering the steps in the operations manual. Ultimately, our data showed that we did in fact create a pump that received an input and delivered a controllable flow rate and shear stress to the cells in the microfluidic devices, all while being compact and easily usable. After inputting a flow rate of 28.8 ml/hr, we measured the delivered flow rate to be 25.5 ml/hr, which was within our target percent error range of 15%. For shear stress, when entering a flow rate of 75.8 uL/hr, our physical testing showed a particle velocity of 295.6 um/s and our COMSOL velocity showed one of 358.91 um/s, putting these within range of our 20% error goal. We measured the bottom surface area of our pump to be 431.85 cm^2, which was well within our specification of 695 cm^2. Lastly, we measured 5 steps to program our device, which was our target specification. There were surely limitations to our data, as when flow rate decreased to smaller and smaller values it was increasingly harder to acquire data, and then additionally extremely difficult to have that data be accurate. Thus, at the flow rate of 0.76 uL/hr, which is the flow rate at which the pump will typically be used at, both the shear stress and flow rate specifications were not met via our testing. There are a multitude of reasons why our data may have been skewed, and we have plans for future testing to discover where errors might be introduced in our pump. Overall, our team learned much about the design process and grew as engineers while designing this syringe pump

Rocaglates as dual-targeting agents for experimental cerebral malaria

Cerebral malaria (CM) is a severe and rapidly progressing complication of infection by Plasmodium parasites that is associated with high rates of mortality and morbidity. Treatment options are currently few, and intervention with artemisinin (Art) has limited efficacy, a problem that is compounded by the emergence of resistance to Art in Plasmodium parasites. Rocaglates are a class of natural products derived from plants of the Aglaia genus that have been shown to interfere with eukaryotic initiation factor 4A (eIF4A), ultimately blocking initiation of protein synthesis. Here, we show that the rocaglate CR-1-31B perturbs association of Plasmodium falciparum eIF4A (PfeIF4A) with RNA. CR-1-31B shows potent prophylactic and therapeutic antiplasmodial activity in vivo in mouse models of infection with Plasmodium berghei (CM) and Plasmodium chabaudi (blood-stage malaria), and can also block replication of different clinical isolates of P. falciparum in human erythrocytes infected ex vivo, including drug-resistant P. falciparum isolates. In vivo, a single dosing of CR-1-31B in P. berghei-infected animals is sufficient to provide protection against lethality. CR-1-31B is shown to dampen expression of the early proinflammatory response in myeloid cells in vitro and dampens the inflammatory response in vivo in P. berghei-infected mice. The dual activity of CR-1-31B as an antiplasmodial and as an inhibitor of the inflammatory response in myeloid cells should prove extremely valuable for therapeutic intervention in human cases of CM.We thank Susan Gauthier, Genevieve Perreault, and Patrick Senechal for technical assistance. This work was supported by a research grant (to P.G.) from the Canadian Institutes of Health Research (CIHR) (Foundation Grant). J.P. and P.G. are supported by a James McGill Professorship salary award. D.L. is supported by fellowships from the Fonds de recherche sante Quebec, the CIHR Neuroinflammation training program. J.P. is supported by CIHR Research Grant FDN-148366. M.S. is supported by a CIHR Foundation grant. J.A.P. is supported by NIH Grant R35 GM118173. Work at the Boston University Center for Molecular Discovery is supported by Grant R24 GM111625. K.C.K. was supported by a CIHR Foundation Grant and the Canada Research Chair program. (Canadian Institutes of Health Research (CIHR); James McGill Professorship salary award; Fonds de recherche sante Quebec; CIHR Neuroinflammation training program; FDN-148366 - CIHR Research Grant; CIHR Foundation grant; R35 GM118173 - NIH; Canada Research Chair program; R24 GM111625

Decreased Acetic Acid in the Stool of Preterm Infants Is Associated with an Increased Risk of Bronchopulmonary Dysplasia

Background: Short-chain fatty acids (SCFAs), microbial metabolites, have been minimally studied in neonatal pathophysiology but have been associated with disease outcomes in adults. The objective of this manuscript was to determine if SCFA levels in maternal breastmilk (BM) and stool from preterm neonates impacted the risk of neonatal morbidities. Methods: SCFA levels were quantified by liquid chromatography with tandem mass spectrometry on maternal BM and neonatal stool for preterm infants < 28 weeks’ gestation (N = 72) on postnatal days 14 and 28. SCFA levels in BM and stool of infants with and without bronchopulmonary disease (BPD) and retinopathy of prematurity (ROP) were compared. Logistic regression was applied to determine the association between stool acetic acid levels and disease. Results: Acetic, propionic, isobutyric, 2-methylbutyric, and isovaleric acid levels increased in BM and neonatal stool between days 14 and 28. Logistic regression demonstrated an inverse relationship between the quartile of fecal acetic acid level and the odds of BPD but not ROP on days 14 and 28. For each quartile increase in fecal acetic acid, the odds ratio (95% CI) of BPD was 0.41 (0.18, 0.83) for day 14 and 0.28 (0.09, 0.64) for day 28. Conclusions: Low acetic acid levels in the stool of preterm infants are associated with increased odds of BPD. These findings support a relationship between intestinal and pulmonary health in preterm infants

Sustained High Basal Motion of the Greenland Ice Sheet Revealed by Borehole Deformation

Ice deformation and basal motion characterize the dynamical behavior of the Greenland ice sheet (GrIS). We evaluate the contribution of basal motion from ice deformation measurements in boreholes drilled to the bed at two sites in the western marginal zone of the GrIS. We find a sustained high amount of basal motion contribution to surface velocity of 44–73% in winter, and up to 90% in summer. Measured ice deformation rates show an unexpected variation with depth that can be explained with the help of an ice-flow model as a consequence of stress transfer from slippery to sticky areas. This effect necessitates the use of high-order ice-flow models, not only in regions of fast-flowing ice streams but in all temperate-based areas of the GrIS. The agreement between modeled and measured deformation rates confirms that the recommended values of the temperature-dependent flow rate factor A are a good choice for ice-sheet models

The endoribonuclease YbeY is linked to proper cellular morphology and virulence in 2 Brucella abortus

The endoribonuclease YbeY is one of the most well conserved proteins across the kingdoms of life. In the present study, we demonstrate that YbeY in Brucella abortus is linked to a variety of important activities, including proper cellular morphology, mRNA transcript levels, and virulence. Deletion of ybeY in B. abortus led to a small colony phenotype when the bacteria were grown on agar medium, as well as significant aberrations in the morphology of the bacterial cell as evidenced by electron microscopy. Additionally, compared to the parental strain, the ΔybeY strain was significantly attenuated in both macrophage and mouse models of infection. The ΔybeY strain also showed increased sensitivities to several in vitro applied stressors, including bile acid, hydrogen peroxide, SDS, and paraquat. Transcriptomic analysis revealed that a multitude of mRNA transcripts are dysregulated in the ΔybeY strain, and many of the identified mRNAs encode proteins involved in metabolism, nutrient transport, transcriptional regulation, and flagellum synthesis. We subsequently constructed gene deletion strains of the most highly dysregulated systems, and several of the YbeY-linked gene deletion strains exhibited defects in the ability of the bacteria to survive and replicate in primary murine macrophages. Altogether, these data establish a clear role for YbeY in the biology and virulence of Brucella, and moreover, this work further illuminates the highly varied roles of this widely conserved endoribonuclease in bacteria. Importance Brucella spp. are highly efficient bacterial pathogens of animals and humans, causing significant morbidity and economic loss worldwide, and relapse of disease often occurs following antibiotic treatment of human brucellosis. As such, novel therapeutic strategies to combat Brucella infections are needed. Ribonucleases in the brucellae are understudied, and these enzymes represent elements that may be potential targets for future treatment approaches. The present work demonstrates the importance of the endoribonuclease YbeY for cellular morphology, efficient control of mRNA levels, and virulence in B. abortus. Overall, this study advances our understanding of the critical roles of YbeY in the pathogenesis of the intracellular brucellae and expands our understanding of this highly conserved ribonuclease.National Institute of General Medical Sciences (U.S.) (Grant GM31030

The association of genetic predisposition to depressive symptoms with non-suicidal and suicidal self-Injuries

Non-suicidal and suicidal self-injury are very destructive, yet surprisingly common behaviours. Depressed mood is a major risk factor for non-suicidal self-injury (NSSI), suicidal ideation and suicide attempts. We conducted a genetic risk prediction study to examine the polygenic overlap of depressive symptoms with lifetime NSSI, suicidal ideation, and suicide attempts in a sample of 6237 Australian adult twins and their family members (3740 females, mean age\ua0=\ua042.4\ua0years). Polygenic risk scores for depressive symptoms significantly predicted suicidal ideation, and some predictive ability was found for suicide attempts; the polygenic risk scores explained a significant amount of variance in suicidal ideation (lowest p\ua0=\ua00.008, explained variance ranging from 0.10 to 0.16\ua0%) and, less consistently, in suicide attempts (lowest p\ua0=\ua00.04, explained variance ranging from 0.12 to 0.23\ua0%). Polygenic risk scores did not significantly predict NSSI. Results highlight that individuals genetically predisposed to depression are also more likely to experience suicidal ideation/behaviour, whereas we found no evidence that this is also the case for NSSI

Life in Hot Carbon Monoxide: The Complete Genome Sequence of Carboxydothermus hydrogenoformans Z-2901

We report here the sequencing and analysis of the genome of the thermophilic bacterium Carboxydothermus hydrogenoformans Z-2901. This species is a model for studies of hydrogenogens, which are diverse bacteria and archaea that grow anaerobically utilizing carbon monoxide (CO) as their sole carbon source and water as an electron acceptor, producing carbon dioxide and hydrogen as waste products. Organisms that make use of CO do so through carbon monoxide dehydrogenase complexes. Remarkably, analysis of the genome of C. hydrogenoformans reveals the presence of at least five highly differentiated anaerobic carbon monoxide dehydrogenase complexes, which may in part explain how this species is able to grow so much more rapidly on CO than many other species. Analysis of the genome also has provided many general insights into the metabolism of this organism which should make it easier to use it as a source of biologically produced hydrogen gas. One surprising finding is the presence of many genes previously found only in sporulating species in the Firmicutes Phylum. Although this species is also a Firmicutes, it was not known to sporulate previously. Here we show that it does sporulate and because it is missing many of the genes involved in sporulation in other species, this organism may serve as a “minimal” model for sporulation studies. In addition, using phylogenetic profile analysis, we have identified many uncharacterized gene families found in all known sporulating Firmicutes, but not in any non-sporulating bacteria, including a sigma factor not known to be involved in sporulation previously

IgG and IgA autoantibodies against L1 ORF1p expressed in granulocytes correlate with granulocyte consumption and disease activity in pediatric systemic lupus erythematosus

BACKGROUND: Most patients with systemic lupus erythematosus (SLE) have IgG autoantibodies against the RNA-binding p40 (ORF1p) protein encoded by the L1 retroelement. This study tested if these autoantibodies are also present in children with pediatric SLE (pSLE) and if the p40 protein itself could be detected in immune cells. METHODS: Autoantibodies in the plasma of pSLE patients (n = 30), healthy children (n = 37), and disease controls juvenile idiopathic arthritis (JIA) (n = 32) and juvenile dermatomyositis (JDM) (n = 60), were measured by ELISA. Expression of p40 in immune cells was assessed by flow cytometry. Markers of neutrophil activation and death were quantitated by ELISA. RESULTS: IgG and IgA autoantibodies reactive with p40 were detected in the pSLE patients, but were low in healthy controls and in JIA or JDM. pSLE patients with active disease (13 of them newly diagnosed) had higher titers than the same patients after effective therapy (p = 0.0003). IgG titers correlated with SLEDAI (r = 0.65, p = 0.0001), ESR (r = 0.43, p = 0.02), and anti-dsDNA antibodies (r = 0.49, p < 0.03), and inversely with complement C3 (r = -0.55, p = 0.002) and C4 (r = -0.51, p = 0.006). p40 protein was detected in a subpopulation of CD66b(+) granulocytes in pSLE, as well as in adult SLE patients. Myeloperoxidase and neutrophil elastase complexed with DNA and the neutrophil-derived S100A8/A9 were elevated in plasma from pSLE patients with active disease and correlated with anti-p40 autoantibodies and disease activity. CONCLUSIONS: Children with active SLE have elevated IgG and IgA autoantibodies against L1 p40, and this protein can be detected in circulating granulocytes in both pediatric and adult SLE patients. P40 expression and autoantibody levels correlate with disease activity. Markers of neutrophil activation and death also correlate with these autoantibodies and with disease activity, suggesting that neutrophils express L1 and are a source of p40. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13075-021-02538-3