Targeting of reactive isolevuglandins in mitochondrial dysfunction and inflammation.

Inflammation is a major cause of morbidity and mortality in Western societies. Despite use of multiple drugs, both chronic and acute inflammation still represent major health burdens. Inflammation produces highly reactive dicarbonyl lipid peroxidation products such as isolevuglandins which covalently modify and cross-link proteins via lysine residues. Mitochondrial dysfunction has been associated with inflammation; however, its molecular mechanisms and pathophysiological role are still obscure. We hypothesized that inflammation-induced isolevuglandins contribute to mitochondrial dysfunction and mortality. To test this hypothesis, we have (a) investigated the mitochondrial dysfunction in response to synthetic 15-E2-isolevuglandin (IsoLG) and its adducts; (b) developed a new mitochondria-targeted scavenger of isolevuglandins by conjugating 2-hydroxybenzylamine to the lipophilic cation triphenylphosphonium, (4-(4-aminomethyl)-3-hydroxyphenoxy)butyl)-triphenylphosphonium (mito2HOBA); (c) tested if mito2HOBA protects from mitochondrial dysfunction and mortality using a lipopolysaccharide model of inflammation. Acute exposure to either IsoLG or IsoLG adducts with lysine, ethanolamine or phosphatidylethanolamine inhibits mitochondrial respiration and attenuates Complex I activity. Complex II function was much more resistant to IsoLG. We confirmed that mito2HOBA markedly accumulates in isolated mitochondria and it is highly reactive with IsoLGs. To test the role of mitochondrial IsoLGs, we studied the therapeutic potential of mito2HOBA in lipopolysaccharide mouse model of sepsis. Mito2HOBA supplementation in drinking water (0.1 g/L) to lipopolysaccharide treated mice increased survival by 3-fold, improved complex I-mediated respiration, and histopathological analyses supported mito2HOBA-mediated protection of renal cortex from cell injury. These data support the role of mitochondrial IsoLG in mitochondrial dysfunction and inflammation. We conclude that reducing mitochondrial IsoLGs may be a promising therapeutic target in inflammation and conditions associated with mitochondrial oxidative stress and dysfunction

An International Collaboration to Promote Inquiry-based Learning in Undergraduate Engineering Classrooms

Abstract Theorists such as Bransford et al. argue that twenty-first century educators need to teach students to do more than simply remember and repeat information. Engineering educators Prince and Felder critique traditional methods of teaching in which instructors focus on mathematics and theory, but fail to convey practical applications of that knowledge. They advocate moving students to a higher level of learning -past the stage of memorizing and reciting data -to more sophisticated methods of analysis, synthesis, and application of knowledge. To enact such transformations, Prince and Felder recommend "inductive teaching methods," including "inquiry-based learning," in which students learn through engaging with challenges and a series of questions. The purpose of this paper is to describe specific techniques of "inquiry-based learning" employed by three instructors in Engineering schools, one in Europe and two in the USA. The paper provides examples of inquiry-based learning activities from each of the authors. The paper then discusses the cross-pollination of ideas and describes how the authors have shared inquiry-based teaching strategies and collaborated to develop new and relevant assignments and approaches to teaching

Hyalotekite, (Ba,Pb,K)(4)(Ca,Y)(2)Si-8(B,Be)(2)(Si,B)(2)O28F, a Tectosilicate Related to Scapolite: New Structure Refinement, Phase Transitions and a Short-Range Ordered 3B Superstructure

Hyalotekite, a framework silicate of composition (Ba,Pb,K)(4)(Ca,Y)(2)Si-8(B,Be)(2) (Si,B)(2)O28F, is found in relatively high-temperature(greater than or equal to 500 degrees C) Mn skarns at Langban, Sweden, and peralkaline pegmatites at Dara-i-Pioz, Tajikistan. A new paragenesis at Dara-i-Pioz is pegmatite consisting of the Ba borosilicates leucosphenite and tienshanite, as well as caesium kupletskite, aegirine, pyrochlore, microcline and quartz. Hyalotekite has been partially replaced by barylite and danburite. This hyalotekite contains 1.29-1.78 wt.% Y2O3, equivalent to 0.172-0.238 Y pfu or 8-11% Y on the Ca site; its Pb/(Pb+Ba) ratio ranges 0.36-0.44. Electron microprobe F contents of Langban and Dara-i-Pioz hyalotekite range 1.04-1.45 wt.%, consistent with full occupancy of the F site. A new refinement of the structure factor data used in the original structural determination of a Langban hyalotekite resulted in a structural formula, (Pb1.96Ba1.86K0.18)Ca-2(B1.76Be0.24)(Si1.56B0.44)Si8O28F, consistent with chemical data and all cations with positive-definite thermal parameters, although with a slight excess of positive charge (+57.14 as opposed to the ideal +57.00). An unusual feature of the hyalotekite framework is that 4 of 28 oxygens are non-bridging; by merging these 4 oxygens into two, the framework topology of scapolite is obtained. The triclinic symmetry of hyalotekite observed at room temperature is obtained from a hypothetical tetragonal parent structure via a sequence of displacive phase transitions. Some of these transitions are associated with cation ordering, either Pb-Ba ordering in the large cation sites, or B-Be and Si-B ordering on tetrahedral sites. Others are largely displacive but affect the coordination of the large cations (Pb, Ba, K, Ca). High-resolution electron microscopy suggests that the undulatory extinction characteristic of hyalotekite is due to a fine mosaic microstructure. This suggests that at least one of these transitions occurs in nature during cooling, and that it is first order with a large volume change. A diffuse superstructure observed by electron diffraction implies the existence of a further stage of short-range cation ordering which probably involves both (Pb,K)-Ba and (BeSi,BB)-BSi

Breastfeeding Awareness and Empowerment (BAE): A Black Women-Led Approach to Promoting a Multigenerational Culture of Health

(1) Background: Critical gaps in the U.S. healthcare system perpetuate adverse reproductive health outcomes for Black people. Grounded in reproductive justice and trauma-informed care, Breastfeeding Awareness and Empowerment (BAE) has developed a program titled BAE Cafe to directly address these gaps by providing community-based lactation and perinatal mental health support. A literature review identified key programmatic gaps, namely, access to knowledge relevant to troubleshooting breastfeeding, peer support, community support and healthcare system support, and system-level factors that impede families and communities from accessing lactation support. (2) Methods: This paper describes BAE Cafe through a group process observation and participant survey. (3) Results: The observation of groups highlighted the core elements of the BAE Cafe model: knowledge, support and mental health support in a peer driven format. Participant survey feedback was overwhelmingly positive and highlighted the critical importance of lactation support for Black women by Black women and BAE’s role in participants’ decisions to continue breastfeeding. (4) Conclusions: BAE Cafe is a replicable, scalable, peer-driven and low-barrier intervention that has the potential to improve outcomes for Black families. Additional research and investment are now needed to assess large-scale implementation to reduce disparities and address health inequity across different contexts and settings

KCNK3 mutation causes altered immune function in pulmonary arterial hypertension patients and mouse models

Loss of function KCNK3 mutation is one of the gene variants driving hereditary pulmonary arterial hypertension (PAH). KCNK3 is expressed in several cell and tissue types on both membrane and endoplasmic reticulum and potentially plays a role in multiple pathological process associated with PAH. However, the role of various stressors driving the susceptibility of KCNK3 mutation to PAH is unknown. Hence, we expose

Modeling perennial groundcover effects on annual maize grain crop growth with the Agricultural Production Systems sIMulator

The inclusion of perennial groundcover (PGC) in maize production offers a tenable solution to natural resources-related concerns associated with conventional maize; however, insight into system management and key information gaps is needed to guide future research. We therefore extended the Agricultural Production Systems sIMulator (APSIM) to an annual and perennial intercrop by integrating annual and perennial APSIM modules. These were parameterized for Kentucky bluegrass (KB) (Poa pratensis L.) or creeping red fescue (CF) (Festuca rubra L.) as PGC using a three-year dataset. Our objectives for this intercropping modeling study were to: i) simultaneously model a PGC and annual cash crop using APSIM software; ii) utilize APSIM to understand interactive processes in the maize-PGC system; and iii) utilize the calibrated model to explore both production and environmental benefits via scenario modeling. For objective I, the integrated model successfully predicted maize total aboveground biomass (TAB) (relative root mean square error, RRMSE of 13- 27%) and PGC above- and belowground tissue N concentration (RRMSE of 11-18%). The calibrated model effectively captured observed trends in PGC biomass accumulation and soil nitrate (NO3). For objective II, model analysis showed that competition for light was the primary maize yield penalty factor from PGC, while water and N impacted maize yield later in the maize growing season. In objective III, we concluded that effective PGC suppression produces minimal maize yield loss and significant environmental benefits; conversely, poor groundcover suppression may produce unfavorable environmental consequences and decrease maize grain yield. Effective PGC suppression is key for long-term system success

IceCube-Gen2: A Vision for the Future of Neutrino Astronomy in Antarctica

The recent observation by the IceCube neutrino observatory of an astrophysical flux of neutrinos represents the "first light" in the nascent field of neutrino astronomy. The observed diffuse neutrino flux seems to suggest a much larger level of hadronic activity in the non-thermal universe than previously thought and suggests a rich discovery potential for a larger neutrino observatory. This document presents a vision for an substantial expansion of the current IceCube detector, IceCube-Gen2, including the aim of instrumenting a $10\,\mathrm{km}^3$ volume of clear glacial ice at the South Pole to deliver substantial increases in the astrophysical neutrino sample for all flavors. A detector of this size would have a rich physics program with the goal to resolve the sources of these astrophysical neutrinos, discover GZK neutrinos, and be a leading observatory in future multi-messenger astronomy programs.Comment: 20 pages, 12 figures. Address correspondence to: E. Blaufuss, F. Halzen, C. Kopper (Changed to add one missing author, no other changes from initial version.

Designing for interaction immediacy to enhance social skills of children with autism

Children with Autism Spectrum Disorder often require therapeutic interventions to support engagement in effective social interactions. In this paper, we present the results of a study conducted in three public schools that use an educational and behavioral intervention for the instruction of social skills in changing situational contexts. The results of this study led to the concept of interaction immediacy to help children maintain appropriate spatial boundaries, reply to conversation initiators, disengage appropriately at the end of an interaction, and identify potential communication partners. We describe design principles for Ubicomp technologies to support interaction immediacy and present an example design. The contribution of this work is twofold. First, we present an understanding of social skills in mobile and dynamic contexts. Second, we introduce the concept of interaction immediacy and show its effectiveness as a guiding principle for the design of Ubicomp applications

Recommendations for Nanomedicine Human Subjects Research Oversight: An Evolutionary Approach for an Emerging Field

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/96363/1/j.1748-720X.2012.00703.x.pd

CKI isoforms α and ε regulate Star–PAP target messages by controlling Star–PAP poly(A) polymerase activity and phosphoinositide stimulation

Star–PAP is a non-canonical, nuclear poly(A) polymerase (PAP) that is regulated by the lipid signaling molecule phosphatidylinositol 4,5 bisphosphate (PI4,5P2), and is required for the expression of a select set of mRNAs. It was previously reported that a PI4,5P2 sensitive CKI isoform, CKIα associates with and phosphorylates Star–PAP in its catalytic domain. Here, we show that the oxidative stress-induced by tBHQ treatment stimulates the CKI mediated phosphorylation of Star–PAP, which is critical for both its polyadenylation activity and stimulation by PI4,5P2. CKI activity was required for the expression and efficient 3′-end processing of its target mRNAs in vivo as well as the polyadenylation activity of Star–PAP in vitro. Specific CKI activity inhibitors (IC261 and CKI7) block in vivo Star–PAP activity, but the knockdown of CKIα did not equivalently inhibit the expression of Star–PAP targets. We show that in addition to CKIα, Star–PAP associates with another CKI isoform, CKIε in the Star–PAP complex that phosphorylates Star–PAP and complements the loss of CKIα. Knockdown of both CKI isoforms (α and ε) resulted in the loss of expression and the 3′-end processing of Star–PAP targets similar to the CKI activity inhibitors. Our results demonstrate that CKI isoforms α and ε modulate Star–PAP activity and regulates Star–PAP target messages