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Developmental exposures can influence life-long health; yet, counteracting negative consequences is challenging due to poor understanding of cellular mechanisms. The aryl hydrocarbon receptor (AHR) binds many small molecules, including numerous pollutants. Developmental exposure to the signature environmental AHR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) significantly dampens adaptive immune responses to influenza A virus in adult offspring. CD8+ cytotoxic T lymphocytes (CTL) are crucial for successful infection resolution, which depends on the number generated and the complexity of their functionality. Prior studies showed developmental AHR activation significantly reduced the number of virus-specific CD8+ T cells, but impact on their functions is less clear. Other studies showed developmental exposure was associated with differences in DNA methylation in CD8+ T cells. Yet, empirical evidence that differences in DNA methylation are causally related to altered CD8+ T-cell function is lacking. The 2 objectives were to ascertain whether developmental AHR activation affects CTL function, and whether differences in methylation contribute to reduced CD8+ T-cell responses to infection. Developmental AHR triggering significantly reduced CTL polyfunctionality, and modified the transcriptional program of CD8+ T cells. S-adenosylmethionine, which increases DNA methylation, but not Zebularine, which diminishes DNA methylation, restored polyfunctionality and boosted the number of virus-specific CD8+ T cells. These findings suggest that diminished methylation, initiated by developmental exposure to an AHR-binding chemical, contributes to durable changes in antiviral CD8+ CTL functions later in life. Thus, deleterious consequence of development exposure to environmental chemicals is not permanently fixed, opening the door for interventional strategies to improve health.

SUMMARYMesenchymal stem/stromal cells (MSCs) within the bone marrow microenvironment (BMME) support normal hematopoietic stem and progenitor cells (HSPCs). However, the heterogeneity of human MSCs has limited the understanding of their contribution to clonal dynamics and evolution to myelodysplastic syndromes (MDS). We combined three MSC cell surface markers, CD271, VCAM-1 (Vascular Cell Adhesion Molecule-1) and CD146, to isolate distinct subsets of human MSCs from bone marrow aspirates of healthy controls (Control BM). Based on transcriptional and functional analysis, CD271+CD106+CD146+(NGFR+/VCAM1+/MCAM+/Lin-;NVML) cells display stem cell characteristics, are compatible with murine BM- derived Leptin receptor positive MSCs and provide superior support for normal HSPCs. MSC subsets from 17 patients with MDS demonstrated shared transcriptional changes in spite of mutational heterogeneity in the MDS clones, with loss of preferential support of normal HSPCs by MDS-derived NVML cells. Our data provide a new approach to dissect microenvironment-dependent mechanisms regulating clonal dynamics and progression to MDS.

The genetics of relapsed pediatric acute myeloid leukemia (AML) has yet to be comprehensively defined. Here, we present the spectrum of genomic alterations in 136 relapsed pediatric AMLs. We identified recurrent exon 13 tandem duplications (TD) in upstream binding transcription factor (UBTF) in 9% of relapsed AML cases. UBTF-TD AMLs commonly have normal karyotype or trisomy 8 with cooccurring WT1 mutations or FLT3-ITD but not other known oncogenic fusions. These UBTF-TD events are stable during disease progression and are present in the founding clone. In addition, we observed that UBTF-TD AMLs account for approximately 4% of all de novo pediatric AMLs, are less common in adults, and are associated with poor outcomes and MRD positivity. Expression of UBTF-TD in primary hematopoietic cells is sufficient to enhance serial clonogenic activity and to drive a similar transcriptional program to UBTF-TD AMLs. Collectively, these clinical, genomic, and functional data establish UBTF-TD as a new recurrent mutation in AML.Significance:We defined the spectrum of mutations in relapsed pediatric AML and identified UBTF-TDs as a new recurrent genetic alteration. These duplications are more common in children and define a group of AMLs with intermediate-risk cytogenetic abnormalities, FLT3-ITD and WT1 alterations, and are associated with poor outcomes.See related commentary by Hasserjian and Nardi, p. 173.This article is highlighted in the In This Issue feature, p. 171.

Supplementary Data from Integrated Genomic Analysis Identifies UBTF Tandem Duplications as a Recurrent Lesion in Pediatric Acute Myeloid Leukemia

Supplementary Figure from Integrated Genomic Analysis Identifies UBTF Tandem Duplications as a Recurrent Lesion in Pediatric Acute Myeloid Leukemia

Venetoclax-based therapy can induce responses in approximately 70% of older previously untreated patients with acute myeloid leukemia (AML). However, up-front resistance as well as relapse following initial response demonstrates the need for a deeper understanding of resistance mechanisms. In the present study, we report that responses to venetoclax +azacitidine in patients with AML correlate closely with developmental stage, where phenotypically primitive AML is sensitive, but monocytic AML is more resistant. Mechanistically, resistant monocytic AML has a distinct transcriptomic profile, loses expression of venetoclax target BCL2, and relies on MCL1 to mediate oxidative phosphorylation and survival. This differential sensitivity drives a selective process in patients which favors the outgrowth of monocytic subpopulations at relapse. Based on these findings, we conclude that resistance to venetoclax + azacitidine can arise due to biological properties intrinsic to monocytic differentiation. We propose that optimal AML therapies should be designed so as to independently target AML subclones that may arise at differing stages of pathogenesis.Significance:Identifying characteristics of patients who respond poorly to venetoclax-based therapy and devising alternative therapeutic strategies for such patients are important topics in AML. We show that venetoclax resistance can arise due to intrinsic molecular/metabolic properties of monocytic AML cells and that such properties can potentially be targeted with alternative strategies.

Supplementary Figures S1-S5 supporting Main Figures 1-5.

Supplementary Tables S1-S6 describing patient characteristics, gene lists, LSC signatures, and reagents.

The genetics of relapsed pediatric acute myeloid leukemia (AML) has yet to be comprehensively defined. Here, we present the spectrum of genomic alterations in 136 relapsed pediatric AMLs. We identified recurrent exon 13 tandem duplications (TD) in upstream binding transcription factor (UBTF) in 9% of relapsed AML cases. UBTF-TD AMLs commonly have normal karyotype or trisomy 8 with cooccurring WT1 mutations or FLT3-ITD but not other known oncogenic fusions. These UBTF-TD events are stable during disease progression and are present in the founding clone. In addition, we observed that UBTF-TD AMLs account for approximately 4% of all de novo pediatric AMLs, are less common in adults, and are associated with poor outcomes and MRD positivity. Expression of UBTF-TD in primary hematopoietic cells is sufficient to enhance serial clonogenic activity and to drive a similar transcriptional program to UBTF-TD AMLs. Collectively, these clinical, genomic, and functional data establish UBTF-TD as a new recurrent mutation in AML. Significance: We defined the spectrum of mutations in relapsed pediatric AML and identified UBTF-TDs as a new recurrent genetic alteration. These duplications are more common in children and define a group of AMLs with intermediate-risk cytogenetic abnormalities, FLT3-ITD and WT1 alterations, and are associated with poor outcomes. See related commentary by Hasserjian and Nardi, p. 173. This article is highlighted in the In This Issue feature, p. 171.

Centrifugally spun polyacrylonitrile (PAN) microfibers surface-coated with Co3O4 nanoparticles were prepared as precursors to produce coated Co3O4 carbon-fiber (CCF) composites for lithium-ion battery anodes. The Co3O4/C composite-fiber anodes were obtained after the stabilization of surface-coated Co3O4/PAN fibers at 200 °C for four hours, and subsequent carbonization at 600 °C for 6 hours. The electrochemical performance of the Co3O4/C composite-fiber anode with different active material loading was evaluated by using galvanostatic charge/discharge, rate performance, cyclic voltammetry, and electrochemical impedance spectroscopy experiments. The CCF anode delivered a specific charge capacity of 632 and 420 mAh g−1 after 100 cycles at 100 and 200 mA g−1, respectively, and exhibited good rate capability. An improved electrochemical performance of the CCF was observed compared to the carbon-fiber (CF) anode (300 mAh g−1), which was attributed to the interaction between CFs and Co3O4 nanoparticles. The synthesis method presented in this work can provide an effective avenue for the fabrication of surface coated-fiber materials, including free-standing anode materials for lithium-ion batteries with increased specific capacity and improved electrochemical performance compared to carbon-fiber electrodes.

Background Recurrent atypical teratoid/rhabdoid tumor (AT/RT) is, most often, a fatal pediatric malignancy with limited curative options. Methods We conducted a phase II study of Aurora kinase A inhibitor alisertib in patients aged Results SD (n = 8) and partial response (PR) (n = 1) were observed among 30 evaluable patients. Progression-free survival (PFS) was 30.0% ± 7.9% at 6 months and 13.3% ± 5.6% at 1 year. One-year overall survival (OS) was 36.7% ± 8.4%. Two patients continued treatment for >12 months. PFS did not differ by AT/RT molecular groups. Neutropenia was the most common adverse effect (n = 23/30, 77%). The 22 patients who received liquid formulation had a higher mean maximum concentration (Cmax) of 10.1 ± 3.0 µM and faster time to Cmax (Tmax = 1.2 ± 0.7 h) than those who received tablets (Cmax = 5.7 ± 2.4 µM, Tmax = 3.4 ± 1.4 h). Conclusions Although the study did not meet predetermined efficacy end point, single-agent alisertib was well tolerated by children with recurrent AT/RT, and SD or PR was observed in approximately a third of the patients.

Inverse vulcanization is the method by which molten sulfur can be combined with comonomers to form stable polymers termed “organically modified chalcogenide” or “ORMOCHALC” polymers. One advantage to ORMOCHALC polymers is that they can possess important optical properties, such as high refractive index and strong infrared (IR) transmission, while being easier to fabricate than glass materials with similar optical properties. In the present work, a new ORMOCHALC is fabricated by using tetravinyltin as a comomoner with sulfur. This is the first example of an organometallic molecule being used as a comonomer to develop ORMOCHALCs. The result is an ORMOCHALC polymer that has the highest refractive index reported for a “sulfur and comonomer” polymer and that demonstrates unprecedented transmission in the IR region.

We discovered an enhanced functionality hammerhead ribozyme (EhhRz), designed to act in trans against human rod opsin (RHO) mRNA, with turnover activity >300 nM min−1 under substrate-excess conditions and physiological Mg2+ levels (1 mM). We developed a real-time moderate-throughput fluorescence quantitative hhRz kinetic assay, which is linear with substrate and product moles and supported by gel-based measures. The EhhRz targets a CUC↓ cleavage site in a substrate with no predicted secondary/tertiary structure and demonstrates classic Michaelis-Menten turnover behavior when the substrate is in 10-fold excess (Vmax/Km up to 1.60 × 108 min−1 M−1), which is comparable to RNase A. EhhRzs show cooperative titration with a Kd of 0.73 ± 0.02 mM at cellular Mg2+ concentrations and a Hill coefficient of 1.73 ± 0.07. The upstream EhhRz antisense flank (bound to a downstream substrate flank) interacts with stem-loop II, and examinations of different variants revealed that a U7 residue in the downstream flank of the substrate is not essential for enhanced activity. Under single-turnover conditions with substrate pre-annealed to enzyme, reaction rates exceeded 1,000 min−1. These findings show that RNA catalysis approaches the efficiency of the ribosome and suggests EhhRz in trans is a druggable nucleic acid therapeutic.

Venetoclax-based therapy can induce responses in approximately 70% of older previously untreated patients with acute myeloid leukemia (AML). However, up-front resistance as well as relapse following initial response demonstrates the need for a deeper understanding of resistance mechanisms. In the present study, we report that responses to venetoclax +azacitidine in patients with AML correlate closely with developmental stage, where phenotypically primitive AML is sensitive, but monocytic AML is more resistant. Mechanistically, resistant monocytic AML has a distinct transcriptomic profile, loses expression of venetoclax target BCL2, and relies on MCL1 to mediate oxidative phosphorylation and survival. This differential sensitivity drives a selective process in patients which favors the outgrowth of monocytic subpopulations at relapse. Based on these findings, we conclude that resistance to venetoclax + azacitidine can arise due to biological properties intrinsic to monocytic differentiation. We propose that optimal AML therapies should be designed so as to independently target AML subclones that may arise at differing stages of pathogenesis. Significance: Identifying characteristics of patients who respond poorly to venetoclax-based therapy and devising alternative therapeutic strategies for such patients are important topics in AML. We show that venetoclax resistance can arise due to intrinsic molecular/metabolic properties of monocytic AML cells and that such properties can potentially be targeted with alternative strategies.

Purpose: The objective of this study is to describe characteristics and short- and long-term outcomes of patients with hematologic malignancies who received cardiopulmonary resuscitation (CPR). Methods: A retrospective review was conducted of all Code Blues at a large comprehensive cancer center. Demographic, clinical, and outcome variables were analyzed for patients with a hematologic malignancy who underwent CPR. Results: Of 258 patients, 60.1% had leukemia. Outcomes included return of spontaneous circulation (70.2%), hospital survival (12%), and 90-day, 6-month, and 1-year survival rates of 9.8%, 8.2%, and 5.9%, respectively. Factors associated with hospital mortality included establishing a do not resuscitate order after CPR (p < .0001), location of CPR (p = .0004), cause of arrest (p = .0019), requiring vasopressors (p = .0130), mechanical ventilation (p = .0423), and acute renal failure post CPR (p = .0006). Although no difference in hospital survival between leukemia and non-leukemia patients was found, more non-leukemia patients were alive at 90 days (p = .0099), 6 months (p = .0023), and 1 year (p = .0119). Conclusions: Factors including organ dysfunction, location of CPR, and cause of arrest are associated with hospital mortality post CPR. However, immediate survival post CPR does not seem to be affected by a diagnosis of leukemia. These data should assist health care providers with discussions regarding advance care planning and goals of care after cardiac arrest.

Mid-wavelength infrared (MWIR, λ = 3 – 5 μm) materials are of great importance due to their applications in optical sensors and devices for military, industry, and non-invasive medical diagnostics. Specifically, MWIR polarimetry are used in biometric recognition and camouflaged detection. Recently, sulfur based organically modified chalcogenides (ORMOCHALC) polymers have been utilized to fabricate MWIR polarizers with competitive extinction coefficient to commercial polarizers, which are mostly made of expensive, brittle, and heavy inorganic materials. On the other hand, to adjust or reinforce the refractive index of the polymer, the chalcogenide content (i.e., sulfur, selenium) needs to be increased, which may result in adverse effects on the thermomechanical characteristics, including Young's modulus and lower glass transition temperature. This reduced thermomechanical stability compromises the structural integrity of ORMOCHALC-based optical devices. In this study, an ORMOCHALC polymer, poly(S–r–DIB), was reinforced with the zinc sulfide (ZnS) nanoparticles to simultaneously improve the refractive index and the thermomechanical properties. The addition of 20 wt% ZnS nanoparticles improves the pure polymer's glass transition temperature (Tg) from 9.6 °C to 31.4 °C, and the refractive index by Δn= 6.58 %. Then, subwavelength wire-grid polarizers were fabricated based on the pure ORMOCHALC first by a simple thermal imprinting method followed by metal deposition. The resulted MWIR polarizer showed a high extinction coefficient which is comparable with commercial polarizers. However, the structural integrity of the polarizers was compromised due to lower glass transition temperature. Finally, finite element analysis was conducted on the possible wire-grid polarizer fabrication utilizing optically and mechanically reinforced composites, as demonstrated in this study. If fabricated, these nanoparticles reinforced polarizers will possess superior structural integrity compared to ORMOCHALC polarizers. Moreover, these polarizers show a spectral selectivity as the transmission curve's resonance wavelength depends on the composite's refractive index, which is tunable by controlling the nanoparticles content. The resonance peak redshifted from 3.12 μm to 3.3 μm for the pure polymer to 20% ZnS reinforced ORMOCHALC polarizer. The extinction coefficient of the polarizer also improved in multiple wavelength bands in the MWIR. These polarizers with superior extinction coefficient, spectral selectivity, and improved thermomechanical stability demonstrate a broader prospect in MWIR optics.

The organization of an integrated coronary vasculature requires the specification of immature endothelial cells (ECs) into arterial and venous fates based on their localization within the heart. It remains unclear how spatial information controls EC identity and behavior. Here we use single-cell RNA sequencing at key developmental timepoints to interrogate cellular contributions to coronary vessel patterning and maturation. We perform transcriptional profiling to define a heterogenous population of epicardium-derived cells (EPDCs) that express unique chemokine signatures. We identify a population of Slit2+ EPDCs that emerge following epithelial-to-mesenchymal transition (EMT), which we term vascular guidepost cells. We show that the expression of guidepost-derived chemokines such as Slit2 are induced in epicardial cells undergoing EMT, while mesothelium-derived chemokines are silenced. We demonstrate that epicardium-specific deletion of myocardin-related transcription factors in mouse embryos disrupts the expression of key guidance cues and alters EPDC-EC signaling, leading to the persistence of an immature angiogenic EC identity and inappropriate accumulation of ECs on the epicardial surface. Our study suggests that EC pathfinding and fate specification is controlled by a common mechanism and guided by paracrine signaling from EPDCs linking epicardial EMT to EC localization and fate specification in the developing heart., It remains unclear how spatial information controls endothelial cell identity and behavior in the developing heart. Here the authors perform single cell RNA sequencing at key developmental timepoints in mice to interrogate cellular contributions to coronary vessel patterning and maturation in the epicardium.

Fast epitaxial growth is an attractive method for reducing III-V photovoltaic device cost. Here, we grow a high-performance, rear-junction GaAs solar cell at 1 µm/min via metal organic chemical vapor deposition. We integrate an epitaxial distributed Bragg reflector with the solar cell to increase the optical path length for photons near the band-edge, enhancing photon recycling without the need for epitaxial lift off. Reflectivity enhancement is evident near the band-edge, permitting up to 96% external quantum efficiency. Device results demonstrate significant performance boost, achieving 1.06 V open-circuit and an efficiency of 24.3% AM1.5G.

Hematopoietic stem cells (HSCs) are capable of entering the cell cycle to replenish the blood system in response to inflammatory cues; however, excessive proliferation in response to chronic inflammation can lead to either HSC attrition or expansion. The mechanism(s) that limit HSC proliferation and expansion triggered by inflammatory signals are poorly defined. Here, we show that long-term HSCs (HSCLT) rapidly repress protein synthesis and cell cycle genes following treatment with the proinflammatory cytokine interleukin (IL)-1. This gene program is associated with activation of the transcription factor PU.1 and direct PU.1 binding at repressed target genes. Notably, PU.1 is required to repress cell cycle and protein synthesis genes, and IL-1 exposure triggers aberrant protein synthesis and cell cycle activity in PU.1-deficient HSCs. These features are associated with expansion of phenotypic PU.1-deficient HSCs. Thus, we identify a PU.1-dependent mechanism triggered by innate immune stimulation that limits HSC proliferation and pool size. These findings provide insight into how HSCs maintain homeostasis during inflammatory stress., Journal of Experimental Medicine, 218 (6), ISSN:0022-1007, ISSN:1540-0069, ISSN:1540-9538

We propose a general formalism, within large deviation theory, giving access to the exact statistics of fluctuations of ballistically transported conserved quantities in homogeneous, stationary states. The formalism is expected to apply to any system with an Euler hydrodynamic description, classical or quantum, integrable or not, in or out of equilibrium. We express the exact scaled cumulant generating function (or full counting statistics) for any (quasi-)local conserved quantity in terms of the flux Jacobian. We show that the "extended fluctuation relations" of Bernard and Doyon follow from the linearity of the hydrodynamic equations, forming a marker of "freeness" much like the absence of hydrodynamic diffusion does. We show how an extension of the formalism gives exact exponential behaviours of spatio-temporal two-point functions of twist fields, with applications to order-parameter dynamical correlations in arbitrary homogeneous, stationary state. We explain in what situations the large deviation principle at the basis of the results fail, and discuss how this connects with nonlinear fluctuating hydrodynamics. Applying the formalism to conformal hydrodynamics, we evaluate the exact cumulants of energy transport in quantum critical systems of arbitrary dimension at low but nonzero temperatures, observing a phase transition for Lorentz boosts at the sound velocity., Comment: 27+22 pages, one figure

Clinical development of catechol-based orthosteric agonists of the dopamine D1 receptor has thus far been unsuccessful due to multiple challenges. To address these issues, we identified LY3154207 (...

In a planar dielectric waveguide, weak confinement of a propagating mode in a high index core leads to a measurable evanescent interaction with the cladding. In this work, we study the effe...

Bone marrow mesenchymal stromal cells (MSCs) constitute one of the important components of the hematopoietic microenvironmental niche. In vivo studies have shown that depletion of marrow MSCs resulted in reduction of hematopoietic stem cell content, and there is in vitro evidence that marrow MSCs are able to support leukemia progenitor cell proliferation and survival and provide resistance to cytotoxic therapies. How MSCs from leukemia marrow differ from normal counterparts and how they are influenced by the presence of leukemia stem and progenitor cells are still incompletely understood. In this work, we compared normal donor (ND) and acute myelogenous leukemia (AML) derived MSCs and found that AML-MSCs had increased adipogenic potential with improved ability to support survival of leukemia progenitor cells. To identify underlying changes, RNA-Seq analysis was performed. Gene ontology and pathway analysis revealed adipogenesis to be among the set of altered biological pathways dysregulated in AML-MSCs as compared with ND-MSCs. Expression of both SOX9 and EGR2 was decreased in AML-MSCs as compared with ND-MSCs. Increasing expression of SOX9 decreased adipogenic potential of AML-MSCs and decreased their ability to support AML progenitor cells. These findings suggest that AML-MSCs possess adipogenic potential which may enhance support of leukemia progenitor cells.

Early life environmental exposures drive lasting changes to the function of the immune system and can contribute to disease later in life. One of the ways environmental factors act is through cellular receptors. The aryl hydrocarbon receptor (AHR) is expressed by immune cells and binds numerous xenobiotics. Early life exposure to chemicals that bind the AHR impairs CD4+ T cell responses to influenza A virus (IAV) infection in adulthood. However, the cellular mechanisms that underlie these durable changes remain poorly defined. Transcriptomic profiling of sorted CD4+ T cells identified changes in genes involved in proliferation, differentiation, and metabolic pathways were associated with triggering AHR during development. Functional bioassays confirmed that CD4+ T cells from infected developmentally exposed offspring exhibit reduced proliferation, differentiation, and cellular metabolism. Thus, developmental AHR activation shapes T cell responsive capacity later in life by affecting integrated cellular pathways, which collectively alter responses later in life. Given that coordinated shifts in T cell metabolism are essential for T cell responses to numerous challenges, and that humans are constantly exposed to many different types of AHR ligands, this has far-reaching implications for how AHR signaling, particularly during development, durably influences T cell mediated immune responses across the lifespan.

Activation of the ligand inducible aryl hydrocarbon receptor (AhR) during primary influenza A virus infection diminishes host responses by negatively regulating the ability of dendritic cells (DC) to prime naive CD8+ T cells, which reduces the generation of CTL. However, AhR-regulated genes and signaling pathways in DCs are not fully known. In this study, we used unbiased gene expression profiling to identify differentially expressed genes and signaling pathways in DCs that are modulated by AhR activation in vivo. Using the prototype AhR agonist TCDD, we identified the lectin receptor Cd209a (DC-SIGN) and chemokine Ccl17 as novel AhR target genes. We further show the percentage of DCs expressing CD209a on their surface was significantly decreased by AhR activation during infection. Whereas influenza A virus infection increased CCL17 protein levels in the lung and lung-draining lymph nodes, this was significantly reduced following AhR activation. Targeted excision of AhR in the hematopoietic compartment confirmed AhR is required for downregulation of CCL17 and CD209a. Loss of AhR’s functional DNA-binding domain demonstrates that AhR activation alone is necessary but not sufficient to drive downregulation. AhR activation induced similar changes in gene expression in human monocyte-derived DCs. Analysis of the murine and human upstream regulatory regions of Cd209a and Ccl17 revealed a suite of potential transcription factor partners for AhR, which may coregulate these genes in vivo. This study highlights the breadth of AhR-regulated pathways within DCs, and that AhR likely interacts with other transcription factors to modulate DC functions during infection.

A single-step, direct silicon-substrate growth of black phosphorus (BP) crystals is achieved in a self-contained short-way transport technique under low-pressure conditions (1.5 MPa). A 115 nm-thick BP hero single crystal is formed with lateral dimensions of 10 × 85 μm. The synthesis proceeds with Sn, SnI

The unique combination of mechanical properties and the ability to be processed using injection molding techniques makes bulk metallic glasses (BMGs) excellent candidates for use in engnineering applications, especially in the medical device industry. Widespread use of BMGs is hindered by their inability to be joined to common engineering materials (ex. titanium) with standard fusion welding techniques (ex. laser welding). In this paper a definitive screening design experiment was performed to optimize a dissimilar Vitreloy 105 to grade 2 titanium laser weld. The optimized weld was then characterized using nanoindentation, scanning electron micrscopy, micro cantilever beam bending, and transmission electron microscopy. It was found that the optimized weld had lower hardness, a more uniform structure, and better performance than the baseline seam weld between the dissimilar materials. The microstructural and micromechanical characterization of the optimized joints showed variation in local mechanical properties that were correlated to chemistry and microstructure ranging from brittle fracture at low loads to ductility and toughness arising from shear band blunting. Not only did the optimized welding process confrim that Vitreloy 105 could be successfully laser joined to grade 2 titanium with properties acceptable for many applications, the investigation into the local structure and properties of the joint revealed the possibility of creating ductile metallic glass composites by controlling the chemistry and structure of the intermetalic zone while processing.

BACKGROUND: Children with recurrent atypical teratoid rhabdoid tumor (recATRT) who fail frontline therapies have dismal outcomes. The association of ATRT molecular groups (SHH, TYR and MYC) and presence of underlying cancer predisposition with survival post-recurrence (postRD) is unknown. METHODS: We previously reported outcomes from a single-institution retrospective study of children

We demonstrate a voltage-controlled exchange bias effect in $\mathrm{CoFeB}/\mathrm{MgO}/\mathrm{CoFeB}$ magnetic tunnel junctions that is related to the interfacial $\mathrm{Fe}(\mathrm{Co}){\mathrm{O}}_{x}$ formed between the CoFeB electrodes and the MgO barrier. The unique combination of interfacial antiferromagnetism, giant tunneling magnetoresistance, and sharp switching of the perpendicularly magnetized CoFeB allows sensitive detection of the exchange bias. We find that the exchange bias field can be isothermally controlled by magnetic fields at low temperatures. More importantly, the exchange bias can also be effectively manipulated by the electric field applied to the MgO barrier due to the voltage-controlled antiferromagnetic anisotropy in this system.

Early life environmental exposures can have lasting effects on the function of the immune system and contribute to disease later in life. Epidemiological studies have linked early life exposure to xenobiotics that bind the aryl hydrocarbon receptor (AhR) with dysregulated immune responses later in life. Among the immune cells influenced by developmental activation of the AhR areOur goal was to identify cellular mechanisms that drive impairedC57BL/6 mice were vertically exposed to the prototype AhR ligand, 2,3,7,8-tetrachlorodibenzo-Gene and protein expression showed that developmental AhR activation reducedTaken together, these results indicate that skewed DNA methylation is one of the mechanisms by which early life exposures can durably change the function of T cells in mice. Furthermore, treatment with DNA methylation-altering drugs after the exposure restored some aspects of

Background: Early life environmental exposures can have lasting effects on the function of the immune system and contribute to disease later in life. Epidemiological studies have linked early life ...