Placentophagia in Nonpregnant Nulliparous Mice: A Genetic Investigation

The genetic influence on the response of nonpregnant nulliparous mice to foster placenta was investigated. Two highly inbred strains (BALB/cBy and C57BL/6By), their F1 hybrids, a backcross generation, and seven recombinant-inbred strains derived from the F2 generation were tested. It was concluded that there is a genetic component to the response of female mice to placenta in the absence of previous experience, and that more than one, but possibly as few as two loci are involved. Alternative explanations of average dominance for placentophagia and for no placentophagia (by the promotion of competing responses) were considered

A rapid turnaround gene panel for severe autoinflammation: Genetic results within 48 hours

There is an important unmet clinical need for fast turnaround next generation sequencing (NGS) to aid genetic diagnosis of patients with acute and sometimes catastrophic inflammatory presentations. This is imperative for patients who require precise and targeted treatment to prevent irreparable organ damage or even death. Acute and severe hyper- inflammation may be caused by primary immunodeficiency (PID) with immune dysregulation, or more typical autoinflammatory diseases in the absence of obvious immunodeficiency. Infectious triggers may be present in either immunodeficiency or autoinflammation. We compiled a list of 25 genes causing monogenetic immunological diseases that are notorious for their acute first presentation with fulminant inflammation and which may be amenable to specific treatment, including hemophagocytic lymphohistiocytosis (HLH); and autoinflammatory diseases that can present with early-onset stroke or other irreversible neurological inflammatory complications. We designed and validated a pipeline that enabled return of clinically actionable results in hours rather than weeks: the Rapid Autoinflammation Panel (RAP). We demonstrated accuracy of this new pipeline, with 100% sensitivity and 100% specificity. Return of results to clinicians was achieved within 48-hours from receiving the patient's blood or saliva sample. This approach demonstrates the potential significant diagnostic impact of NGS in acute medicine to facilitate precision medicine and save "life or limb" in these critical situations

Machinability of Clean Thin-Wall Gray and Ductile Iron Castings. Final Report

First phase was to develop a laboratory technique for evaluating the machinability of gray and ductile iron; longer term goal is to learn how to modify the foundry process to produce castings meeting all specified mechanical properties while providing improved machining behavior. Microcarbides present in the irons were found to dominate the machinability of iron. Pearlitic irons with acceptable machinability contain 8.9 to 10.5 wt% microcarbides. The weight fraction microcarbides in the iron is influenced by carbide forming element concentrations, presence of elements that retard carbon diffusion, and cooling rate from the eutectic through the eutectoid temperature range. Tool wear rate increased at higher surface machining speeds and fraction microcarbides; all irons containing above 11.5% microcarbides had poor machinability. Graphite size, shape, distribution, etc. had a lesser effect on machinability. Reducing the addition of a foundry grade Ca and Al bearing 75% FeSi inoculant from 0.5 to 0.2% increased the tool life 100%. Inoculation test castings were also poured in a class 40 gray iron; laboratory analysis is currently underway. Exploratory studies were conducted to determine if tool force could be used to predict tool life: torque and feed forces were found to correlate with machinability

Lentiviral Mediated ADA2 Gene Transfer Corrects the Defects Associated With Deficiency of Adenosine Deaminase Type 2

Deficiency of adenosine deaminase type 2 (DADA2) is an autosomal recessive disease caused by bi-allelic loss-of-function mutations in ADA2. Treatment with anti-TNF is effective for the autoinflammatory and vasculitic components of the disease but does not correct marrow failure or immunodeficiency; and anti-drug antibodies cause loss of efficacy over time. Allogeneic haematopoietic stem cell transplantation may be curative, but graft versus host disease remains a significant concern. Autologous gene therapy would therefore be an attractive longer-term therapeutic option. We investigated whether lentiviral vector (LV)–mediated ADA2 gene correction could rescue the immunophenotype of DADA2 in primary immune cells derived from patients and in cell line models. Lentiviral transduction led to: i) restoration of ADA2 protein expression and enzymatic activity; (ii) amelioration of M1 macrophage cytokine production, IFN-γ and phosphorylated STAT1 expression in patient-derived macrophages; and (iii) amelioration of macrophage-mediated endothelial activation that drives the vasculitis of DADA2. We also successfully transduced human CD34+ haematopoietic stem progenitor cells (HSPC) derived from a DADA2 patient with pure red cell aplasia and observed restoration of ADA2 expression and enzymatic activity in CD34+HSPC, alongside recovery of stem-cell proliferative and colony forming unit capacity. These preclinical data now expand the evidence for the efficacy of gene transfer strategies in DADA2, and strongly support clinical translation of a lentivirus-mediated gene therapy approach to treat DADA2

Nonlinear Localization in Metamaterials

Metamaterials, i.e., artificially structured ("synthetic") media comprising weakly coupled discrete elements, exhibit extraordinary properties and they hold a great promise for novel applications including super-resolution imaging, cloaking, hyperlensing, and optical transformation. Nonlinearity adds a new degree of freedom for metamaterial design that allows for tuneability and multistability, properties that may offer altogether new functionalities and electromagnetic characteristics. The combination of discreteness and nonlinearity may lead to intrinsic localization of the type of discrete breather in metallic, SQUID-based, and ${\cal PT}-$symmetric metamaterials. We review recent results demonstrating the generic appearance of breather excitations in these systems resulting from power-balance between intrinsic losses and input power, either by proper initialization or by purely dynamical procedures. Breather properties peculiar to each particular system are identified and discussed. Recent progress in the fabrication of low-loss, active and superconducting metamaterials, makes the experimental observation of breathers in principle possible with the proposed dynamical procedures.Comment: 19 pages, 14 figures, Invited (Review) Chapte

Innovative Technologies for District Heating and Cooling: InDeal Project

The paper discusses the outcomes of the conference organized by the InDeal project. The conference took place on 12 December 2018 in Montpellier as part of the EnerGaia energy forum 2018. A holistic interdisciplinary approach for district heating and cooling (DHC) networks is presented that integrates heterogeneous innovative technologies from various scientific sectors. The solution is based on a multi-layer control and modelling framework that has been designed to minimize the total plant production costs and optimize heating/cooling distribution. Artificial intelligence tools are employed to model uncertainties associated with weather and energy demand forecasts, as well as quantify the energy storage capacity. Smart metering devices are utilized to collect information about all the crucial heat substations’ parameters, whereas a web-based platform offers a unique user environment for network operators. Three new technologies have been further developed to improve the efficiency of pipe design of DHC systems: (i) A new sustainable insulation material for reducing heat losses, (ii) a new quick-fit joint for an easy installation, and (iii) a new coating for reducing pressure head losses. The results of a study on the development and optimization of two energy harvesting systems are also provided. The assessment of the environmental, economic and social impact of the proposed holistic approach is performed through a life cycle analysis. The validation methodology of the integrated solution is also described, whereas conclusions and future work are finally given

Neuroinflammation, autoinflammation, splenomegaly and anemia caused by bi-allelic mutations in IRAK4

We describe a novel, severe autoinflammatory syndrome characterized by neuroinflammation, systemic autoinflammation, splenomegaly, and anemia (NASA) caused by bi-allelic mutations in IRAK4. IRAK-4 is a serine/threonine kinase with a pivotal role in innate immune signaling from toll-like receptors and production of pro-inflammatory cytokines. In humans, bi-allelic mutations in IRAK4 result in IRAK-4 deficiency and increased susceptibility to pyogenic bacterial infections, but autoinflammation has never been described. We describe 5 affected patients from 2 unrelated families with compound heterozygous mutations in IRAK4 (c.C877T (p.Q293*)/c.G958T (p.D320Y); and c.A86C (p.Q29P)/c.161 + 1G>A) resulting in severe systemic autoinflammation, massive splenomegaly and severe transfusion dependent anemia and, in 3/5 cases, severe neuroinflammation and seizures. IRAK-4 protein expression was reduced in peripheral blood mononuclear cells (PBMC) in affected patients. Immunological analysis demonstrated elevated serum tumor necrosis factor (TNF), interleukin (IL) 1 beta (IL-1β), IL-6, IL-8, interferon α2a (IFN-α2a), and interferon β (IFN-β); and elevated cerebrospinal fluid (CSF) IL-6 without elevation of CSF IFN-α despite perturbed interferon gene signature. Mutations were located within the death domain (DD; p.Q29P and splice site mutation c.161 + 1G>A) and kinase domain (p.Q293*/p.D320Y) of IRAK-4. Structure-based modeling of the DD mutation p.Q29P showed alteration in the alignment of a loop within the DD with loss of contact distance and hydrogen bond interactions with IRAK-1/2 within the myddosome complex. The kinase domain mutation p.D320Y was predicted to stabilize interactions within the kinase active site. While precise mechanisms of autoinflammation in NASA remain uncertain, we speculate that loss of negative regulation of IRAK-4 and IRAK-1; dysregulation of myddosome assembly and disassembly; or kinase active site instability may drive dysregulated IL-6 and TNF production. Blockade of IL-6 resulted in immediate and complete amelioration of systemic autoinflammation and anemia in all 5 patients treated; however, neuroinflammation has, so far proven recalcitrant to IL-6 blockade and the janus kinase (JAK) inhibitor baricitinib, likely due to lack of central nervous system penetration of both drugs. We therefore highlight that bi-allelic mutation in IRAK4 may be associated with a severe and complex autoinflammatory and neuroinflammatory phenotype that we have called NASA (neuroinflammation, autoinflammation, splenomegaly and anemia), in addition to immunodeficiency in humans

Intermittent implosion and pattern formation of trapped Bose-Einstein condensates with attractive interaction

The collapsing dynamics of a trapped Bose-Einstein condensate (BEC) with attractive interaction are revealed to exhibit two previously unknown phenomena. During the collapse, BEC undergoes a series of rapid implosions that occur {\it intermittently} within a very small region. When the sign of the interaction is suddenly switched from repulsive to attractive, e.g., by the Feshbach resonance, density fluctuations grow to form various patterns such as a shell structure.Comment: 5 pages, 2 figures, RevTeX, epsf.sty, corrected loss rate

Power laws and collapsing dynamics of a trapped Bose-Einstein condensate with attractive interactions

The critical behavior of collective modes and the collapsing dynamics of trapped Bose-Einstein condensates with attractive interactions are studied analytically and numerically. The time scales of these dynamics both below and above the critical point of the collapse are found to obey power laws with a single parameter of N/N_c - 1, where N is the number of condensate atoms and N_c is the critical number. The collapsing condensate eventually undergoes rapid implosion, which occurs several times intermittently, and then the implosion turns to an explosion. The release energy of the explosion is found to be proportional to the square of the interaction strength, inversely proportional to the three-body recombination rate, and independent of the number of condensate atoms and the trap frequency.Comment: 9 pages, RevTeX, 7 figures, epsf.sty, corrected loss rate