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The immune system must be able to respond to a myriad of different threats, each requiring a distinct type of response. Here, we demonstrate that the cytoplasmic lysine deacetylase HDAC7 in macrophages is a metabolic switch that triages danger signals to enable the most appropriate immune response. Lipopolysaccharide (LPS) and soluble signals indicating distal or far-away danger trigger HDAC7-dependent glycolysis and proinflammatory IL-1β production. In contrast, HDAC7 initiates the pentose phosphate pathway (PPP) for NADPH and reactive oxygen species (ROS) production in response to the more proximal threat of nearby bacteria, as exemplified by studies on uropathogenic Escherichia coli (UPEC). HDAC7-mediated PPP engagement via 6-phosphogluconate dehydrogenase (6PGD) generates NADPH for antimicrobial ROS production, as well as D-ribulose-5-phosphate (RL5P) that both synergizes with ROS for UPEC killing and suppresses selective inflammatory responses. This dual functionality of the HDAC7-6PGD-RL5P axis prioritizes responses to proximal threats. Our findings thus reveal that the PPP metabolite RL5P has both antimicrobial and immunomodulatory activities and that engagement of enzymes in catabolic versus anabolic metabolic pathways triages responses to different types of danger for generation of inflammatory versus antimicrobial responses, respectively.

Cellular delivery of plasmid DNA (pDNA) specifically into dendritic cells (DCs) has provoked wide attention in various applications. However, delivery tools that achieve effective pDNA transfection in DCs are rare. Herein, we report that tetrasulphide bridged mesoporous organosilica nanoparticles (MONs) have enhanced pDNA transfection performance in DC cell lines compared to conventional mesoporous silica nanoparticles (MSNs). The mechanism of enhanced pDNA delivery efficacy is attributed to the glutathione (GSH) depletion capability of MONs. Reduction of initially high GSH levels in DCs further increases the mammalian target of rapamycin complex 1 (mTORc1) pathway activation, enhancing translation and protein expression. The mechanism was further validated by showing that the increased transfection efficiency was apparent in high GSH cell lines but not in low GSH ones. Our findings may provide a new design principle of nano delivery systems where the pDNA delivery to DCs is important.

Dual-energy x-ray absorptiometry (DXA) is an accurate means to assess bone mineral density (BMD), determine the risk of a fragility fracture, and monitor response to therapy. Despite its seemingly straightforward nature - the review of two-to-three non-diagnostic images and a few automatically generated numbers - the proper performance and interpretation of DXA can often be complex. It is complex because it is highly dependent on many factors, such as image acquisition, processing, analysis, and subsequent exam interpretation. Each step is subject to potential errors, artifacts, and diagnostic pitfalls; hence meticulous attention must be paid to the technique by both the technologist and interpreting physician to provide high-quality results and, in turn, maximize the exam's clinical utility. This article is part 1 of a two-part series. Part 1 will begin with a review of bone physiology and osteoporosis etiology, followed by a discussion of the principles underlying DXA and the technical procedure. Part 2 will focus on DXA interpretation and discuss scanning pitfalls and clues to recognizing issues and improving scan quality.

The self-assembled monolayer FDTS (1H,1H,2H, 2H-Perfluorodecyltrichlorosilane) is presented as suitable dewetting coating material for an electrowetting on dielectrics (EWOD) controlled silicon photonics switch deployed in fiber optic telecommunication systems. The anti-sticking characteristics of Perfluorodecyltrichlorosilane (FDTS) are compared to those of polytetrafluoroethylene (PTFE) as most common dewetting coating for EWOD devices. It is shown that FDTS could outperform other materials such as PTFE when an extremely thin, long-term stable, and uniform layer is required. In the specific case, FDTS is applied in vapor phase as anti-sticking coating to the active optical surface of the integrated silicon photonics switch thus enabling the EWOD driven liquid motion. The suitability of the coating is presented by contact angle measurements and durability tests carried out with the switching liquids. Finally, it is demonstrated by optical measurements that the FDTS coating has a neglectable influence on the optical switching performance.

Introduction Les consequences a long terme des formes severes de pneumonie a SARS-CoV-2 (COVID-19) restent meconnues mais le risque de sequelles pulmonaires, de handicap fonctionnel, notamment respiratoire, d’impact psychologique et d’alteration de la qualite de vie des patients semble indeniable. Methodes RE 2 COVERI est une etude de cohorte observationnelle multicentrique (14 centres) francaise visant a inclure 625 participants. Les criteres d’inclusion sont: âge ≥ 18 ans; PCR SARS-CoV-2 positive ou TDM typique de COVID-19 au diagnostic; infection COVID-19 severe (hospitalisation ≥ 7 jours et oxygenotherapie ≥ 3L/min) ou tres severe (SDRA necessitant le recours a la ventilation mecanique pendant au moins 48 h). L’objectif principal de l’etude est de determiner la trajectoire de recuperation de la fonction respiratoire (spirometrie, plethysmographie, diffusion du monoxyde de carbone) des pneumonies COVID-19 severes ou tres severes (evaluation a M3, M6 et M12). Les objectifs secondaires sont de: determiner la trajectoire de recuperation et la proportion de patients presentant des anomalies en termes de capacite d’exercice (test de marche, test du lever de chaise), de lesions pulmonaires (scanner thoracique) et de force musculaire (hand grip et pinch test; mesure de la force des muscles respiratoires); determiner les relations entre les alterations fonctionnelles, la capacite d’exercice et l’etendue initiale des lesions; evaluer la dyspnee et les autres symptomes residuels, la fatigue, l’anxiete et la depression, le stress post-traumatique et l’impact sur la qualite de vie; comparer les alterations fonctionnelles et de la capacite d’exercice selon la severite clinique initiale, en tenant compte de l’impact des comorbidites et des therapeutiques et interventions proposees, tant initialement que secondairement; evaluer la consommation de soins de sante chez les patients severes ou tres severes, en mettant l’accent sur l’utilisation des soins de rehabilitation. Cette etude a recu un soutien financier de la Fondation du Souffle dans le cadre de l’appel a projet “SARSCohorte-Covid2020”. Resultats Les resultats preliminaires de cette etude (evaluation a M3 et M6) seront presentes lors du congres. Conclusion Nos resultats devraient permettre de preciser les facteurs influencant la recuperation a distance d’une forme severe a tres severe de pneumonie a SARS-CoV-2 et de preciser quels patients justifient d’une attention et d’un suivi particuliers.

We present the proof of concept of the first non-volatile bistable fiber optic switch combining integrated optics and electrowetting-actuated microfluidics. Design and realization of both EWOD and photonic layer are presented and successful switching of a $2\times 4$ network is demonstrated.

Background Current diagnostic tools for prostate cancer lack specificity and sensitivity for detecting very early lesions. DNA methylation is a stable genomic modification that is detectable in peripheral patient fluids such as urine and blood plasma that could serve as a non-invasive diagnostic biomarker for prostate cancer. Methods We measured genome-wide DNA methylation patterns in 73 clinically annotated fresh-frozen prostate cancers and 63 benign-adjacent prostate tissues using the Illumina Infinium HumanMethylation450 BeadChip array. We overlaid the most significantly differentially methylated sites in the genome with transcription factor binding sites measured by the Encyclopedia of DNA Elements consortium. We used logistic regression and receiver operating characteristic curves to assess the performance of candidate diagnostic models. Results We identified methylation patterns that have a high predictive power for distinguishing malignant prostate tissue from benign-adjacent prostate tissue, and these methylation signatures were validated using data from The Cancer Genome Atlas Project. Furthermore, by overlaying ENCODE transcription factor binding data, we observed an enrichment of enhancer of zeste homolog 2 binding in gene regulatory regions with higher DNA methylation in malignant prostate tissues. Conclusions DNA methylation patterns are greatly altered in prostate cancer tissue in comparison to benign-adjacent tissue. We have discovered patterns of DNA methylation marks that can distinguish prostate cancers with high specificity and sensitivity in multiple patient tissue cohorts, and we have identified transcription factors binding in these differentially methylated regions that may play important roles in prostate cancer development. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3252-2) contains supplementary material, which is available to authorized users.

Despite advances in cancer diagnosis and treatment strategies, robust prognostic signatures remain elusive in most cancers. Cell proliferation has long been recognized as a prognostic marker in cancer, but the generation of comprehensive, publicly available datasets allows examination of the links between cell proliferation and cancer characteristics such as mutation rate, stage, and patient outcomes. Here we explore the role of cell proliferation across 19 cancers (n = 6,581 patients) by using tissue-based RNA sequencing data from The Cancer Genome Atlas Project and calculating a 'proliferative index' derived from gene expression associated with Proliferating Cell Nuclear Antigen (PCNA) levels. This proliferative index is significantly associated with patient survival (Cox, p-value < 0.05) in 7 of 19 cancers, which we have defined as "proliferation-informative cancers" (PICs). In PICs, the proliferative index is strongly correlated with tumor stage and nodal invasion. PICs demonstrate reduced baseline expression of proliferation machinery relative to non-PICs. Additionally, we find the proliferative index is significantly associated with gross somatic mutation burden (Spearman, p = 1.76 x 10-23) as well as with mutations in individual driver genes. This analysis provides a comprehensive characterization of tumor proliferation indices and their association with disease progression and prognosis in multiple cancer types and highlights specific cancers that may be particularly susceptible to improved targeting of this classic cancer hallmark.

This paper presents the design and experimental characterization of a microfluidic system comprising a novel bi-phasic liquid combination actuated by EWOD (electrowetting-on-dielectrics). The two immiscible liquids feature a high difference in refractive indices (0.16–0.23) and a low absorption (

Despite advances in cancer diagnosis and treatment strategies, robust prognostic signatures remain elusive in most cancers. Cell proliferation has long been recognized as a prognostic marker in cancer, but it has not been thoroughly investigated across multiple cancers. Here we explore the role of cell proliferation across 19 cancers (n=6,581 patients) using tissue-based RNA sequencing from The Cancer Genome Atlas project by employing a ‘proliferative index’ derived from gene expression associated with PCNA expression. This proliferative index is significantly associated with patient survival (Cox, p-value−23) as well mutations in individual driver genes. This analysis provides a comprehensive characterization of tumor proliferation rates and their association with disease progression and prognosis across cancer types and highlights specific cancers that may be particularly susceptible to improved targeting of this classic cancer hallmark.

INTRODUCTION: Substituted indoles and related structures have been shown to exhibit potent anticancer activity against breast cancer cell lines. Here, the effects of structurally similar substituted indoles against the human glial cancer cell lines, 1321N1 and U87MG, have been investigated by comparing the effects of these compounds to conventional anti cancer drugs. METHODS: Cell viability in the presence of the test compounds was measured using an MTS assay and corroborated by an ATP cell proliferation assay as well as a Trypan blue exclusion test. The significance of reactive oxygen species (ROS) in the process was determined using an Image-iT® LIVE ROS kit from Invitrogen. RESULTS: Both cell lines were treated with four commercial anticancer drugs and IC50 values were only reached at concentrations of 20 µM for cisplatin and 50 µM for gemcitabine over 48hrs on the 1321N1 cell line. However, the more malignant U87MG cell line was resistant to all the drugs, except for cisplatin where the IC50 value was reached at 300 µM after treatment for 48hrs. Similar studies were carried out with various substituted indoles and the cytotoxicity results on both cell lines showed that the IC50 value was reached within 90 minutes for the most potent compound at a concentration of 600 µM (1321N1) and 800 µM (U87MG). The idea that the mechanism of action of these compounds may work through the generation of ROS was investigated and this was confirmed over a similar time course using a suitable fluorogenic marker. Moreover, it was shown that the addition of an antioxidant (ascorbic acid) abolished the potency of the most active compound. CONCLUSION: Here, it has been demonstrated that certain substituted indoles are able to have a rapid, deleterious effect on the viability of two glioma cell lines and indicated that ROS generation may induce cell death.

The polarity-dependent device degradation during AC stress of polysicilicon-oxide-nitride-oxide-silicon (SONOS) transistor poses considerable reliability challenges for scaled SONOS gate oxide thicknesses. However, the mechanism responsible for the endurance degradation has been scarcely studied so far. Especially electrons injected from the gate are supposed to be responsible for the degradation. An on-chip test circuit was developed to measure those gate currents. A clear correlation was found with retention-after-cycling experiments and interface degradation measured with the pulsed-capacitance technique. Based on the results, defect generation in the tunnel oxide was identified as the main degradation mechanism. The results are supported by electrical simulation of the transient behavior of the SONOS gate dielectric during program and erase.

With technology scaling of embedded nonvolatile memories, voltage scaling below 12 V is a primary goal to maintain the area efficiency of the memory module. The SONOS technology shows promise as a technology for present and future low voltage memory cells. This paper examines the physics of scaled SONOS gate dielectrics in relation to reducing the operational voltage. In particular, we have examined the influence of tunnel oxide, nitride and top oxide thicknesses. The results are supported by electrical simulation of the SONOS gate dielectric. By properly scaling the dielectric films and utilizing electrical simulation we have determined a limit for scalability of the SONOS technology in terms of operation voltage.

The tissue-specific transcriptional coactivator OCA-B is required for antigen-dependent B cell differentiation events, including germinal center formation. However, the identity of OCA-B target genes involved in this process is unknown. This study has used large-scale cDNA arrays to monitor changes in gene expression patterns that accompany mature B cell differentiation. B cell receptor ligation alone induces many genes involved in B cell expansion, whereas B cell receptor and helper T cell costimulation induce genes associated with B cell effector function. OCA-B expression is induced by both B cell receptor ligation alone and helper T cell costimulation, suggesting that OCA-B is involved in B cell expansion as well as B cell function. Accordingly, several genes involved in cell proliferation and signaling, such asLck, Kcnn4, Cdc37, cyclin D3, B4galt1, andMs4a11, have been identified as OCA-B-dependent genes. Further studies on the roles played by these genes in B cells will contribute to an understanding of B cell differentiation.

Defined patterns of gene expression during cell differentiation are likely to be ensured by multiple factors playing redundant roles. By generating mice deficient in both NFKB1 and OCA-B, we show here that the two transcription factors are required for B-1 cell differentiation and serum IgM production. In addition, relative to Nfkb1−/− or Oca-b−/− mice, the Nfkb1−/−Oca-b−/− mice show a decrease in conventional B cell frequencies in the spleen and augmented reductions in T-independent and T-dependent Ab responses. These results suggest that NFKB1 and OCA-B play compensatory roles in multiple aspects of B cell differentiation.

The error behaviour of the extended Kalman filter is analysed. It is proved that the estimation error remains bounded if the system satisfies a detectability condition and both the initial estimation error and the disturbing noise terms are small enough. Moreover, some selected cases with both bounded and unbounded estimation error are demonstrated by numerical simulations.

The behaviour of FeAl during disordering on milling and re-ordering on annealing has been extensively studied and characterised. The mechanisms by which changes occur are not, however, well established. The role of defects created during milling on bringing about disorder is not clear; neither is the importance of their movement and annihilation during re-ordering. The structures of FeAl samples given a variety of thermal and mechanical pre-treatments have been examined here, as well as their behaviour on annealing. Three material preparations have been examined to distinguish the separate roles of vacancies and dislocations, with their associated APB faults, on disordering and re-ordering. Samples quenched from high temperature have large numbers of thermal vacancies: they show low temperature recovery as local atomic movement and re-ordering takes place, but full recovery by long range point defect movement is only possible at high temperatures. Heavily deformed samples recover at very low temperatures by easy dislocation glide and APB annihilation, with higher temperature recovery occurring by dislocation cross slip, reactions and decompositions. Deformation-induced disordering, and reordering on annealing, can largely be described through the large density of APBs, with each fault representing a thin plane of disorder. Lightly milled powder samples behave similarly to the deformed samples, with simultaneous dislocation recovery and re-ordering occurring on annealing, but after large amounts of milling dislocation movement is difficult and recovery is delayed to higher temperatures where diffusional mechanisms can assist.

Fe Al alloys containing slightly less than 25% Al have a two-phase mixture of disordered and DO 3 -ordered phases at temperatures somewhat below 550°C. The microstructure of such alloys is similar to that of Ni-base γ-γ′ superalloys, well known for their good high temperature strength and creep resistance. Analysis of the high temperature strength of the two-phase Fe Al alloys suggests that their high temperature strength is good under conditions of slow strain rate or creep. Their deformation behaviour differs from that of the γ-γ′ superalloys, however, since it is relatively easier to shear the ordered particles than to bow dislocations down channels between the particles. The relatively low ductility of these materials seems to be related to the localization of shear by the cutting of particles rather than to environmental sensitivity, as suggested for Fe 3 Al alloys.

Textures, or orientation distributions of crystals, are produced during the thermal and mechanical processing of materials and reflect the operative slip systems during deformation and the mechanisms leading to new grain formation and growth. The development of such textures is important since these can affect formability during processing as well as the uniformity and isotropy of the final product materials. The present study examines the textures produced during rolling and annealing of Fe-Al alloy samples covering a wide range of Al contents (25%--32%) (throughout this article compositions are given as atomic percent) as well as examining the influence of Cr addition on a fe-28%Al alloy. In addition the role of initial material state, whether the material is essentially disordered, has B2 order, or DO{sub 3} order, is examined. The importance of some of these observations, in terms of influencing the final properties of the sheet, as well as leading to differential surface-bulk properties, will be considered.

Fe Al alloys containing slightly less than 25% Al are a two phase mixture of disordered plus DO3-ordered phases at temperatures somewhat below 550°C. The morphology and stability of microstructure has been examined in one such binary Fe Al alloy when in the two-phase state, and compared with a ternary Fe Al Si alloy showing similar phase mixtures at similar temperatures. Phase changes in these alloys can be understood on the basis of the equilibrium phase diagram, including metastable phase boundary extensions and conditional spinodal decompositions to account for order changes occurring faster than chemical diffusional changes. Such two-phase microstructures are relatively stable against coarsening at these intermediate temperatures, particualrly for the Fe Al Si alloy which is believed to be due to its lower diffusivity and smaller interface energy. Such two-phase alloys, particularly when the composition is carefully chosen for the required stability and ordered volume fraction at a given temperature, should represent an Fe-base b.c.c. equivalent to the Ni-base superalloys.

Titanium trialuminide alloys stabilised to the cubic crystal structure show strength variations with temperature that vary from one alloy to another. For some alloys significant strength increases are seen at low temperatures, while for other alloys such strengthening may occur at high temperatures. These strength increases are not explained by dislocation core structures or cross-slip processes but by solute effects or by fine Al 2 Ti precipitate particles present in the material or formed during testing. Analysis of dislocation mobility at low temperatures by measurements of activation volume suggests that mobility at very low temperatures is controlled by a mechanism of unblocking and blocking of dislocation segments through Peierls valleys, probably influenced by solute additions.

It has been proposed that adenosine mediates the renal hemodynamic changes in acute renal failure (ARF) and that these changes are pathogenic in reducing glomerular filtration rate. Consistently, adenosine-receptor antagonists such as theophylline have been shown to have protective effects in several experimental models of ARF. The present experiments were designed to explore the potential role of adenosine in HgCl2-induced ARF in rats. In isolated perfused rat kidneys, HgCl2 increased adenosine production and induced a concentration-dependent vasoconstriction. However, the vasoconstriction was unrelated to adenosine production and was not antagonized by theophylline. During the initiation phase of HgCl2-induced ARF in intact rats (first 4 h after injection), theophylline failed to reverse the reduction in inulin clearance, and this failure could not be attributed to a loss of vascular responsiveness to adenosine, since N6-cyclohexyladenosine, a receptor agonist, produced a further reduction in inulin clearance. Furthermore, theophylline actually had deleterious effects during the maintenance phase of HgCl2-induced ARF in intact unanesthetized rats, as evidenced by higher mean serum creatinine values in theophylline-injected rather than in saline-injected rats, on both the second and third days after HgCl2 injection. Therefore HgCl2 acutely increases renal adenosine production, but increased adenosine does not mediate acute HgCl2-induced renal vasoconstriction, and adenosine-receptor antagonism does not have protective effects during the initiation or the maintenance phases of HgCl2-induced ARF in rats. These results provide no support for the hypothesis that increased adenosine mediates the hemodynamic changes in HgCl2-induced ARF.

The Pediatric Balance Scale (PBS), a modification of Berg's Balance Scale, was developed as a balance measure for school-age children with mild to moderate motor impairments. The purpose of this study was to determine the test-retest and interrater reliability of the PBS.To determine test-retest reliability, 20 children (aged five to 15 years) with known balance impairments were tested by one examiner on the PBS. Ten pediatric physical therapists independently scored 10 randomly selected videotaped test sessions.There was no significant difference in total test scores [intraclass correlation coefficient (ICC) model 3,1 = 0.998] or individual items (Kappa Coefficients, k = 0.87 to 1.0; Spearman Rank Correlation Coefficients, r = 0.89 to 1.0) measured by one therapist on two occasions. No significant difference among ratings by different physical therapists was found on the PBS for total test score (ICC 3,1 = 0.997).The PBS has been demonstrated to have good test-retest and interrater reliability when used with school-age children with mild to moderate motor impairments.

A pair of distinct proteins in one organism may most closely match different parts of the same protein in another organism. A comparison of all proteins from the genome of Saccharomyces cerevisiae and all proteins from 24 prokaryotic genomes yields 1010 pairs of yeast proteins whose homologs are parts of one protein from a prokaryotic genome. Marcotte et al. (Science 285:751-3) showed that proteins related in this manner are more likely to interact than proteins chosen at random. In this paper, we investigated whether genes coding for such proteins are also likely to be concurrently transcribed. We identified 1010 fused pairs of proteins encoded in the yeast genome and analyzed expression of the corresponding genes at the transcriptional level. We found that the transcriptional profiles of fused gene pairs are significantly closer than those of randomly selected pairs. This finding is reproducible and established by multiple distance metrics. Moreover, such pairs frequently share additional biologically relevant properties. Thus, while protein fusion patterns are not predictive of co-expression, they are an important element in explaining co-expression. This justifies the use of curated protein fusion events to help characterize gene co-expression clusters.