Miracle-dz/UniFAR-FTUs huggingface dataset:
Application of Functional Genomics to Pathway Optimization for Increased Isoprenoid Production

ABSTRACT Producing complex chemicals using synthetic metabolic pathways in microbial hosts can have many advantages over chemical synthesis but is often complicated by deleterious interactions between pathway intermediates and the host cell metabolism. With the maturation of functional genomic analysis, it is now technically feasible to identify modes of toxicity associated with the accumulation of foreign molecules in the engineered bacterium. Previously, Escherichia coli was engineered to produce large quantities of isoprenoids by creating a mevalonate-based isopentenyl pyrophosphate biosynthetic pathway (V. J. J. Martin et al., Nat. Biotechnol. 21:796-802, 2003). The engineered E. coli strain produced high levels of isoprenoids, but further optimization led to an imbalance in carbon flux and the accumulation of the pathway intermediate 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA), which proved to be cytotoxic to E. coli. Using both DNA microarray analysis and targeted metabolite profiling, we have studied E. coli strains inhibited by the intracellular accumulation of HMG-CoA. Our results indicate that HMG-CoA inhibits fatty acid biosynthesis in the microbial host, leading to generalized membrane stress. The cytotoxic effects of HMG-CoA accumulation can be counteracted by the addition of palmitic acid (16:0) and, to a lesser extent, oleic acid (cis-Δ9-18:1) in the growth medium. This work demonstrates the utility of using transcriptomic and metabolomic methods to optimize synthetic biological systems.
New insights into relationships between active and dormant organisms, phylogenetic diversity and ecosystem productivity

Marine microbes make up a key part of ocean food webs and drive ocean chemistry through a range of metabolic processes. A fundamental question in ecology is whether the diversity of organisms in a community shapes the ecological functions of that community. While there is substantial evidence to support a positive link between diversity and ecological productivity for macro‐organisms in terrestrial environments, this relationship has not previously been verified for marine microbial communities. One factor complicating the understanding of this relationship is that many marine microbes are dormant and are easily dispersed by ocean currents, making it difficult to ensure that the organisms found in a given environmental sample accurately reflect processes occurring in that environment. Another complication is that, due to microbes great range of genotypic and phenotypic variability, communities with distantly related species may have greater range of metabolic functions than communities have the same richness and evenness, but in which the species present are more closely related to each other. In this issue of Molecular Ecology, Galand et al. (2015) provide compelling evidence that the most metabolically active communities are those in which the nondormant portion of the microbial community has the highest phylogenetic diversity. They also illustrate that focusing on the active portion of the community allows for detection of temporal patterns in community structure that would not be otherwise evident. The authors’ point out that the presence of many dormant organisms that do not contribute to ecosystem functioning is a feature that makes microbial ecosystems fundamentally different from macro‐ecosystems and that this difference needs to be accounted for in microbial ecology theory.
Microwave Signatures of Snow Cover Using Numerical Maxwell Equations Based on Discrete Dipole Approximation in Bicontinuous Media and Half-Space Dyadic Green's Function

A three-dimensional snowpack scattering and emission model is developed by numerically solving Maxwell's equations (NMM3D) over the entire snowpack on an underlying half-space. The solutions are crucial to microwave remote sensing that requires the preservation of coherent phase information. The heterogeneous snowpack is represented as a bicontinuous medium. Effects of the underlying half-space are included through a half-space Green's function in a volume integral equation formulation. The volume integral equation is then solved using the discrete dipole approximation. The fast Fourier transform is effectuated for all three dimensions with half-space Green's function rather than the conventional free space Green's function. To overcome the snow volume truncation in the finite numerical calculations, periodic boundary conditions are applied in the lateral extent. Thus, in NMM3D, the physical microwave scattering and emission problem is solved without using any radiative transfer equations. In this formulation, the scattering matrix of the snowpack accounts for both the magnitude and phase. The NMM3D simulations are demonstrated at Ku-band frequency for a snow cover up to 25-cm thick. The results are applicable to remote sensing of snow over sea ice, and thin layers of terrestrial snow. Quantitative values of backscattering and bistatic scattering coefficients are derived for active microwave remote sensing, and brightness temperatures for passive microwave remote sensing. The full wave simulation results are compared with those of the partially coherent approach of the dense media radiative transfer (DMRT). The NMM3D results capture effects of backscattering enhancement and coherent layering that are missed in DMRT. The full wave solution to Maxwell equations is important to advance radar polarimetry, interferometry, and tomography that require the preservation of the full phase information and all interface interactions for applications to radar remote sensing of snow cover on land and on sea ice.
FACTORS ON NEW ENERGY DEVELOPMENT BASED ON CASES STUDIES FROM CO-INTEGRATION AND GRANGER TEST

During low-carbon economic times,development and utilization of new energies will be a vital means to raise global competitiveness for each country.In order to discover the factors on new energy development,this paper,based on carbon dioxide emission,energy prices and new energy consumption to total energy consumption data from 1990 to 2008,establishes a regress equation to analyze the factors.Environmental issues triggered by industrial emission have no limits on development of new energy,which largely depends upon prices.To develop new energy is a useful way to avoid global market risks.By analyzing the costs of new energy,the factors on new energy development comprises high production cost and poor technology,so a technical innovation will play a key role in new energy development.
PD-L1 Expression and Immune Escape in Melanoma Resistance to MAPK Inhibitors

Purpose: To examine the relationship between immune activity, PD-L1 expression, and tumor cell signaling, in metastatic melanomas prior to and during treatment with targeted MAPK inhibitors. Experimental Design: Thirty-eight tumors from 17 patients treated with BRAF inhibitor (n = 12) or combination BRAF/MEK inhibitors (n = 5) with known PD-L1 expression were analyzed. RNA expression arrays were performed on all pretreatment (PRE, n = 17), early during treatment (EDT, n = 8), and progression (PROG, n = 13) biopsies. HLA-A/HLA-DPB1 expression was assessed by IHC. Results: Gene set enrichment analysis (GSEA) of PRE, EDT, and PROG melanomas revealed that transcriptome signatures indicative of immune cell activation were strongly positively correlated with PD-L1 staining. In contrast, MAPK signaling and canonical Wnt/-β-catenin activity was negatively associated with PD-L1 melanoma expression. The expression of PD-L1 and immune activation signatures did not simply reflect the degree or type of immune cell infiltration, and was not sufficient for tumor response to MAPK inhibition. Conclusions: PD-L1 expression correlates with immune cells and immune activity signatures in melanoma, but is not sufficient for tumor response to MAPK inhibition, as many PRE and PROG melanomas displayed both PD-L1 positivity and immune activation signatures. This confirms that immune escape is common in MAPK inhibitor–treated tumors. This has important implications for the selection of second-line immunotherapy because analysis of mechanisms of immune escape will likely be required to identify patients likely to respond to such therapies. Clin Cancer Res; 23(20); 6054–61. ©2017 AACR.
Vers un renouvellement de l'analyse segmentationniste

L'auteur suggere de renouveler l'approche segmentationniste des marches internes, marches professionnels et marche externe en vue d'une prise en compte des changements en cours depuis une vingtaine d'annees sur le marche du travail et dans l'organisation des entreprises. La destabilisation des anciens marches internes fondes sur l'echange entre haut niveau de subordination et haut niveau de protection des salaries ne debouche pas sur le regne generalise du marche externe. La proposition est plutot de prendre en compte les processus pluriels et parfois instables de rearticulation entre marches internes (et professionnels) et marche externe. Concernant les trajectoires individuelles, l'accent est mis sur les flux de passage de plus en plus nombreux et diversifies entre espaces heterogenes et sur le deplacement continuel des frontieres entre ces espaces. Le processus d'insertion professionnelle des jeunes fournit une illustration de la transformation diachronique des regles de restructuration des marches internes et de mobilite de la main-d'oeuvre.
Effects of daytime ingestion of melatonin on short-term athletic performance

The immediate effects of ingesting melatonin in the daytime include decreased alertness and body temperature. To date, no researcher has examined whether daytime ingestion of melatonin leads to impairments in variables relevant to short-term (<10 min) athletic performance. Twelve physically active participants (mean ± s age = 25.2 ± 5.0 years, body mass = 81.4 ± 12.1 kg and chronotype = 33.8 ± 6.3 units) ingested 5 mg of melatonin or placebo at 11:45 hours in a double-blind experiment. At 13:00 and 17:00 hours, subjective alertness was measured, together with intra-aural temperature, reaction time (two-, four- and eight-choice), short-term memory recall and grip strength. Performance, ratings of perceived exertion (RPE) and heart rate were also recorded during a 4-km cycling time trial. At 13:00 hours, the mean ± s intra-aural temperature was 0.49 ± 0.79°C lower after ingestion of melatonin than after placebo (p = 0.015), but this difference was not apparent at 17:00 hours. At both 13:00 and 17:00 hours, melatonin reduced (p < 0.05) alertness, short-term memory and exercise heart rate by 1.5 ± 1.8 units, 1 ± 1 digits and 6 ± 9 beats.min−1, respectively (mean ± s). Eight-choice reaction time was also slower at both times of day after ingesting melatonin. Melatonin did not influence time trial performance or RPE (p > 0.05). The effects of 5 mg of melatonin seem more pronounced for mental rather than physical components of short-term athletic performance, although the cardiovascular responses to exercise are affected. Some effects of melatonin were apparent 5 h after ingestion when the hypothermic effects of melatonin had dissipated.
Speech perception with a cochlear implant used in conjunction with a hearing aid in the opposite ear

The aim of this study was to determine the improvement in speech recognition provided by a cochlear implant (CI) in conjunction with a hearing aid (HA) in the opposite ear. The study was a retrospective cohort study in the context of a university teaching hospital CI programme. Seven CI patients who still use their HA in the opposite ear were tested. The scores with the CI alone and the CI in conjunction with an HA were evaluated by using three speech perception tests in quiet (Freiburger Numbers, Freiburger Monosyllables, and Innsbrucker Sentence Test). In the majority of tests and subjects, the CI alone performed better than the HA alone, and the bimodal (CI+HA) condition was superior to the CI alone. On the sentence test, the patients as a group improved from 47-96% (mean: 79%; CI alone) to 50-100% (mean: 88.1%; CI+HA, pv<0.05). With the more difficult monosyllable test, the scores improved from 15-52% (mean: 37.2%; CI alone) to 15-82% (mean: 48.7%; CI+ HA, p<0.05). On the numbers test, scores increased from 65-98% (mean: 83%; CI alone) to 75-98% (mean: 88.7%; CI+ HA, p<0.05). All patients in this study were implanted in the poorer ear. The results of the present study suggest the advantage of CI usage in conjunction with an HA in the opposite ear. Sumario El propósito de este estudio fue determinar la mejoría en el reconocimiento del lenguaje, aportado por un implante coclear (CI) y por el uso simultáneo de un auxiliar auditivo (HA) en el oído contralateral. El estudio fue una investigación retrospectiva de cohorte en el contexto de un programa de implantes cocleares en un hospital universitario. Se evaluó a siete pacientes con CI que aún utilizan su auxiliar auditivo en el oído opuesto. Se evaluaron las puntuaciones obtenidas con el IC sólo y utilizado simultáneamente con el HA, utilizando tres pruebas de percepción del lenguaje (los Números de Freiburguer, los Monosilábicos de Freiburguer y la Prueba de Frases de Innsbrucker). En la mayoría de las pruebas y los sujetos, el rendimiento del CI solo fue mejor que con el uso del HA aislado, y la condición bimodal (CI + HA) fue superior al uso del CI solo. En la prueba de frases, los pacientes como grupo mejoraron de 47-96% (media: 79%; CI solo) a 50-100% (media: 88.1%; CI + HA, p < 0.05). Con la prueba más difícil de monosilábicos, los puntajes mejoraron de 15-52% (media: 37.2%; CI solo) a 15-82% (media; 48.7%; CI + HA; p < 0.05). En la prueba de números, los puntajes aumentaron de 65-98% (media: 83%; CI solo) a 75-98% (media: 88.7%; CI + HA; p < 0.05). Todos los pacientes de este estudio fueron implantados en el peor oído. Los resultados del presente estudio sugieren la ventaja en el uso del CI en conjunto con un HA en el oído opuesto.
Grafting the Nasal Dorsum with Tandem Ear Cartilage

A technique for autogenous grafting of the nasal dorsum with ear cartilage is suggested based on the results of 25 consecutive cases. The technique involves (1) harvesting the entire cymba conchae and cavum conchae of the ear; (2) separating them and suturing them to each other in tandem fashion; (3) filling the underside concavity of the cymba conchae part of the graft with scraps of cartilage; (4) avoiding any bruising or crushing of the graft; and (5) filling any minor residual irregularities of the dorsum with soft tissue or cartilage from the cephalic trim of the lateral crus. The results suggest a consistent augmentation of the nasal dorsum for deficiencies from 3 to 6 mm in size. Four of the 25 cases did require secondary correction for dorsal convexity, inadequate augmentation, and surface irregularities. The technique, however, has been helpful in that ear cartilage is invariably available, allowing septum to be used for more important grafts. The procedure is easily performed under local anesthesia with no significant distortion to the donor site.
Effects of ductus arteriosus occlusion on pulmonary artery pressure during in utero ventilation in fetal sheep

Seven fetal sheep were prepared to study the short‐term effects of in utero ventilation and ductus arteriosus occlusion on pulmonary artery pressure and on fetal right ventricular function assessed using the right atrial pressure‐right ventricular stroke volume relationship. Nine days post‐surgery (140 days gestation), blood gas and haemodynamic values were obtained before and during in utero ventilation with 100% O2, and during ventilation with the ductus arteriosus occluded. Oxygen content increased significantly from 7.2 to 14.5 ml dl‐1 with ventilation and remained elevated at 14.4 ml dl‐1 with ventilation with the ductus arteriosus occluded. In utero ventilation produced a left to right atrial pressure gradient and depression of the right atrial pressure‐right ventricular stroke volume relationship. Ductus arteriosus occlusion during in utero ventilation reduced the left to right atrial pressure gradient, and along with a decrease in pulmonary artery pressure, resulted in an upward shift of the right atrial pressure‐right ventricular stroke volume relationship, but only to the preventilation level. This study indicates that the fetal right atrial pressure‐right ventricular stroke volume relationship is significantly altered, both by changes in the left to right atrial pressure gradient and by changes in pulmonary artery pressure seen with in utero ventilation and subsequent ductus arteriosus occlusion.
Gradual DNA demethylation of the Oct4 promoter in cloned mouse embryos

During differentiation, somatic cell nuclei acquire unique patterns of epigenetic modifications, such as DNA methylation, which affect the transcriptional activity of specific genes. Upon transfer into oocytes, however, the somatic nucleus undergoes reprogramming of these epigenetic modifications to achieve pluripotency. Oct4 is one of the critical pluripotency regulators, and is expressed in the germ line, including the pluripotent early embryonic cells. Previous studies showed that the upstream regulatory sequences of the Oct4 gene are distinctly methylated in somatic cells, and the DNA methylation of the regulatory sequences suppresses the transcriptional activity. Thus, successful reprogramming of the somatic cell nucleus to gain pluripotency must be accompanied by the demethylation of the Oct4 regulatory sequences. Here, we investigated the methylation pattern of the Oct4 promoter during early development of cloned mouse embryos. We found that the Oct4 promoter was only gradually demethylated during the early cleavage stages and that the ineffective demethylation of the promoter was associated with developmental retardation. We also found that the upstream sequences of the other pluripotency regulators, namely Nanog, Sox2, and Foxd3, were considerably under‐methylated in cumulus cells. These results suggest that the Oct4 gene, as compared to the other pluripotency regulators, needs to undergo extensive demethylation during nuclear reprogramming, and that the failure of such demethylation is associated with inefficient development of cloned somatic cell embryos. Mol. Reprod. Dev. © 2005 Wiley‐Liss, Inc.
Genome Sequence of Stenotrophomonas maltophilia S028, an Isolate Harboring the AmpR-L2 Resistance Module

ABSTRACT Multidrug-resistant Stenotrophomonas maltophilia has emerged as an important cause of nosocomial infections, which is attributable mainly to the production of diverse β-lactamases by S. maltophilia. The L2 β-lactamase mediated by the AmpR-L2 module is the most represented lactamase. Here, we announce the genome sequence of S028, an isolate harboring the AmpR-L2 module.
Formation of a pathogen vacuole according to Legionella pneumophila: how to kill one bird with many stones

Legionella species are ubiquitous, waterborne bacteria that thrive in numerous ecological niches. Yet, in contrast to many other environmental bacteria, Legionella spp. are also able to grow intracellularly in predatory protozoa. This feature mainly accounts for the pathogenicity of Legionella pneumophila, which causes the majority of clinical cases of a severe pneumonia termed Legionnaires' disease. The pathomechanism underlying L. pneumophila infection is based on macrophage resistance, which in turn is largely defined by the opportunistic pathogen's resistance towards amoebae. L. pneumophila replicates in macrophages or amoebae in a unique membrane‐bound compartment, the Legionella‐containing vacuole (LCV). LCV formation requires the bacterial intracellular multiplication/defective for organelle trafficking (Icm/Dot) type IV secretion system and involves a plethora of translocated effector proteins, which subvert pivotal processes in the host cell. Of the ca. 300 different experimentally validated Icm/Dot substrates, about 50 have been studied and attributed a cellular function to date. The versatility and ingenuity of these effectors' mode of actions is striking. In this review, we summarize insight into the cellular functions and biochemical activities of well‐characterized L. pneumophila effector proteins and the host pathways they target. Recent studies not only substantially increased our knowledge about pathogen–host interactions, but also shed light on novel biological mechanisms.
Unraveling the Leloir Pathway of Bifidobacterium bifidum: Significance of the Uridylyltransferases

ABSTRACT The GNB/LNB (galacto-N-biose/lacto-N-biose) pathway plays a crucial role in bifidobacteria during growth on human milk or mucin from epithelial cells. It is thought to be the major route for galactose utilization in Bifidobacterium longum as it is an energy-saving variant of the Leloir pathway. Both pathways are present in B. bifidum, and galactose 1-phosphate (gal1P) is considered to play a key role. Due to its toxic nature, gal1P is further converted into its activated UDP-sugar through the action of poorly characterized uridylyltransferases. In this study, three uridylyltransferases (galT1, galT2, and ugpA) from Bifidobacterium bifidum were cloned in an Escherichia coli mutant and screened for activity on the key intermediate gal1P. GalT1 and GalT2 showed UDP-glucose-hexose-1-phosphate uridylyltransferase activity (EC 2.7.7.12), whereas UgpA showed promiscuous UTP-hexose-1-phosphate uridylyltransferase activity (EC 2.7.7.10). The activity of UgpA toward glucose 1-phosphate was about 33-fold higher than that toward gal1P. GalT1, as part of the bifidobacterial Leloir pathway, was about 357-fold more active than GalT2, the functional analog in the GNB/LNB pathway. These results suggest that GalT1 plays a more significant role than previously thought and predominates when B. bifidum grows on lactose and human milk oligosaccharides. GalT2 activity is required only during growth on substrates with a GNB core such as mucin glycans.
Use of dual-phase contrast computed tomography for evaluation of the normal canine male genital tract.

OBJECTIVES To evaluate the use of dual-phase contrast-enhanced computed tomography for the depiction of the features of the male genital tract, highlighting differences between entire and neutered dogs. METHODS Computed tomography exams of 23 entire and 23 neutered male dogs with no history of urogenital disease were included in this retrospective study, with exams acquired pre-, 30 and 98·9 ±27·4 seconds after intravenous contrast administration. The genital structures were subjectively evaluated for visibility, contrast enhancement and enhancement pattern and differences between entire and neutered dogs were described. Objective measurements of attenuation and size of the prostatic tissue were acquired. RESULTS The root, body and glans of the penis could be evaluated in all dogs and appeared larger in entire dogs, though objective measurements could not be reliably made because these structures are small and curved. There was contrast enhancement of the cavernous structures, most reliably in the bulb and corpus spongiosum and most frequently in entire dogs in the delayed post-contrast phase. In entire dogs, the small testicular vessels most commonly had a vermiform shape in the early post-contrast phase, and a homogeneous appearance in the delayed phase. Sternal recumbency with the coxofemoral joints extended improved visibility of the genital structures. CLINICAL SIGNIFICANCE Dual-phase contrast-enhanced computed tomography is useful for depiction of the structures of the male genital tract, with the early phase especially highlighting the vascular and the delayed phase the cavernous structures.