1,253 research outputs found
The Role of the Glyoxylate Cycle in the Pathogenesis of Mycobacterium tuberculosis
According to the World Health Organization a third of the world\u27s population is infected with Mycobacterium tuberculosis. The unparalleled success of M. tuberculosis as a pathogen reflects the bacterium\u27s extraordinary ability to persist in its host in spite of eliciting a robust immune response. Currently available treatment is inadequate and drug resistance is rapidly spreading. New antibiotics are desperately needed. The substrates and metabolic pathways utilized by pathogens during infection are largely unknown and represent an under-exploited area of investigation. Uniquely, evolution of the genus Mycobacterium has involved extensive duplication of fatty acid metabolism genes, including two homologs encoding prokaryotic- and eukaryotic-like isoforms of the glyoxylate cycle enzyme isocitrate lyase (ICL). The glyoxylate cycle is employed by cells when fatty acids are the main carbon source available. Here, we show that these enzymes are jointly required by M. tuberculosis for growth on fatty acids and for virulence in experimental infections. Although deletion of icll or icl2 had little impact on replication of M. tuberculosis in macrophages and mice, deletion of both genes abrogated intracellular growth, and resulted in rapid bacterial clearance from the lungs. A dual-specificity ICL inhibitor similarly blocked replication of M. tuberculosis on fatty acids in vitro and in macrophages. The absence of ICL orthologs in mammals, and recent findings implicating the glyoxylate pathway in the virulence of other bacterial and fungal pathogens makes this metabolic pathway an attractive novel target for drug development
The Discovery of New Export Products in Ecuador
This paper examines export diversification in Ecuador in the cases of fresh cut flowers, canned tuna, palm heart, broccoli and mangoes, using the theoretical framework on “pioneers” and “discoveries” developed by Hausmann and Rodrik(2003), as well as work by Sánchez and Butler (2006) on export costs and related uncertainties. It is found that the discoveries were mainly of traditional competitive advantage, with various degrees of technology adoption. The following policy implications are derived: i) innovative mechanisms to share the costs of new discoveries must be found and intellectual property rights strengthened; ii) cooperation among industry experts needs to improve; iii) deeper collective action to promote public-private partnerships should be undertaken; iv) relevant information and knowledge should be made available to all interested parties; and v) a national-level agenda should be undertaken to increase private investment in promising sectors while promoting the creation of public goods and minimizing rent-seeking behavior.Export diversification, Ecuador
Prior Military Combat Experience and Domestic Policing Use-of-Force Decisions
Use-of-force decisions are made in both the military combat and domestic policing environments. In this phenomenological study I aimed to examine what, if any, the effect of military combat experience has on domestic policing use-of-force decisions for military combat veteran police officers. Schneider and Shiffrin’s dual process of automatic and controlled processing theory offered the theoretical framework that was applied to how military combat veteran police officers may be affected by their military combat experience in the application of domestic policing use-of-force decisions. This qualitative study was designed to collect lived experiences of military combat veteran police officers who transitioned from military combat to domestic policing jobs. The 5 participants for this study were police officers solicited from the California Peace Officers Association and represented various law enforcement departments from throughout the state of California. Data were collected from one-on-one interviews using scripted questions regarding use-of-force application and training. The interviews were audio recorded, transcribed, and then analyzed using NVivo qualitative analysis software to identify themes. The results showed there were no significant effects experienced by participants regarding use-of-force decisions during the transition from military combat to domestic policing. The similarities and areas applicable to both environments indicated that prior military combat experience positively contributes to domestic policing use-of-force decisions. The results of this study may be used to improve police and community relations, as well as benefit the citizens, police officers, departments, and the communities in which they serve
The Caribbean low-level jet: Its structure and interannual variability
The Caribbean region shows maxima in easterly winds greater than 12 m/s at 925 hPa in July and February referred herein as the summer and winter Caribbean low-level jet (CBNLLJ), respectively. The purpose of this study is to identify the mechanisms of the CBNLLJ formation and variability and their association to the regional hydroclimate. To study the climatological aspects of the CBNLLJ, climatological fields are calculated from 1979 to 2001. It is observed that the low-level (925-hPa) zonal wind over the Caribbean basin has a semi-annual cycle. The semi-annual cycle has peaks in February and July that are regional amplifications of the large-scale circulation by means of a meridional pressure gradient. High mountains to the south of the Caribbean Sea influence the air temperature meridional gradient providing a baroclinic structure that favors a stronger easterly wind. The boreal summer strengthening of the CBNLLJ is associated with subsidence over the subtropical North Atlantic from the May-to-July evolution of the Central American monsoon. Additionally, the mid-summer minimum of Caribbean precipitation is related to the Caribbean LLJ through greater moisture flux divergence.
The CBNLLJ has interannual variability with greater standard deviation during boreal summer. The summer interannual variability of the CBNLLJ is due to variability of the meridional pressure gradient across the Caribbean basin influenced by sea surface temperature (SST) gradients between the tropical Pacific and the tropical Atlantic. To determine the inter-decadal changes statistical diagnostics of summer CBNLLJ anomalies are analyzed for different periods, in particular 1958-1978 and 1979-2001. Also analyzed were inter-basin SLP and SST gradient indices. The CBNLLJ showed more intense events and greater persistence during 1979-2001 than during 1958-1978 as a result of more extreme SLP and SST inter-basin gradients during the more recent decades. These are due to changes in the relation between the Pacific and the Atlantic after the late 1970's. The results of the present study are important in the context of understanding an intrinsic component of the Caribbean climate, i.e., the Caribbean low-level jet
How strong is carbon cycle‐climate feedback under global warming?
The behavior of the coupled carbon cycle and physical climate system in a global warming scenario is studied using an Earth system model including the atmosphere, land, ocean, and the carbon cycle embedded in these components. A fully coupled carbon‐climate simulation and several sensitivity runs were conducted for the period of 1860–2100 with prescribed IPCC‐SRES‐A1B emission scenario. Results indicate a positive feedback to global warming from the interactive carbon cycle, with an additional increase of 90 ppmv in the atmospheric CO2, and 0.6 degree additional warming, thus confirming recent results from the Hadley Centre and IPSL. However, the changes in various carbon pools are more modest, largely due to the multiple limiting factors constraining terrestrial productivity and carbon loss. The large differences among the three models are manifestations of some of the poorly constrained processes such as the global strength of the CO2 fertilization effect and the turnover time and rates of soil decomposition
A Novel Methodology for the Determination of Impulse Response Coefficients Applied to Transmission Line Protection Relays
Impulse Response Coefficients (IRC) of digital filters is an imperative step in the development of transmission line protection relay algorithms. Traditionally, Fourier-based filters are used in real applications, where IRC are fixed values of sine and cosine functions with a data window of one or more cycles. Based on state-of-the-art, Mother Wavelet coefficients used in Multiresolution Analysis, and Structuring Element coefficients used in Mathematical Morphology are usually proposed to develop protection algorithms. However, the proper choice of these coefficients is based on empirical process of trial and error. This paper proposes a novel methodology for optimally determining coefficients that depend on the waveform structure analyzed, which is determined using variance as the metric. Assessment of methodology for three case studies considering requirements of relay manufactures (response time, design, harmonic attenuation and other) is presented. The first assessment is to extract coefficients useful for distinguishing among non-fault conditions, harmonics, and arcing faults. The second one is to extract coefficients to filter harmonic components. The assessment is carried out considering different data windows and sampling rates. Test results highlight the efficiency of the model to determine specific coefficients for each case study analyzed. Interestingly, results also showed that the discovered coefficients can be used in another filtering technique. Thus, the third case study involves developing two fault classifiers, which are developed using mathematical morphology where the structuring elements used correspond to the coefficient vectors determined through the proposed methodology. There is a notable paucity of scientific literature focusing on this topic. Therefore, there are several important areas where this study makes an original contribution regarding protection relays.Fil: Morales Garcia, John Armando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Instituto de Energía Eléctrica. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Energía Eléctrica; ArgentinaFil: Quizhpi, Flavio. Universidad de Cuenca.; EcuadorFil: Villarroel Gutiérrez, Héctor Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Instituto de Energía Eléctrica. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Energía Eléctrica; ArgentinaFil: Munoz, Eduardo. Universidad de Cuenca.; EcuadorFil: Orduna, Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Instituto de Energía Eléctrica. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Energía Eléctrica; ArgentinaFil: Vasquez, Ernesto. Universidad Autonoma de Nuevo Leon.; Méxic
Interactions between land use change and carbon cycle feedbacks
Author Posting. © American Geophysical Union, 2017. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Global Biogeochemical Cycles 31 (2017): 96–113, doi:10.1002/2016GB005374.Using the Community Earth System Model, we explore the role of human land use and land cover change (LULCC) in modifying the terrestrial carbon budget in simulations forced by Representative Concentration Pathway 8.5, extended to year 2300. Overall, conversion of land (e.g., from forest to croplands via deforestation) results in a model-estimated, cumulative carbon loss of 490 Pg C between 1850 and 2300, larger than the 230 Pg C loss of carbon caused by climate change over this same interval. The LULCC carbon loss is a combination of a direct loss at the time of conversion and an indirect loss from the reduction of potential terrestrial carbon sinks. Approximately 40% of the carbon loss associated with LULCC in the simulations arises from direct human modification of the land surface; the remaining 60% is an indirect consequence of the loss of potential natural carbon sinks. Because of the multicentury carbon cycle legacy of current land use decisions, a globally averaged amplification factor of 2.6 must be applied to 2015 land use carbon losses to adjust for indirect effects. This estimate is 30% higher when considering the carbon cycle evolution after 2100. Most of the terrestrial uptake of anthropogenic carbon in the model occurs from the influence of rising atmospheric CO2 on photosynthesis in trees, and thus, model-projected carbon feedbacks are especially sensitive to deforestation.National Science Foundation Grant Numbers: AGS 1049033, CCF-15220542017-07-2
Guselkumab for hidradenitis suppurativa:a phase II, open-label, mode-of-action study
BACKGROUND: The effectiveness of available biologics for the treatment of hidradenitis suppurativa (HS) is limited. Additional therapeutic options are needed. OBJECTIVES: To investigate the efficacy and mode of action of guselkumab [an anti-interleukin (IL)-23p19 monoclonal antibody] 200 mg subcutaneously every 4 weeks for 16 weeks in patients with HS. METHODS: An open-label, multicentre, phase IIa trial in patients with moderate-to-severe HS was carried out (NCT04061395). The pharmacodynamic response in skin and blood was measured after 16 weeks of treatment. Clinical efficacy was assessed using the Hidradenitis Suppurativa Clinical Response (HiSCR), the International Hidradenitis Suppurativa Severity Score System (IHS4), and the abscess and inflammatory nodule (AN) count. The protocol was reviewed and approved by the local institutional review board (METC 2018/694), and the study was conducted in accordance with good clinical practice guidelines and applicable regulatory requirements. RESULTS: Thirteen of 20 patients (65%) achieved HiSCR with a statistically significant decrease in median IHS4 score (from 8.5 to 5.0; P = 0.002) and median AN count (from 6.5 to 4.0; P = 0.002). The overall patient-reported outcomes did not show a similar trend. One serious adverse event, likely to be unrelated to guselkumab treatment, was observed. In lesional skin, transcriptomic analysis revealed the upregulation of various genes associated with inflammation, including immunoglobulins, S100, matrix metalloproteinases, keratin, B-cell and complement genes, which decreased in clinical responders after treatment. Immunohistochemistry revealed a marked decrease in inflammatory markers in clinical responders at week 16. CONCLUSIONS: Sixty-five per cent of patients with moderate-to-severe HS achieved HiSCR after 16 weeks of treatment with guselkumab. We could not demonstrate a consistent correlation between gene and protein expression and clinical responses. The main limitations of this study were the small sample size and absence of a placebo arm. The large placebo-controlled phase IIb NOVA trial for guselkumab in patients with HS reported a lower HiSCR response of 45.0-50.8% in the treatment group and 38.7% in the placebo group. Guselkumab seems only to be of benefit in a subgroup of patients with HS, indicating that the IL-23/T helper 17 axis is not central to the pathophysiology of HS.</p
- …