Frequency of Drug Resistance Gene Amplification in Clinical Leishmania Strains

Experimental studies about Leishmania resistance to metal and antifolates have pointed out that gene amplification is one of the main mechanisms of drug detoxification. Amplified genes code for adenosine triphosphate-dependent transporters (multidrug resistance and P-glycoproteins P), enzymes involved in trypanothione pathway, particularly gamma glutamyl cysteine synthase, and others involved in folates metabolism, such as dihydrofolate reductase and pterine reductase. The aim of this study was to detect and quantify the amplification of these genes in clinical strains of visceral leishmaniasis agents: Leishmania infantum, L. donovani, and L. archibaldi. Relative quantification experiments by means of real-time polymerase chain reaction showed that multidrug resistance gene amplification is the more frequent event. For P-glycoproteins P and dihydrofolate reductase genes, level of amplification was comparable to the level observed after in vitro selection of resistant clones. Gene amplification is therefore a common phenomenon in wild strains concurring to Leishmania genomic plasticity. This finding, which corroborates results of experimental studies, supports a better understanding of metal resistance selection and spreading in endemic areas

Sextupole RDTs in the LHC at injection and in the ramp

During 2023, examination of the action dependence of sextupolar resonance driving terms (RDT) in the LHC at injection, as measured with an AC-dipole, demonstrated that a robust measurement of the RDTs could still be achieved even with very small amplitude kicks, typically used for linear optics studies. Consequently, analysis of optics measurements from 2022 to 2024 during the LHC energy ramp allowed a first measurement of the sextupole resonance evolution. A large asymmetry was observed between the two LHC beams, with the clockwise circulating beam (LHCB1) being significantly worse than the counter-clockwise circulating beam (LHCB2), and a clear increase in the RDT strength during the ramp was observed. During 2024 commissioning, a first attempt was made to correct the 1020 RDT of LHCB1 at injection. Results are presented in this report

Chemical, Structural, and Morphological Changes of a MoVTeNb Catalyst during Oxidative Dehydrogenation of Ethane

MoVTeNb mixed oxide, a highly active and selective catalyst for the oxidative dehydrogenation of ethane to produce ethylene, exhibits the so-called M1 and M2 crystalline phases. The thermal stability of the MoVTeNb catalytic system was assessed under varying reaction conditions; to this end, the catalyst was exposed to several reaction temperatures spanning from 440 to 550 °C. Both the pristine and spent materials were analyzed by several characterization techniques. The catalyst was stable below 500 °C; a reaction temperature of ≥500 °C brings about the removal of tellurium from the intercalated framework channels of the M1 crystalline phase. Rietveld refinement of X-ray diffraction patterns and microscopy results showed that the tellurium loss causes the progressive partial destruction of the M1 phase, thus decreasing the number of active sites and forming a MoO2 crystalline phase, which is inactive for this reaction. Raman spectroscopy confirmed the MoO2 phase development as a function of reaction temperature. From highresolution transmission electron microscopy and energy-dispersive X-ray spectroscopy analyses it was noticed that tellurium departure occurs preferentially from the end sides of the needlelike M1 crystals, across the [001] plane. Detailed analysis of a solid deposited at the reactor outlet showrf that it consisted mainly of metallic tellurium, suggesting that the tellurium detachment occurs via reduction of Te4+ to Te0 due to a combination of reaction temperature and feed composition. Thus, in order to sustain the catalytic performance exhibited by MoVTeNb mixed oxide, hot spots along the reactor bed should be avoided or controlled, maintaining the catalytic bed temperature below 500 °C.This work was financially supported by the Instituto Mexicano del Petroleo.Valente, JS.; Armendariz-Herrera, H.; Quintana-Solorzano, R.; Del Angel, P.; Nava, N.; Masso Ramírez, A.; López Nieto, JM. (2014). Chemical, Structural, and Morphological Changes of a MoVTeNb Catalyst during Oxidative Dehydrogenation of Ethane. ACS Catalysis. 4:1292-1301. doi:10.1021/cs500143jS12921301

A cortical motor nucleus drives the basal ganglia-recipient thalamus in singing birds

The pallido-recipient thalamus transmits information from the basal ganglia to the cortex and is critical for motor initiation and learning. Thalamic activity is strongly inhibited by pallidal inputs from the basal ganglia, but the role of nonpallidal inputs, such as excitatory inputs from cortex, remains unclear. We simultaneously recorded from presynaptic pallidal axon terminals and postsynaptic thalamocortical neurons in a basal ganglia–recipient thalamic nucleus that is necessary for vocal variability and learning in zebra finches. We found that song-locked rate modulations in the thalamus could not be explained by pallidal inputs alone and persisted following pallidal lesion. Instead, thalamic activity was likely driven by inputs from a motor cortical nucleus that is also necessary for singing. These findings suggest a role for cortical inputs to the pallido-recipient thalamus in driving premotor signals that are important for exploratory behavior and learning.National Institutes of Health (U.S.) (Grant R01DC009183)National Institutes of Health (U.S.) (Grant K99NS067062)Damon Runyon Cancer Research Foundation (Postdoctoral Fellowship)Charles A. King Trust (Postdoctoral Fellowship

Naringenin Prevents Dyslipidemia, Apolipoprotein B Overproduction, and Hyperinsulinemia in LDL Receptor–Null Mice With Diet-Induced Insulin Resistance

OBJECTIVE: The global epidemic of metabolic syndrome and its complications demands rapid evaluation of new and accessible interventions. Insulin resistance is the central biochemical disturbance in the metabolic syndrome. The citrus-derived flavonoid, naringenin, has lipid-lowering properties and inhibits VLDL secretion from cultured hepatocytes in a manner resembling insulin. We evaluated whether naringenin regulates lipoprotein production and insulin sensitivity in the context of insulin resistance in vivo. RESEARCH DESIGN AND METHODS: LDL receptor-null (Ldlr(-/-)) mice fed a high-fat (Western) diet (42% calories from fat and 0.05% cholesterol) become dyslipidemic, insulin and glucose intolerant, and obese. Four groups of mice (standard diet, Western, and Western plus 1% or 3% wt/wt naringenin) were fed ad libitum for 4 weeks. VLDL production and parameters of insulin and glucose tolerance were determined. RESULTS: We report that naringenin treatment of Ldlr(-/-) mice fed a Western diet corrected VLDL overproduction, ameliorated hepatic steatosis, and attenuated dyslipidemia without affecting caloric intake or fat absorption. Naringenin 1) increased hepatic fatty acid oxidation through a peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1alpha/PPARalpha-mediated transcription program; 2) prevented sterol regulatory element-binding protein 1c-mediated lipogenesis in both liver and muscle by reducing fasting hyperinsulinemia; 3) decreased hepatic cholesterol and cholesterol ester synthesis; 4) reduced both VLDL-derived and endogenously synthesized fatty acids, preventing muscle triglyceride accumulation; and 5) improved overall insulin sensitivity and glucose tolerance. CONCLUSIONS: Thus, naringenin, through its correction of many of the metabolic disturbances linked to insulin resistance, represents a promising therapeutic approach for metabolic syndrome

The LHC Injection Tests

A series of LHC injection tests was performed in August and September 2008. The first saw beam injected into sector 23; the second into sectors 78 and 23; the third into sectors 78-67 and sectors 23-34-45. The fourth, into sectors 23-34-45, was performed the evening before the extended injection test on the 10th September which saw both beams brought around the full circumference of the LHC. The tests enabled the testing and debugging of a number of critical control and hardware systems; testing and validation of instrumentation with beam for the first time; deployment, and validation of a number of measurement procedures. Beam based measurements revealed a number of machine configuration issues that were rapidly resolved. The tests were undoubtedly an essential precursor to the successful start of LHC beam commissioning. This paper provides an outline of preparation for the tests, the machine configuration and summarizes the measurements made and individual system performance

Codominant scoring of AFLP in association panels

A study on the codominant scoring of AFLP markers in association panels without prior knowledge on genotype probabilities is described. Bands are scored codominantly by fitting normal mixture models to band intensities, illustrating and optimizing existing methodology, which employs the EM-algorithm. We study features that improve the performance of the algorithm, and the unmixing in general, like parameter initialization, restrictions on parameters, data transformation, and outlier removal. Parameter restrictions include equal component variances, equal or nearly equal distances between component means, and mixing probabilities according to Hardy–Weinberg Equilibrium. Histogram visualization of band intensities with superimposed normal densities, and optional classification scores and other grouping information, assists further in the codominant scoring. We find empirical evidence favoring the square root transformation of the band intensity, as was found in segregating populations. Our approach provides posterior genotype probabilities for marker loci. These probabilities can form the basis for association mapping and are more useful than the standard scoring categories A, H, B, C, D. They can also be used to calculate predictors for additive and dominance effects. Diagnostics for data quality of AFLP markers are described: preference for three-component mixture model, good separation between component means, and lack of singletons for the component with highest mean. Software has been developed in R, containing the models for normal mixtures with facilitating features, and visualizations. The methods are applied to an association panel in tomato, comprising 1,175 polymorphic markers on 94 tomato hybrids, as part of a larger study within the Dutch Centre for BioSystems Genomics

Substrate cycling between de novo lipogenesis and lipid oxidation: a thermogenic mechanism against skeletal muscle lipotoxicity and glucolipotoxicity

Life is a combustion, but how the major fuel substrates that sustain human life compete and interact with each other for combustion has been at the epicenter of research into the pathogenesis of insulin resistance ever since Randle proposed a 'glucose-fatty acid cycle' in 1963. Since then, several features of a mutual interaction that is characterized by both reciprocality and dependency between glucose and lipid metabolism have been unravelled, namely: 1. the inhibitory effects of elevated concentrations of fatty acids on glucose oxidation (via inactivation of mitochondrial pyruvate dehydrogenase or via desensitization of insulin-mediated glucose transport), 2. the inhibitory effects of elevated concentrations of glucose on fatty acid oxidation (via malonyl-CoA regulation of fatty acid entry into the mitochondria), and more recently 3. the stimulatory effects of elevated concentrations of glucose on de novo lipogenesis, that is, synthesis of lipids from glucose (via SREBP1c regulation of glycolytic and lipogenic enzymes). This paper first revisits the physiological significance of these mutual interactions between glucose and lipids in skeletal muscle pertaining to both blood glucose and intramyocellular lipid homeostasis. It then concentrates upon emerging evidence, from calorimetric studies investigating the direct effect of leptin on thermogenesis in intact skeletal muscle, of yet another feature of the mutual interaction between glucose and lipid oxidation: that of substrate cycling between de novo lipogenesis and lipid oxidation. It is proposed that this energy-dissipating substrate cycling that links glucose and lipid metabolism to thermogenesis could function as a 'fine-tuning' mechanism that regulates intramyocellular lipid homeostasis, and hence contributes to the protection of skeletal muscle against lipotoxicity

Gene regulatory network reveals oxidative stress as the underlying molecular mechanism of type 2 diabetes and hypertension

<p>Abstract</p> <p>Background</p> <p>The prevalence of diabetes is increasing worldwide. It has been long known that increased rates of inflammatory diseases, such as obesity (OBS), hypertension (HT) and cardiovascular diseases (CVD) are highly associated with type 2 diabetes (T2D). T2D and/or OBS can develop independently, due to genetic, behavioral or lifestyle-related variables but both lead to oxidative stress generation. The underlying mechanisms by which theses complications arise and manifest together remain poorly understood. Protein-protein interactions regulate nearly every living process. Availability of high-throughput genomic data has enabled unprecedented views of gene and protein co-expression, co-regulations and interactions in cellular systems.</p> <p>Methods</p> <p>The present work, applied a systems biology approach to develop gene interaction network models, comprised of high throughput genomic and PPI data for T2D. The genes differentially regulated through T2D were 'mined' and their 'wirings' were studied to get a more complete understanding of the overall gene network topology and their role in disease progression.</p> <p>Results</p> <p>By analyzing the genes related to T2D, HT and OBS, a highly regulated gene-disease integrated network model has been developed that provides useful functional linkages among groups of genes and thus addressing how different inflammatory diseases are connected and propagated at genetic level. Based on the investigations around the 'hubs' that provided more meaningful insights about the cross-talk within gene-disease networks in terms of disease phenotype association with oxidative stress and inflammation, a hypothetical co-regulation disease mechanism model been proposed. The results from this study revealed that the oxidative stress mediated regulation cascade is the common mechanistic link among the pathogenesis of T2D, HT and other inflammatory diseases such as OBS.</p> <p>Conclusion</p> <p>The findings provide a novel comprehensive approach for understanding the pathogenesis of various co-associated chronic inflammatory diseases by combining the power of pathway analysis with gene regulatory network evaluation.</p

A Comparative Neuroanatomical Study of the Red Nucleus of the Cat, Macaque and Human

BACKGROUND:The human red nucleus (Nr) is comparatively less well-studied than that of cats or monkeys. Given the functional importance of reticular and midbrain structures in control of movement and locomotion as well as from an evolutionary perspective, we investigated the nature and extent of any differences in Nr projections to the olivary complex in quadrupedal and bipedal species. Using neuroanatomical tract-tracing techniques we developed a "neural sheet" hypothesis allowing us to propose how rubro-olivary relations differ among the three species. METHODS AND FINDINGS:Wheat germ agglutinin-horseradish peroxidase staining supports findings that the cat's nucleus accessories medialis of Bechtrew (NB) projects mainly to the lateral bend of the principal olive. We clarified boundaries among nucleus of Darkschewitsch (ND), NB and parvicellular red nucleus (pNr) of the cat's neural sheet. The macaque's ND-medial accessory olivary projection is rostro-caudally organized and the dorsomedial and ventrolateral parts of the macaque's pNr may project to the principal olive's rostral and caudal dorsal lamella; in cat it projects as well to pNr. Myelin- and Nissl-stained sections show that a well-developed dorsomedial part of the human Nr consists of densely packed cells, deriving small myelinated fibers that continue into the medial central tegmental tract. CONCLUSIONS:Based on these findings we suggest there are distinct bipedal-quadrupedal differences for Nr projections to the olivary complex. We propose the Nr of cats and monkeys comprise the ND, NB and pNr in a zonal sheet-like structure, retaining clear nuclear boundaries and an isolated, well-developed mNr. The human NB may be distinguished from its more specialised ND (ND lies alongside a well-developed pNr) in the human central gray. Phylogenetically, the NB may have been translocated into a roll-shaped Nr in the reticular formation, the dorsomedial portion of which might correspond to the cat's and monkey's NB