OXPHOS Inhibition via LUC7L2 as a Target for SF3B1-Mutant Myelodysplastic Syndrome

SF3B1 gene mutations are the most common spliceosome mutations seen in myelodysplastic syndrome (MDS) patients. Though it is well known SF3B1 mutations cause downstream changes in erythroid differentiation and the cell cycle, which leads to malignancy, metabolic changes arising from this mutation are unknown. We conducted RNA sequencing from SF3B1-mutant MDS patient samples and found several genes related to metabolism were alternatively spliced. Of these, LUC7L2 was selected as our target as previous studies show its involvement in promoting oxidative phosphorylation (OXPHOS) via various downstream mechanisms when knocked down.We show that OXPHOS is increased in MOLM-13 myeloid malignant cells when LUC7L2 is inhibited. The results suggested that this gene, which is alternatively spliced and shows lower expression in SF3B1-mutant MDS, increases myeloid malignant dependence on OXPHOS

DISEÑO DE UN DEMODULADOR DE FM MEDIANTE PLL PARA LA INTERROGACIÓN DE SENSORES INTERFEROMÉTRICOS DE FIBRA ÓPTICA

ResumenEn este trabajo se diseñó y se construyó un sistema de interrogación de sensores interferométricos. El sistema está constituido por una etapa que emula la señal interferométrica típica de un sensor de este tipo: Primeramente, una etapa de acondicionamiento que convierte esta señal en una señal de FM convencional y finalmente una etapa de demodulación de frecuencia; mediante el uso de la técnica de amarre de fase PLL, (del inglés: Phase Lock Loop). El proceso de demodulación, denominado en la literatura como “heterodino sintético”, utiliza un par de osciladores locales sintonizados a la frecuencia de la señal portadora y al doble de ésta. Así mismo, se requirieron una serie de filtros pasabanda tipo Butterworth de segundo orden para acotar el espectro de las señales de interés centrados en la frecuencia de la armónica necesaria para realizar el proceso de mezclado. Finalmente, la señal acondicionada se usó como entrada a un demodulador de FM mediante un PLL. Se consiguió recuperar señales del orden de miliradianes en el rango de 90 a 260 Hz. Se observó que este rango dependió del ancho de banda de los filtros pasabanda utilizados en el circuito. Se optó por esta técnica de demodulación basada en un PLL, pues logra la sintonización de una amplia gama de frecuencias, al ser también sintonizable el PLL a través de su VCO.Palabras Claves: Demoduladores de FM, fase óptica, sensores interferométricos, PLL. DESIGN OF AN FM DEMODULATOR THROUGH PLL FOR THE INTERROGATION OF OPTICAL FIBER INTERFEROMETRIC SENSORSAbstractIn this work, an interrogation system of interferometric sensors was designed and constructed. The system consists of a stage emulating the interferometric signal typical of such sensor: First a conditioning stage that converts the above signal into a conventional FM signal and finally a frequency demodulation stage, based in the Phase Lock Loop technique o demodulate FM signals (PLL). The demodulation process used here, referred in the literature as "synthetic heterodyne", uses a pair of local oscillators, one tuned to the frequency of the carrier signal and the other one tuned at twice of the carrier frequency. It also requires a series of second-order Butterworth bandpass filters to limit the signals of interest and maintain a constant amplitude in the passband. As well as a trimmer to minimize the amplitude changes, in the final part of the conditioning stage. Finally, the conditioned signal was used as input to an FM demodulator via a PLL and signals of the order of miliradianes were achieved; with frequencies of modulating signals in the range of 90 to 260 Hz. It was observed that this range depended on the bandwidth of the bandpass filters used in the circuit.Keywords: FM demodulators, Interferometric sensors, optical phase, PLL

Resonant Spin-Flavor Conversion of Supernova Neutrinos and Deformation of the Electron Antineutrino Spectrum

The neutrino spin-flavor conversion of \bar\nu_e and \nu_\mu which is induced by the interaction of the Majorana neutrino magnetic moment and magnetic fields in the collapse-driven supernova is investigated in detail. We calculate the conversion probability by using the latest precollapse models of Woosley and Weaver (1995), and also those of Nomono and Hashimoto (1988), changing the stellar mass and metallicity in order to estimate the effect of the astrophysical uncertainties. Contour maps of the conversion probability are given for all the models as a function of neutrino mass squared difference and the neutrino magnetic moment times magnetic fields. It is shown that in the solar metallicity models some observational effects are expected with \Delta m^2 = 10^{-5}--10^{-1} [eV^2] and \mu_\nu >~ 10^{-12} (10^9 G / B_0) [\mu_B], where B_0 is the strength of the magnetic fields at the surface of the iron core. We also find that although the dependence on the stellar models or stellar mass is not so large, the metallicity of precollapse stars has considerable effects on this conversion. Such effects may be seen in a supernova in the Large or Small Magellanic Clouds, and should be taken into account when one considers an upper bound on \mu_\nu from the SN1987A data.Comment: 19 pages, LaTeX, using revtex. To appear in Phys. Rev. D. 16 figures attatche

Simultaneous free-volume modeling of the self-diffusion coefficient and dynamic viscosity at high pressure

International audienceA free-volume model of the dynamic viscosity and the self-diffusion coefficients was discussed. The temperature-pressure variations of the dynamic viscosity and the self-diffusion coefficients of small molecules were predicted. The compounds, carbon tetrachloride, cyclohexane, benzene, chlorotrifluoromethane, tetramethylsilane and methylcyclohexane were used for the investigation. The relation between microstructure, free volume and different complex thermophysical properties were emphasized by the model

Pre-Conceptual Design of a Fluoride-Salt-Cooled Small Modular Advanced High Temperature Reactor (SmAHTR)

This document presents the results of a study conducted at Oak Ridge National Laboratory during 2010 to explore the feasibility of small modular fluoride salt-cooled high temperature reactors (FHRs). A preliminary reactor system concept, SmATHR (for Small modular Advanced High Temperature Reactor) is described, along with an integrated high-temperature thermal energy storage or salt vault system. The SmAHTR is a 125 MWt, integral primary, liquid salt cooled, coated particle-graphite fueled, low-pressure system operating at 700 C. The system employs passive decay heat removal and two-out-of-three , 50% capacity, subsystem redundancy for critical functions. The reactor vessel is sufficiently small to be transportable on standard commercial tractor-trailer transport vehicles. Initial transient analyses indicated the transition from normal reactor operations to passive decay heat removal is accomplished in a manner that preserves robust safety margins at all times during the transient. Numerous trade studies and trade-space considerations are discussed, along with the resultant initial system concept. The current concept is not optimized. Work remains to more completely define the overall system with particular emphasis on refining the final fuel/core configuration, salt vault configuration, and integrated system dynamics and safety behavior

Adherence to recommendations by infectious disease consultants and its influence on outcomes of intravenous antibiotic-treated hospitalized patients

BACKGROUND: Consultation to infectious diseases specialists (ID), although not always performed by treating physicians, is part of hospital's daily practice. This study analyses adherence by treating physicians to written ID recommendations (inserted in clinical records) and its effect on outcome in hospitalized antibiotic-treated patients in a tertiary hospital in Spain. METHODS: A prospective, randomized, one-year study was performed. Patients receiving intravenous antimicrobial therapy prescribed by treating physicians for 3 days were identified and randomised to intervention (insertion of written ID recommendations in clinical records) or non-intervention. Appropriateness of empirical treatments (by treating physicians) was classified as adequate, inadequate or unnecessary. In the intervention group, adherence to recommendations was classified as complete, partial or non-adherence. RESULTS: A total of 1173 patients were included, 602 in the non-intervention and 571 in the intervention group [199 (34.9%) showing complete adherence, 141 (24.7%) partial adherence and 231 (40.5%) non-adherence to recommendations]. In the multivariate analysis for adherence (R2 Cox=0.065, p=0.009), non-adherence was associated with prolonged antibiotic prophylaxis (p=0.004; OR=0.37, 95%CI=0.19-0.72). In the multivariate analysis for clinical failure (R2 Cox=0.126, p<0.001), Charlson index (p<0.001; OR=1.19, 95%CI=1.10-1.28), malnutrition (p=0.006; OR=2.00, 95%CI=1.22-3.26), nosocomial infection (p<0.001; OR=4.12, 95%CI=2.27-7.48) and length of hospitalization (p<0.001; OR=1.01, 95%CI=1.01-1.02) were positively associated with failure, while complete adherence (p=0.001; OR=0.35, 95%CI=0.19-0.64) and adequate initial treatment (p=0.010; OR=0.39, 95%CI=0.19-0.80) were negatively associated. CONCLUSIONS: Adherence to ID recommendations by treating physicians was associated with favorable outcome, in turn associated with shortened length of hospitalization. This may have important health-economic benefits and stimulates further investigation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN83234896. http://www.controlled-trials.com/isrctn/sample_documentation.asp

Proteomic Analysis of the Cyst Stage of Entamoeba histolytica

We used tandem mass spectrometry to identify E. histolytica cyst proteins in 5 cyst positive stool samples. We report the identification of 417 non-redundant E. histolytica proteins including 195 proteins that were not identified in existing trophozoite derived proteome or EST datasets, consistent with cyst specificity. Because the cysts were derived directly from patient samples with incomplete purification, a limited number of proteins were identified (N = 417) that probably represent only a partial proteome. Nevertheless, the study succeeded in identifying proteins that are likely to be abundant in the cyst stage of the parasite. Several of these proteins may play roles in E. histolytica stage conversion or cyst function. Proteins identified in this study may be useful markers for diagnostic detection of E. histolytica cysts. Overall, the data generated in this study promises to aid the understanding of the cyst stage of the parasite which is vital for disease transmission and pathogenesis in E. histolytica

<i>Trypanosoma brucei</i> DHRF-TS revisited:characterisation of a bifunctional and highly unstable recombinant dihydrofolate reductase-thymidylate synthase

<div><p>Bifunctional dihydrofolate reductase–thymidylate synthase (DHFR-TS) is a chemically and genetically validated target in African trypanosomes, causative agents of sleeping sickness in humans and nagana in cattle. Here we report the kinetic properties and sensitivity of recombinant enzyme to a range of lipophilic and classical antifolate drugs. The purified recombinant enzyme, expressed as a fusion protein with elongation factor Ts (Tsf) in ThyA^- <i>Escherichia coli</i>, retains DHFR activity, but lacks any TS activity. TS activity was found to be extremely unstable (half-life of 28 s) following desalting of clarified bacterial lysates to remove small molecules. Stability could be improved 700-fold by inclusion of dUMP, but not by other pyrimidine or purine (deoxy)-nucleosides or nucleotides. Inclusion of dUMP during purification proved insufficient to prevent inactivation during the purification procedure. Methotrexate and trimetrexate were the most potent inhibitors of DHFR (<i>K</i>_i 0.1 and 0.6 nM, respectively) and FdUMP and nolatrexed of TS (<i>K</i>_i 14 and 39 nM, respectively). All inhibitors showed a marked drop-off in potency of 100- to 1,000-fold against trypanosomes grown in low folate medium lacking thymidine. The most potent inhibitors possessed a terminal glutamate moiety suggesting that transport or subsequent retention by polyglutamylation was important for biological activity. Supplementation of culture medium with folate markedly antagonised the potency of these folate-like inhibitors, as did thymidine in the case of the TS inhibitors raltitrexed and pemetrexed.</p></div