Bestrophin1 Channels are Insensitive to Ethanol and Do not Mediate Tonic GABAergic Currents in Cerebellar Granule Cells

The granule cell layer of the cerebellum functions in spatio-temporal encoding of information. Granule cells (GCs) are tonically inhibited by spillover of GABA released from Golgi cells and this tonic inhibition is facilitated by acute ethanol. Recently, it was demonstrated that a specialized Ca2+-activated anion-channel, bestrophin1 (Best1), found on glial cells, can release GABA that contributes up to 50–75% of the tonic GABAergic current. However, it is unknown if ethanol has any actions on Best1 function. Using whole-cell electrophysiology, we found that recombinant Best1 channels expressed in HEK-293 cells were insensitive to 40 and 80 mM ethanol. We attempted to measure the Best1-mediated component of the tonic current in slices using 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB). We confirmed that this agent blocks recombinant Best1 channels. Unexpectedly, we found that NPPB significantly potentiated the tonic current and the area and decay of GABAA-mediated spontaneous inhibitory post-synaptic currents (IPSCs) in GCs in rodent slices under two different recording conditions. To better isolate the Best1-dependent tonic current component, we blocked the Golgi cell component of the tonic current with tetrodotoxin and found that NPPB similarly and significantly potentiated the tonic current amplitude and decay time of miniature IPSCs. Two other Cl−-channel blockers were also tested: 4′-diisothiocyanatostilbene-2,2′-disulfonic acid disodium salt hydrate (DIDS) showed no effect on GABAergic transmission, while niflumic acid (NFA) significantly suppressed the tonic current noise, as well as the mIPSC frequency, amplitude, and area. These data suggest that acute ethanol exposure does not modulate Best1 channels and these findings serve to challenge recent data indicating that these channels participate in the generation of tonic GABAergic currents in cerebellar GCs

Stable Isotope Analysis of the Inca Mummy from Nevado de Chuscha (Salta, Argentina)

This paper presents the carbon (13C/12C), nitrogen (15N/14N), oxygen (18O/16O), hydrogen (2H/1H) and sulfur (34S/32S) stable isotope values measured in the hair of a female individual from north-western Argentina. The analysis of segments of this tissue allows for the recording of the diet and migratory changes with a short time resolution. The sample is from a mummified young female individual discovered in Chuscha mount, Salta province. It was found at more than 5000 masl, in a mountain sanctuary of the Inca expansion (capacochas). The paper discusses the paleodiet and mobility patterns of this individual in the period before her death, focusing on the isotopic variations in a limited time scale. The results indicate that the individual moved from a different region to the place where she was sacrificed. Furthermore, in the last year the individual was alive, a shift in the isotopic composition of the food consumed is detected: a variation in the importance of C4 over C3 resources is evident. The results are compared with the isotopic estimations for other children and young people recovered in archaeological contexts associated with capacochas to infer variability in the geographical trajectories covered during their last months of life.Fil: Killian Galván, Violeta Anahí. Universidad de Buenos Aires. Facultad de Filosofía y Letras. Instituto Interdisciplinario Tilcara; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Tessone, Augusto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Geocronología y Geología Isotópica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Geocronología y Geología Isotópica; ArgentinaFil: Valenzuela, Luciano Oscar. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Sociales. Departamento de Arqueología. Laboratorio de Ecología Evolutiva Humana (Sede Quequén); Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Sharp, Z. D.. Universidad de Nuevo México.; Estados UnidosFil: Panarello, Hector Osvaldo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Geocronología y Geología Isotópica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Geocronología y Geología Isotópica; Argentin

Blinatumomab vs historical standard therapy of adult relapsed/refractory acute lymphoblastic leukemia

We compared outcomes from a single-arm study of blinatumomab in adult patients with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia (R/R ALL) with a historical data set from Europe and the United States. Estimates of complete remission (CR) and overall survival (OS) were weighted by the frequency distribution of prognostic factors in the blinatumomab trial. Outcomes were also compared between the trial and historical data using propensity score methods. The historical cohort included 694 patients with CR data and 1112 patients with OS data compared with 189 patients with CR and survival data in the blinatumomab trial. The weighted analysis revealed a CR rate of 24% (95% CI: 20-27%) and a median OS of 3.3 months (95% CI: 2.8-3.6) in the historical cohort compared with a CR/CRh rate of 43% (95% CI: 36-50%) and a median OS of 6.1 months (95% CI: 4.2-7.5) in the blinatumomab trial. Propensity score analysis estimated increased odds of CR/CRh (OR=2.68, 95% CI: 1.67-4.31) and improved OS (HR=0.536, 95% CI: 0.394-0.730) with blinatumomab. The analysis demonstrates the application of different study designs and statistical methods to compare novel therapies for R/R ALL with historical data

Effect of Sweet Wormwood Artemisia annua Crude Leaf Extracts on Some Biological and Physiological Characteristics of the Lesser Mulberry Pyralid, Glyphodes pyloalis

The lesser mulberry pyralid, Glyphodes pyloalis Walker (Lepidoptera: Pyralidae) is a monophagous and dangerous pest of mulberry that has been recently observed in Guilan province, northern Iran. In this study, the crude methanol extract of sweet wormwood Artemisia annua L. (Asterales: Asteracaea) was investigated on toxicity, biological and physiological characteristics of this pest under controlled conditions (24 ± 1 °C, 75 ± 5% RH, and 16:8 L:D photoperiod). The effect of acute toxicity and sublethal doses on physiological characteristics was performed by topical application. The LC50 and LC20 values on fourth instar larvae were calculated as 0.33 and 0.22 gram leaf equivalent/ mL, respectively. The larval duration of fifth instar larvae in LC50 treatment was prolonged (5.8 ± 0.52 days) compared with the control group (4.26 ± 0.29 days). However larval duration was reduced in the LC20 treatment. The female adult longevity in the LC50 dose was the least (4.53 ± 0.3 days), while longevity among controls was the highest (9.2 ± 0.29 days). The mean fecundity of adults after larval treatment with LC50 was recorded as 105.6 ± 16.84 eggs/female, while the control was 392.74 ± 22.52 eggs/female. The percent hatchability was reduced in all treatments compared with the control. The effect of extract in 0.107, 0.053, 0.026 and 0.013 gle/mL on biochemical characteristics of this pest was also studied. The activity of α-amylase and protease 48 hours post—treatment was significantly reduced compared with the control. Similarly lipase, esterase, and glutathione S-transferase activity were significantly affected by A. annua extract

Identity-by-descent filtering as a tool for the identification of disease alleles in exome sequence data from distant relatives

Large-scale, deep resequencing may be the next logical step in the genetic investigation of common complex diseases. Because each individual is likely to carry many thousands of variants, the identification of causal alleles requires an efficient strategy to reduce the number of candidate variants. Under many genetic models, causal alleles can be expected to reside within identity-by-descent (IBD) regions shared by affected relatives. In distant relatives, IBD regions constitute a small portion of the genome and can thus greatly reduce the search space for causal alleles. However, the effectiveness of this strategy is unknown. We test the simulated mini-exome data set in extended pedigrees provided by Genetic Analysis Workshop 17. At the fourth- and fifth-degree level of relatedness, case-case pairs shared between 1% and 9% of the genome identical by descent. As expected, no genes were shared identical by descent by all case subjects, but 43 genes were shared by many case subjects across at least 50 replicates. We filtered variants in these genes based on population frequency, function, informativeness, and evidence of association using the family-based association test. This analysis highlighted five genes previously implicated in triglyceride, lipid, and cholesterol metabolism. Comparison with the list of true risk alleles revealed that strict IBD filtering followed by association testing of the rarest alleles was the most sensitive strategy. IBD filtering may be a useful strategy for narrowing down the list of candidate variants in exome data, but the optimal degree of relatedness of affected pairs will depend on the genetic architecture of the disease under study