X chromosome aneuploidies have long been associated with human cancers, but causality has not been established. In mammals, X chromosome inactivation (XCI) is triggered by Xist RNA to equalize gene ...expression between the sexes. Here we delete Xist in the blood compartment of mice and demonstrate that mutant females develop a highly aggressive myeloproliferative neoplasm and myelodysplastic syndrome (mixed MPN/MDS) with 100% penetrance. Significant disease components include primary myelofibrosis, leukemia, histiocytic sarcoma, and vasculitis. Xist-deficient hematopoietic stem cells (HSCs) show aberrant maturation and age-dependent loss. Reconstitution experiments indicate that MPN/MDS and myelofibrosis are of hematopoietic rather than stromal origin. We propose that Xist loss results in X reactivation and consequent genome-wide changes that lead to cancer, thereby causally linking the X chromosome to cancer in mice. Thus, Xist RNA not only is required to maintain XCI but also suppresses cancer in vivo.
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► Deleting Xist causes blood cancer ► Overdosage of the X chromosome causes cancer ► Xist is required for hematopoietic stem cell survival and function ► Deleting Xist causes marrow fibrosis, leukemia, and histiocytic sarcoma
Deletion of Xist in the blood cells of female mice causes an aggressive and highly penetrant hematopoietic cancer.
Soybean hulls are a by-product of soybean processing for oil and meal production; Pleurotus eryngii stalk residues (PE SR) are by-products of the edible portion of the fruiting body enriched in ...bioactive metabolites. This study evaluated the effects of co-fermented PE SR and soybean hulls with Aureobasidium pullulans on performance and intestinal morphology in broiler chickens. The in vitro experimental results showed that xylananse and mannanase activity of solid-state fermented soybean hulls (100% SBH) and soybean hulls partially replaced with PE SR (75:25, SHP) reached peak at day 12; solid-state fermentation (SSF) enhanced the total phenolic content and trolox equivalency in both products as well. Additionally, FSHP had higher xylotriose and mannobiose levels than fermented FSBH did. A total of 400 broilers (Ross 308) were assigned randomly into four groups receiving the basal diet (control) or the basal diet supplemented with 0.5% fermented SBH (0.5% FSBH), 0.5% fermented SBHP (0.5% FSHP) and 1.0% fermented SBHP (1.0% FSHP) until 35 d of age, respectively. Results demonstrated that 0.5% FSHP addition increased body weight gain as compared with corresponding normal diet fed control in birds during entire experimental period. Compared with the control group, 0.5% FSHP group significantly increased the ratio of lactic acid bacteria to Clostridium perfringens in ceca as well as ileum villus height and jejunum villus height/crypt depth ratio of 35 d old birds. In conclusion, 0.5% FSHP supplementation in the diet could obtain not only improved body weight gain, but optimal intestinal morphology by exerting its bioactive metabolite properties when fed to broilers.
Spinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide ...drug that modifies pre-messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein.
We conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis.
In the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants 41% vs. 0 of 27 0%, P<0.001), and this result prompted early termination of the trial. In the final analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (37 of 73 infants 51% vs. 0 of 37 0%), and the likelihood of event-free survival was higher in the nusinersen group than in the control group (hazard ratio for death or the use of permanent assisted ventilation, 0.53; P=0.005). The likelihood of overall survival was higher in the nusinersen group than in the control group (hazard ratio for death, 0.37; P=0.004), and infants with a shorter disease duration at screening were more likely than those with a longer disease duration to benefit from nusinersen. The incidence and severity of adverse events were similar in the two groups.
Among infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug. (Funded by Biogen and Ionis Pharmaceuticals; ENDEAR ClinicalTrials.gov number, NCT02193074 .).
Silicon is an attractive material for anodes in energy storage devices, because it has ten times the theoretical capacity of its state-of-the-art carbonaceous counterpart. Silicon anodes can be used ...both in traditional lithium-ion batteries and in more recent Li-O2 and Li-S batteries as a replacement for the dendrite-forming lithium metal anodes. The main challenges associated with silicon anodes are structural degradation and instability of the solid-electrolyte interphase caused by the large volume change (∼300%) during cycling, the occurrence of side reactions with the electrolyte, and the low volumetric capacity when the material size is reduced to a nanometre scale. Here, we propose a hierarchical structured silicon anode that tackles all three of these problems. Our design is inspired by the structure of a pomegranate, where single silicon nanoparticles are encapsulated by a conductive carbon layer that leaves enough room for expansion and contraction following lithiation and delithiation. An ensemble of these hybrid nanoparticles is then encapsulated by a thicker carbon layer in micrometre-size pouches to act as an electrolyte barrier. As a result of this hierarchical arrangement, the solid-electrolyte interphase remains stable and spatially confined, resulting in superior cyclability (97% capacity retention after 1,000 cycles). In addition, the microstructures lower the electrode-electrolyte contact area, resulting in high Coulombic efficiency (99.87%) and volumetric capacity (1,270 mAh cm(-3)), and the cycling remains stable even when the areal capacity is increased to the level of commercial lithium-ion batteries (3.7 mAh cm(-2)).
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