A mutation in Sec15l1 causes anemia in hemoglobin deficit (hbd) mice

Hemoglobin deficit (hbd) mice carry a spontaneous mutation that impairs erythroid iron assimilation but does not cause other defects. Normal delivery of iron to developing erythroid precursors is highly dependent on the transferrin cycle. Through genetic mapping and complementation experiments, we show that the hbd mutation is an in-frame deletion of a conserved exon of the mouse gene Sec15l1, encoding one of two Sec15 proteins implicated in the mammalian exocyst complex. Sec15l1 is linked to the transferrin cycle through its interaction with Rab11, a GTPase involved in vesicular trafficking. We propose that inactivation of Sec15l1 alters recycling of transferrin cycle endosomes and increases the release of transferrin receptor exocytic vesicles. This in turn decreases erythroid iron uptake. Determining the molecular basis of the hbd phenotype provides new insight into the intricate mechanisms necessary for normal erythroid iron uptake and the function of a mammalian exocyst protein.     

Soil-site relationships of white locoweed on the Raft River Mountains

White locoweed ( Oxytropis sericea Nutt.) is restricted to the top and windswept ridges of the Raft River Mountains. Elevation and soil characteristics have the greatest effect on its occurrence. It is most abundant on the subalpine windswept ridge ecological site (9.2 plants/m 2 ) above 2,380 m. White locoweed apparently can tolerate the extreme environmental stresses of the shallow, rocky, windswept ridges where it is one of the dominant species. White locoweed also occurs in the deep, subalpine loam site (3.8 plants/m 2 ) above 2,865 m, but it is a minor component of this plant community. It is apparently less competitive on the deeper soils, and its population fluctuates more. It exhibits an opportunistic survival strategy on the subalpine loam site by having a large reserve of viable seeds in the soil ready to germinate and establish when environmental conditions are favorable, and then declines with competition from more robust species.     

A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response

Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored. Here we use genetically engineered mouse models to conduct a 'co-clinical' trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies.     

Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation

We used resequencing and genotyping in African Americans with sickle cell anemia (SCA) to characterize associations with fetal hemoglobin (HbF) levels at the BCL11A, HBS1L-MYB and β-globin loci. Fine-mapping of HbF association signals at these loci confirmed seven SNPs with independent effects and increased the explained heritable variation in HbF levels from 38.6% to 49.5%. We also identified rare missense variants that causally implicate MYB in HbF production.     

人体生理、物理因素对血管结构和功能的影响

大动脉血管功能测定越来越多的被用作预测心血管疾病的替代指标，然而非常重要的是需要确定非病理因素是否可能影响到这些测量参数。对年龄、身高、体重指数、心率和血压等生理因素与脉搏波速度（PWV）、系统动脉顺应性（SAC）、中心动脉压增加指数（AI）和颈动脉壁内中膜厚度（IMT）之间的相关性和影响进行评估。共选择285个正常志愿，其中男性98例，女性187例，年龄50-82岁。结果经年龄校正后，脉搏波速度、系统动脉顺应性、颈动脉壁内中膜厚度和中心动脉压增加指数有显的性别差异。系统动脉顺应性、中心动脉压增加指数与高度相关，而且此相关在性别上有明显差异。经年龄和性别校正后身体体重指数与SAC正相关，与AI负相关。经年龄、性别和身高校正后，脉搏波速度、中心动脉压增加指数与心率、中心脉压差呈显地直线相关。这些结果可能意味着与心血管功能障碍的相关性：对矮身材的人来说，大动脉顺应性地降低和中心压力附加值的增大是增加其心血管危险因素的潜在的生理因素；对于老年人来说，缓慢心率可能导致潜在的反效果即中心静脉压的增加。