Predictive thresholds for plague in Kazakhstan

In Kazakhstan and elsewhere in central Asia, the bacterium Yersinia pestis circulates in natural populations of gerbils, which are the source of human cases of bubonic plague. Our analysis of field data collected between 1955 and 1996 shows that plague invades, fades out, and reinvades in response to fluctuations in the abundance of its main reservoir host, the great gerbil (Rhombomys opimus). This is a rare empirical example of the two types of abundance thresholds for infectious disease-invasion and persistence- operating in a single wildlife population. We parameterized predictive models that should reduce the costs of plague surveillance in central Asia and thereby encourage its continuance.     

Cartilage acidic protein-1B (LOTUS), an endogenous Nogo receptor antagonist for axon tract formation

Neural circuitry formation depends on the molecular control of axonal projection during development. By screening with fluorophore-assisted light inactivation in the developing mouse brain, we identified cartilage acidic protein-1B as a key molecule for lateral olfactory tract (LOT) formation and named it LOT usher substance (LOTUS). We further identified Nogo receptor-1 (NgR1) as a LOTUS-binding protein. NgR1 is a receptor of myelin-derived axon growth inhibitors, such as Nogo, which prevent neural regeneration in the adult. LOTUS suppressed Nogo-NgR1 binding and Nogo-induced growth cone collapse. A defasciculated LOT was present in lotus-deficient mice but not in mice lacking both lotus- and ngr1. These findings suggest that endogenous antagonism of NgR1 by LOTUS is crucial for normal LOT formation.     

RH 5849, a Nonsteroidal Ecdysone Agonist: Effects on Larval Lepidoptera

The ecdysone agonist RH 5849 (1,2-dibenzoyl-1-tert-butylhydrazine) causes the premature initiation of molting at all stages of larval development of the tobacco hornworm, Manduca sexta. This phenomenon occurs without an increase in the endogenous ecdysone (20-hydroxyecdysone) titers. RH 5849 likewise provokes the initiation of molting in larval abdomens in the absence of a source of endogenous hormone. Although substantially less active than 20-hydroxyecdysone in vitro, RH 5849 was 30 to >670 times as active as the authentic molting hormone in bioassays with isolated larval abdomens or intact hornworms. This reversal in potency can be attributed to the superior transport properties and metabolic stability of RH 5849 relative to 20-hydroxyecdysone. Thus RH 5849 and its analogs are relatively persistent ecdysone agonists that halt feeding in larval lepidoptera by forcing an ultimately lethal, developmentally premature molt.     

Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's disease

The sirtuins are members of the histone deacetylase family of proteins that participate in a variety of cellular functions and play a role in aging. We identified a potent inhibitor of sirtuin 2 (SIRT2) and found that inhibition of SIRT2 rescued alpha-synuclein toxicity and modified inclusion morphology in a cellular model of Parkinson's disease. Genetic inhibition of SIRT2 via small interfering RNA similarly rescued alpha-synuclein toxicity. Furthermore, the inhibitors protected against dopaminergic cell death both in vitro and in a Drosophila model of Parkinson's disease. The results suggest a link between neurodegeneration and aging.     

Yeast Rtt109 promotes genome stability by acetylating histone H3 on lysine 56

Posttranslational modifications of the histone octamer play important roles in regulating responses to DNA damage. Here, we reveal that Saccharomyces cerevisiae Rtt109p promotes genome stability and resistance to DNA-damaging agents, and that it does this by functionally cooperating with the histone chaperone Asf1p to maintain normal chromatin structure. Furthermore, we show that, as for Asf1p, Rtt109p is required for histone H3 acetylation on lysine 56 (K56) in vivo. Moreover, we show that Rtt109p directly catalyzes this modification in vitro in a manner that is stimulated by Asf1p. These data establish Rtt109p as a member of a new class of histone acetyltransferases and show that its actions are critical for cell survival in the presence of DNA damage during S phase.     

甜瓜属野生种及其与黄瓜种间杂交后代抗根结线虫初步研究

为了鉴定甜瓜属野生种酸黄瓜 (CucumishystrixChakr.)对南方根结线虫 [Meloidogyneincognit(Kofoid&White)Chit wood]的抗性 ,进而评估抗性向酸黄瓜与栽培黄瓜种间杂种的转移 ,选用了酸黄瓜、 4个栽培黄瓜材料、两种倍性水平的 3个正反交杂种F1和 1个回交后代作为试材 ,在温室中进行抗性鉴定和筛选。结果表明 ,酸黄瓜对南方根结线虫具有高度抗性 ,而 4个栽培黄瓜材料均为高度敏感。酸黄瓜平均每株根系形成约 3个根结 ,栽培黄瓜材料每株根系的根结数超过 10 0个。酸黄瓜通过与栽培黄瓜的正反交 ,其抗性已被部分转移到杂种之中。当杂种作为供体亲本与栽培黄瓜进行回交时 ,抗性又被进一步转移到回交一代 (BCF1)中     

Inactivation of TNF signaling by rationally designed dominant-negative TNF variants

Tumor necrosis factor (TNF) is a key regulator of inflammatory responses and has been implicated in many pathological conditions. We used structure-based design to engineer variant TNF proteins that rapidly form heterotrimers with native TNF to give complexes that neither bind to nor stimulate signaling through TNF receptors. Thus, TNF is inactivated by sequestration. Dominant-negative TNFs represent a possible approach to anti-inflammatory biotherapeutics, and experiments in animal models show that the strategy can attenuate TNF-mediated pathology. Similar rational design could be used to engineer inhibitors of additional TNF superfamily cytokines as well as other multimeric ligands.     

A zinc clasp structure tethers Lck to T cell coreceptors CD4 and CD8

The T cell coreceptors CD4 and CD8 both associate via their cytoplasmic tails with the N-terminus of the Src-family tyrosine kinase Lck. These interactions require zinc and are critical for T cell development and activation. We examined the folding and solution structures of ternary CD4-Lck-Zn2+ and CD8alpha-Lck-Zn2+ complexes. The coreceptor tails and the Lck N-terminus are unstructured in isolation but assemble in the presence of zinc to form compactly folded heterodimeric domains. The cofolded complexes have similar "zinc clasp" cores that are augmented by distinct structural elements. A dileucine motif required for clathrin-mediated endocytosis of CD4 is masked by Lck.     

Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia

Very rare cases of human T cell acute lymphoblastic leukemia (T-ALL) harbor chromosomal translocations that involve NOTCH1, a gene encoding a transmembrane receptor that regulates normal T cell development. Here, we report that more than 50% of human T-ALLs, including tumors from all major molecular oncogenic subtypes, have activating mutations that involve the extracellular heterodimerization domain and/or the C-terminal PEST domain of NOTCH1. These findings greatly expand the role of activated NOTCH1 in the molecular pathogenesis of human T-ALL and provide a strong rationale for targeted therapies that interfere with NOTCH signaling.     

Extinct 244Pu in ancient zircons

We have found evidence, in the form of fissiogenic xenon isotopes, for in situ decay of 244Pu in individual 4.1- to 4.2-billion-year-old zircons from the Jack Hills region of Western Australia. Because of its short half-life, 82 million years, 244Pu was extinct within 600 million years of Earth's formation. Detrital zircons are the only known relics to have survived from this period, and a study of their Pu geochemistry will allow us to date ancient metamorphic events and determine the terrestrial Pu/U ratio for comparison with the solar ratio.