213国道,毁灭与抢通

都江堰至汶川的公路在地震后最初的"黄金72小时"里成了使全中国揪心的一条生命之路,它因穿过震中,而集各种罕见地质灾害于一身,遭受到毁灭性打击。三个月后这条公路被奇迹般地抢通。举世空前的经历,使它当然地拥有了遗产价值,成为一条地震遗迹与地震文化之路,记载着人类在与次生地质灾害的博弈中以性命换得的真知。     

Rescuing neurons in prion disease

One of the major current challenges to both medicine and neuroscience is the treatment of neurodegenerative diseases, which pose an ever-increasing medical, social and economic burden in the developed world. These disorders, which include Alzheimer's, Huntington's and Parkinson's diseases, and the rarer prion diseases, are separate entities clinically but have common features, including aggregates of misfolded proteins and varying patterns of neurodegeneration. A key barrier to effective treatment is that patients present clinically with advanced, irreversible, neuronal loss. Critically, mechanisms of neurotoxicity are poorly understood. Prevention of neuronal loss, ideally by targeting underlying pathogenic mechanisms, must be the aim of therapy. The present review describes the rationale and experimental approaches that have allowed such prevention, rescuing neurons in mice with prion disease. This rescue cured animals of a rapidly fatal neurodegenerative condition, resulting in symptom-free survival for their natural lifespan. Early pathological changes were reversed; behavioural, cognitive and neurophysiological deficits were recovered; and there was no neuronal loss. This was achieved by targeting the central pathogenic process in prion disease rather than the presumed toxic species, first by proof-of-principle experiments in transgenic mice and then by treatment using RNA interference for gene knockdown. The results have been a new therapeutic target for prion disease, further insight into mechanisms of prion neurotoxicity and the discovery of a window of reversibility in neuronal damage. Furthermore, the work gives rise to new concepts for treatment strategies for other neurodegenerative disorders, and highlights the need for clinical detection of early neuronal dysfunction, so that similar early rescue can also be achieved for these disorders.     

213国道，毁灭与抢通

都江堰至汶川的公路在地震后最初的“黄金72小时”里成了使全中国揪心的一条生命之路,它因穿过震中,而集各种罕见地质灾害于一身,遭受到毁灭性打击。三个月后这条公路被奇迹般地抢通。举世空前的经历,使它当然地拥有了遗产价值,成为一条地震遗迹与地震文化之路,记载着人类在与次生地质灾害的博弈中以性命换得的真知。     

Rescuing developing thymocytes from death by neglect

The major function of the thymus is to eliminate developing thymocytes that are potentially useless or autoreactive, and select only those that bear functional T cell antigen receptors (TCRs) through fastidious screening. It is believed that glucocorticoids (GCs) are at least in part responsible for cell death during death by neglect. In this review, we will mainly cover the topic of the GC-induced apoptosis of developing thymocytes. We will also discuss how thymocytes that are fated to die by GCs can be rescued from GC-induced apoptosis in response to a variety of signals with antagonizing properties for GC receptor (GR) signaling. Currently, a lot of evidence supports the notion that the decision is made as a result of the integration of the multiple signal transduction networks that are triggered by GR, TCR, and Notch. A few candidate molecules at the converging point of these multiple signaling pathyways will be discussed. We will particularly describe the role of the SRG3 protein as a potent modulator of GC-induced apoptosis in the crosstalk.     

Rescuing Loading Induced Bone Formation at Senescence

The increasing incidence of osteoporosis worldwide requires anabolic treatments that are safe, effective, and, critically, inexpensive given the prevailing overburdened health care systems. While vigorous skeletal loading is anabolic and holds promise, deficits in mechanotransduction accrued with age markedly diminish the efficacy of readily complied, exercise-based strategies to combat osteoporosis in the elderly. Our approach to explore and counteract these age-related deficits was guided by cellular signaling patterns across hierarchical scales and by the insight that cell responses initiated during transient, rare events hold potential to exert high-fidelity control over temporally and spatially distant tissue adaptation. Here, we present an agent-based model of real-time Ca²⁺/NFAT signaling amongst bone cells that fully described periosteal bone formation induced by a wide variety of loading stimuli in young and aged animals. The model predicted age-related pathway alterations underlying the diminished bone formation at senescence, and hence identified critical deficits that were promising targets for therapy. Based upon model predictions, we implemented an in vivo intervention and show for the first time that supplementing mechanical stimuli with low-dose Cyclosporin A can completely rescue loading induced bone formation in the senescent skeleton. These pre-clinical data provide the rationale to consider this approved pharmaceutical alongside mild physical exercise as an inexpensive, yet potent therapy to augment bone mass in the elderly. Our analyses suggested that real-time cellular signaling strongly influences downstream bone adaptation to mechanical stimuli, and quantification of these otherwise inaccessible, transient events in silico yielded a novel intervention with clinical potential.     

Rescuing yeast mutants with human genes.

The fission yeast Schizosaccharomyces pombe and the budding yeast Saccharomyces cerevisiae have, in addition to being extensively studied themselves, both been utilized for the last quarter century as experimental systems for the isolation of genes from other organisms. Mutations conferring growth defects in either of the two yeast strains have frequently been complemented by expression of cDNA libraries from heterologous species, often human. Many successful experiments have utilized available yeast mutations to allow successful complementation by a human gene, which can thus be deduced to have the same, or an overlapping function as the mutated yeast gene. However complementation in yeast has also been used with success to study two fields, apoptosis and steroid receptor signalling, which, at first glance, seem to be foreign to the yeast life cycle.     

Rescuing a destabilized protein fold through backbone cyclization

We describe the physicochemical characterization of various circular and linear forms of the approximately 60 residue N-terminal Src homology 3 (SH3) domain from the murine c-Crk adapter protein. Structural, dynamic, thermodynamic, kinetic and biochemical studies reveal that backbone circularization does not prevent the adoption of the natural folded structure in any of the circular proteins. Both the folding and unfolding rate of the protein increased slightly upon circularization. Circularization did not lead to a significant thermodynamic stabilization of the full-length protein, suggesting that destabilizing enthalpic effects (e.g. strain) negate the expected favorable entropic contribution to overall stability. In contrast, we find circularization results in a dramatic stabilization of a truncated version of the SH3 domain lacking a key glutamate residue. The ability to rescue the destabilized mutant indicates that circularization may be a useful tool in protein engineering programs geared towards generating minimized proteins.     

家蚕二分浓核病毒在家蚕细胞中的体外拯救

家蚕二分浓核病毒(Bombyx mori bidensovirus,Bm BDV)是特异性感染家蚕中肠引起慢性浓核病症的致病原,基因组含有2套单链DNA分子(VD1和VD2),复制机制尚不清楚。为了能够在体外拯救出有感染性的病毒粒子,构建了Bm BDV的基因组全长的克隆质粒p MD18T-VD1和p UC-VD2,并通过酶切构建的克隆质粒来获得双链的基因组片段VD1和VD2,利用脂质体包埋的方法,线性化共转染Bm N细胞。提取转染后的Bm N细胞总DNA,经去甲基化处理后,通过PCR检测到病毒基因的复制;提取转染后的Bm N细胞和添食回感的家蚕中肠的总蛋白,分别进行蛋白质印记杂交检测,检测到病毒基因的表达。由此首次表明,该病毒线性化的基因组片段通过共转染Bm N细胞的方法,可以在体外条件下拯救出具有感染性的病毒粒子。     

Eastern Suburbs Banksia Scrub: Rescuing an endangered ecological community

On‐ground works prove an important mechanism for gaining knowledge about this near‐extinct ecological community, providing new insights into ways to manage and restore it.     

Rescuing Rhythms from Noise: A New Method of Analysis

The analysis of a temporal series usually begins with a visual inspection of the raw data, from which a proper method for the detection of periodicities is chosen. Some of the methods currently used, as circular statistics, Cosinor, or spectral analyses, are useful when it comes to ascertain the existence of some periods, expected ‘a priori’ or to detect unknown frequencies. Even though some of the methods allow a wide scanning of possibilities, difficulties arise when signals are weak and concealed in larger amplitude noise. The register of the activity of a cave cricket, Strinatia brevipennis, under constant conditions, showed an intricate pattern of small peaks, interspersed with rare ones of much higher amplitudes. Attempts to analyse these data with the usual methods gave inconsistent results and sometimes did not detect rhythms. The results are mostly biased by the large amplitude components which hamper the detection of rhythms from weak signals. Schimmel and Paulssen (1997) proposed a noise-reduction method, which detects weak but coherent signals. This new tool was developed for the analysis of seismic data, being afterwards adapted to the analysis of temporal series of biological data. The method is called phase weighted stack (PWS) and performs a weighted summation of temporal series according to their coherence. The results are stacked time series which are cleaned up from incoherent noise, allowing the detection of weak signals that otherwise would be undistinguishable from noises. The method also enables the identification of the time (hour) of every periodic signal. The use of PWS in the analysis of cricketsÕ activity data cleared out frequencies, exposing a circadian component in all records.