Rapid strengthening of thalamo-amygdala synapses mediates cue-reward learning

What neural changes underlie individual differences in goal-directed learning? The lateral amygdala (LA) is important for assigning emotional and motivational significance to discrete environmental cues, including those that signal rewarding events. Recognizing that a cue predicts a reward enhances an animal's ability to acquire that reward; however, the cellular and synaptic mechanisms that underlie cue-reward learning are unclear. Here we show that marked changes in both cue-induced neuronal firing and input-specific synaptic strength occur with the successful acquisition of a cue-reward association within a single training session. We performed both in vivo and ex vivo electrophysiological recordings in the LA of rats trained to self-administer sucrose. We observed that reward-learning success increased in proportion to the number of amygdala neurons that responded phasically to a reward-predictive cue. Furthermore, cue-reward learning induced an AMPA (alpha-amino-3-hydroxy-5-methyl-isoxazole propionic acid)-receptor-mediated increase in the strength of thalamic, but not cortical, synapses in the LA that was apparent immediately after the first training session. The level of learning attained by individual subjects was highly correlated with the degree of synaptic strength enhancement. Importantly, intra-LA NMDA (N-methyl-d-aspartate)-receptor blockade impaired reward-learning performance and attenuated the associated increase in synaptic strength. These findings provide evidence of a connection between LA synaptic plasticity and cue-reward learning, potentially representing a key mechanism underlying goal-directed behaviour.     

Synthesis and medical applications of oligosaccharides

Our understanding of the different glycoconjugates present on cells, proteins and entire organisms is lagging far behind advances in genomics and proteomics. Carbohydrate sequencing and the synthesis of defined oligosaccharides are two key technologies that have contributed to progress in glycomics research. Synthetic tools and high-throughput experiments such as carbohydrate arrays are beginning to affect biological research. These techniques are now being applied to the development of carbohydrate-based diagnostics, vaccines and therapeutics.     

Reductive carboxylation supports growth in tumour cells with defective mitochondria

Mitochondrial metabolism provides precursors to build macromolecules in growing cancer cells. In normally functioning tumour cell mitochondria, oxidative metabolism of glucose- and glutamine-derived carbon produces citrate and acetyl-coenzyme A for lipid synthesis, which is required for tumorigenesis. Yet some tumours harbour mutations in the citric acid cycle (CAC) or electron transport chain (ETC) that disable normal oxidative mitochondrial function, and it is unknown how cells from such tumours generate precursors for macromolecular synthesis. Here we show that tumour cells with defective mitochondria use glutamine-dependent reductive carboxylation rather than oxidative metabolism as the major pathway of citrate formation. This pathway uses mitochondrial and cytosolic isoforms of NADP(+)/NADPH-dependent isocitrate dehydrogenase, and subsequent metabolism of glutamine-derived citrate provides both the acetyl-coenzyme A for lipid synthesis and the four-carbon intermediates needed to produce the remaining CAC metabolites and related macromolecular precursors. This reductive, glutamine-dependent pathway is the dominant mode of metabolism in rapidly growing malignant cells containing mutations in complex I or complex III of the ETC, in patient-derived renal carcinoma cells with mutations in fumarate hydratase, and in cells with normal mitochondria subjected to acute pharmacological ETC inhibition. Our findings reveal the novel induction of a versatile glutamine-dependent pathway that reverses many of the reactions of the canonical CAC, supports tumour cell growth, and explains how cells generate pools of CAC intermediates in the face of impaired mitochondrial metabolism.     

Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung

Cystic fibrosis (CF) is a life-shortening disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Although bacterial lung infection and the resulting inflammation cause most of the morbidity and mortality, how the loss of CFTR function first disrupts airway host defence has remained uncertain. To investigate the abnormalities that impair elimination when a bacterium lands on the pristine surface of a newborn CF airway, we interrogated the viability of individual bacteria immobilized on solid grids and placed onto the airway surface. As a model, we studied CF pigs, which spontaneously develop hallmark features of CF lung disease. At birth, their lungs lack infection and inflammation, but have a reduced ability to eradicate bacteria. Here we show that in newborn wild-type pigs, the thin layer of airway surface liquid (ASL) rapidly kills bacteria in vivo, when removed from the lung and in primary epithelial cultures. Lack of CFTR reduces bacterial killing. We found that the ASL pH was more acidic in CF pigs, and reducing pH inhibited the antimicrobial activity of ASL. Reducing ASL pH diminished bacterial killing in wild-type pigs, and, conversely, increasing ASL pH rescued killing in CF pigs. These results directly link the initial host defence defect to the loss of CFTR, an anion channel that facilitates HCO(3)(-) transport. Without CFTR, airway epithelial HCO(3)(-) secretion is defective, the ASL pH falls and inhibits antimicrobial function, and thereby impairs the killing of bacteria that enter the newborn lung. These findings suggest that increasing ASL pH might prevent the initial infection in patients with CF, and that assaying bacterial killing could report on the benefit of therapeutic interventions.     

We find them here, we find them there: Functional bacterial amyloid

Protein amyloid is often deposited in connection with neurodegenerative diseases. Such deposits generally possess three principal drawbacks: cytotoxicity, lack of spatial control in their deposition and structural polymorphism. These are typical features of biologically non-optimized systems which have not been exposed to evolutionary pressure. Nevertheless, Nature uses the cross-beta self-organizing principle in many structural contexts where a strong but pliable material is needed. Functional amyloid is found in humans, invertebrates, fungi and, not least, bacteria, in which amyloid may be the rule rather than the exception. Detailed case studies reveal how directed nucleation can use tailor-made proteins optimized to assume a specific amyloid conformation, leading to remarkably robust assemblies. This makes it highly challenging to purify and analyze the products formed in vivo. We contrast pathogenic and in-vitro-formed amyloid with functional amyloid, paying particular reference to bacterial amyloid, and discuss challenges and perspectives in identifying and characterizing this class of protein.     

20世纪最伟大的技术成就

“在过去１００年里，我们生活的几乎所有方面都因为杰出工程师的工作而经历了深刻的变化……”──尼尔·阿姆斯特朗     

重构原子

重构原子ＩａｎＨｕｓｈｅｓ等著朱湘晓译许国平校迎接中空的原子，它拥有美好的未来。物理学家们认为，他们可以开发它的能量，用以制造任何东西，从Ｘ线全息图到ＣＤ。把自然界的建筑材料放回到制图板上：原子正在被重建。在美国和荷兰的实验室里，物理学家正在剥除包住...