Saccadic oscillations facilitate ocular perfusion from the avian pecten

THE evolution of the eye is constrained by two conflicting requirements--good vascular perfusion of the retina, and an optical path through the retina that is unobstructed by blood vessels. Birds are interesting in that they have higher metabolic rates and thicker retinas than mammals, but have no retinal blood vessels. Nutrients and oxygen must thus reach the neurons of the inner retina either from the choroid through 300 micron of metabolically very active retina, or from the pecten, a pleated vascular structure protruding from the head of the optic nerve into the vitreous chamber, and more than a centimetre away from some retinal neurons. Despite the diffusional distance involved, several lines of evidence indicate that the pecten is the primary source of nutrients for the inner retina: the presence of an oxygen gradient from pecten to retina, the large surface area produced by macroscopic folds and by microscopic infoldings of the luminal and external surfaces of the capillary endothelium, extrusion of circulating fluorescein, high content of carbonic anhydrase and alkaline phosphatase, and retinal impairments after pecten ablation. Another peculiarity of birds, their saccadic oscillations, occur with a large cyclotor-sional component during every saccadic eye movement. In different species, saccades, which occur at intervals of 0.5-40 s, have up to 13 oscillations with frequencies of 15-30 Hz and ampliá-tudes of about 10 degrees. Therefore, as much as 12% of some birds' total viewing time may be subject to the image instability caused by the oscillations. Using fluorescein angiography, we show here that during every saccade, the pecten acts as an agitator which propels perfusate towards the central retina much more effectively than is observed during intersaccadic intervals.     

Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7

Microtubules have pivotal roles in fundamental cellular processes and are targets of antitubulin chemotherapeutics. Microtubule-targeted agents such as Taxol and vincristine are prescribed widely for various malignancies, including ovarian and breast adenocarcinomas, non-small-cell lung cancer, leukaemias and lymphomas. These agents arrest cells in mitosis and subsequently induce cell death through poorly defined mechanisms. The strategies that resistant tumour cells use to evade death induced by antitubulin agents are also unclear. Here we show that the pro-survival protein MCL1 (ref. 3) is a crucial regulator of apoptosis triggered by antitubulin chemotherapeutics. During mitotic arrest, MCL1 protein levels decline markedly, through a post-translational mechanism, potentiating cell death. Phosphorylation of MCL1 directs its interaction with the tumour-suppressor protein FBW7, which is the substrate-binding component of a ubiquitin ligase complex. The polyubiquitylation of MCL1 then targets it for proteasomal degradation. The degradation of MCL1 was blocked in patient-derived tumour cells that lacked FBW7 or had loss-of-function mutations in FBW7, conferring resistance to antitubulin agents and promoting chemotherapeutic-induced polyploidy. Additionally, primary tumour samples were enriched for FBW7 inactivation and elevated MCL1 levels, underscoring the prominent roles of these proteins in oncogenesis. Our findings suggest that profiling the FBW7 and MCL1 status of tumours, in terms of protein levels, messenger RNA levels and genetic status, could be useful to predict the response of patients to antitubulin chemotherapeutics.     

Interpreting the Wigner–Eckart Theorem

The Wigner–Eckart theorem is central to the application of symmetry principles throughout atomic, molecular, and nuclear physics. Nevertheless, the theorem has a puzzling feature: it is dispensable for solving problems within these domains, since elementary methods suffice. To account for the significance of the theorem, I first contrast it with an elementary approach to calculating matrix elements. Next, I consider three broad strategies for interpreting the theorem: conventionalism, fundamentalism, and conceptualism. I argue that the conventionalist framework is unnecessarily pragmatic, while the fundamentalist framework requires more ontological commitments than necessary. Conceptualism avoids both defects, accounting for the theorem’s significance in terms of how it epistemically restructures the calculation of matrix elements. Specifically, the Wigner–Eckart theorem modularizes and unifies matrix element problems, thereby changing what we need to know to solve them.     

Neuronal circuitry mechanism regulating adult quiescent neural stem-cell fate decision

Adult neurogenesis arises from neural stem cells within specialized niches. Neuronal activity and experience, presumably acting on this local niche, regulate multiple stages of adult neurogenesis, from neural progenitor proliferation to new neuron maturation, synaptic integration and survival. It is unknown whether local neuronal circuitry has a direct impact on adult neural stem cells. Here we show that, in the adult mouse hippocampus, nestin-expressing radial glia-like quiescent neural stem cells (RGLs) respond tonically to the neurotransmitter γ-aminobutyric acid (GABA) by means of γ2-subunit-containing GABAA receptors. Clonal analysis of individual RGLs revealed a rapid exit from quiescence and enhanced symmetrical self-renewal after conditional deletion of γ2. RGLs are in close proximity to terminals expressing 67-kDa glutamic acid decarboxylase (GAD67) of parvalbumin-expressing (PV+) interneurons and respond tonically to GABA released from these neurons. Functionally, optogenetic control of the activity of dentate PV+ interneurons, but not that of somatostatin-expressing or vasoactive intestinal polypeptide (VIP)-expressing interneurons, can dictate the RGL choice between quiescence and activation. Furthermore, PV+ interneuron activation restores RGL quiescence after social isolation, an experience that induces RGL activation and symmetrical division. Our study identifies a niche cell–signal–receptor trio and a local circuitry mechanism that control the activation and self-renewal mode of quiescent adult neural stem cells in response to neuronal activity and experience.     

Cortical representations of olfactory input by trans-synaptic tracing

In the mouse, each class of olfactory receptor neurons expressing a given odorant receptor has convergent axonal projections to two specific glomeruli in the olfactory bulb, thereby creating an odour map. However, it is unclear how this map is represented in the olfactory cortex. Here we combine rabies-virus-dependent retrograde mono-trans-synaptic labelling with genetics to control the location, number and type of 'starter' cortical neurons, from which we trace their presynaptic neurons. We find that individual cortical neurons receive input from multiple mitral cells representing broadly distributed glomeruli. Different cortical areas represent the olfactory bulb input differently. For example, the cortical amygdala preferentially receives dorsal olfactory bulb input, whereas the piriform cortex samples the whole olfactory bulb without obvious bias. These differences probably reflect different functions of these cortical areas in mediating innate odour preference or associative memory. The trans-synaptic labelling method described here should be widely applicable to mapping connections throughout the mouse nervous system.