The gating mechanism of the large mechanosensitive channel MscL

The mechanosensitive channel of large conductance, MscL, is a ubiquitous membrane-embedded valve involved in turgor regulation in bacteria. The crystal structure of MscL from Mycobacterium tuberculosis provides a starting point for analysing molecular mechanisms of tension-dependent channel gating. Here we develop structural models in which a cytoplasmic gate is formed by a bundle of five amino-terminal helices (S1), previously unresolved in the crystal structure. When membrane tension is applied, the transmembrane barrel expands and pulls the gate apart through the S1-M1 linker. We tested these models by substituting cysteines for residues predicted to be near each other only in either the closed or open conformation. Our results demonstrate that S1 segments form the bundle when the channel is closed, and crosslinking between S1 segments prevents opening. S1 segments interact with M2 when the channel is open, and crosslinking of S1 to M2 impedes channel closing. Gating is affected by the length of the S1-M1 linker in a manner consistent with the model, revealing critical spatial relationships between the domains that transmit force from the lipid bilayer to the channel gate.     

Effects of burning and clipping on five bunchgrasses in eastern Oregon

Response of five perennial bunchgrasses following clipping and burning was evaluated in eastern Oregon. Burned plants were compared with clipped plants on several dates from spring to fall with respect to mortality and change in basal area. Basal area was generally reduced for one year but did not change the second year after defoliation. Treatments rarely affected yield. Burning in May was most detrimental, reducing basal area of all species. Fall clipping was least harmful, producing little or no change in basal area. Plant mortality was significant only for burned Thurber needlegrass ( Stipa thurberiana ).     

Exponential smoothing: Estimation by maximum likelihood

In this paper several forecasting methods based on exponential smoothing with an underlying seasonal autoregressive-moving average (SARIMA) model are considered. The relations between the smoothing constants and the coefficients of the autoregressive and moving average polynomials are used. On that basis, a maximum likelihood procedure for parameter estimation is described. The approach rules out the need for initial smoothed values. Prediction intervals are also obtained as a by-product of the approach and a fast algorithm for implementing the method is outlined.     

Three-dimensional optical metamaterial with a negative refractive index

Metamaterials are artificially engineered structures that have properties, such as a negative refractive index, not attainable with naturally occurring materials. Negative-index metamaterials (NIMs) were first demonstrated for microwave frequencies, but it has been challenging to design NIMs for optical frequencies and they have so far been limited to optically thin samples because of significant fabrication challenges and strong energy dissipation in metals. Such thin structures are analogous to a monolayer of atoms, making it difficult to assign bulk properties such as the index of refraction. Negative refraction of surface plasmons was recently demonstrated but was confined to a two-dimensional waveguide. Three-dimensional (3D) optical metamaterials have come into focus recently, including the realization of negative refraction by using layered semiconductor metamaterials and a 3D magnetic metamaterial in the infrared frequencies; however, neither of these had a negative index of refraction. Here we report a 3D optical metamaterial having negative refractive index with a very high figure of merit of 3.5 (that is, low loss). This metamaterial is made of cascaded 'fishnet' structures, with a negative index existing over a broad spectral range. Moreover, it can readily be probed from free space, making it functional for optical devices. We construct a prism made of this optical NIM to demonstrate negative refractive index at optical frequencies, resulting unambiguously from the negative phase evolution of the wave propagating inside the metamaterial. Bulk optical metamaterials open up prospects for studies of 3D optical effects and applications associated with NIMs and zero-index materials such as reversed Doppler effect, superlenses, optical tunnelling devices, compact resonators and highly directional sources.     

The dopamine D4 receptor: biochemical and signalling properties

Dopamine is an important neurotransmitter that regulates several key functions in the brain, such as motor output, motivation and reward, learning and memory, and endocrine regulation. Dopamine does not mediate fast synaptic transmission, but rather modulates it by triggering slow-acting effects through the activation of dopamine receptors, which belong to the G-protein-coupled receptor superfamily. Besides activating different effectors through G-protein coupling, dopamine receptors also signal through interaction with a variety of proteins, collectively termed dopamine receptor-interacting proteins. We focus on the dopamine D4 receptor, which contains an important polymorphism in its third intracellular loop. This polymorphism has been the subject of numerous studies investigating links with several brain disorders, such as attention-deficit hyperactivity disorder and schizophrenia. We provide an overview of the structure, signalling properties and regulation of dopamine D4 receptors, and briefly discuss their physiological and pathophysiological role in the brain.     

Inactivation of the p53 pathway in retinoblastoma

Most human tumours have genetic mutations in their Rb and p53 pathways, but retinoblastoma is thought to be an exception. Studies suggest that retinoblastomas, which initiate with mutations in the gene retinoblastoma 1 (RB1), bypass the p53 pathway because they arise from intrinsically death-resistant cells during retinal development. In contrast to this prevailing theory, here we show that the tumour surveillance pathway mediated by Arf, MDM2, MDMX and p53 is activated after loss of RB1 during retinogenesis. RB1-deficient retinoblasts undergo p53-mediated apoptosis and exit the cell cycle. Subsequently, amplification of the MDMX gene and increased expression of MDMX protein are strongly selected for during tumour progression as a mechanism to suppress the p53 response in RB1-deficient retinal cells. Our data provide evidence that the p53 pathway is inactivated in retinoblastoma and that this cancer does not originate from intrinsically death-resistant cells as previously thought. In addition, they support the idea that MDMX is a specific chemotherapeutic target for treating retinoblastoma.     

Do abnormal responses show utilitarian bias?

Neuroscience has recently turned to the study of utilitarian and non-utilitarian moral judgement. Koenigs et al. examine the responses of normal subjects and those with ventromedial-prefrontal-cortex (VMPC) damage to moral scenarios drawn from functional magnetic resonance imaging studies by Greene et al., and claim that patients with VMPC damage have an abnormally "utilitarian" pattern of moral judgement. It is crucial to the claims of Koenigs et al. that the scenarios of Greene et al. pose a conflict between utilitarian consequence and duty: however, many of them do not meet this condition. Because of this methodological problem, it is too early to claim that VMPC patients have a utilitarian bias.