Sensing the anomeric effect in a solvent-free environment

The anomeric effect is a chemical phenomenon that refers to an observed stabilization of six-membered carbohydrate rings when they contain an electronegative substituent at the C1 position of the ring. This stereoelectronic effect influences the three-dimensional shapes of many biological molecules. It can be manifested not only in this classical manner involving interaction of the endocyclic oxygen atom (O5) found in such sugars with the C1 substituent (endo-anomeric effect) but also through a corresponding interaction of the electronegative exocyclic substituent with O5 (exo-anomeric effect). However, the underlying physical origin(s) of this phenomenon is still not clear. Here we show, using a combination of laser spectroscopy and computational analysis, that a truncated peptide motif can engage the two anomers of an isolated sugar in the gas phase, an environment lacking extraneous factors which could confound the analysis. (Anomers are isomers that differ in the orientation of the substituent at C1.) Complexes formed between the peptide and the α- or β-anomers of d-galactose are nearly identical structurally; however, the strength of the polarization of their interactions with the peptide differs greatly. Natural bond order calculations support this observation, and together they reveal the dominance of the exo- over the endo-anomeric effect. As interactions between oxygen atoms at positions C1 and C2 (O1 and O2, respectively) on the pyranose ring can alter the exo/endo ratio of a carbohydrate, our results suggest that it will be important to re-evaluate the influence, and biological effects, of substituents at position C2 in sugars.     

Real-time quantum feedback prepares and stabilizes photon number states

Feedback loops are central to most classical control procedures. A controller compares the signal measured by a sensor (system output) with the target value or set-point. It then adjusts an actuator (system input) to stabilize the signal around the target value. Generalizing this scheme to stabilize a micro-system's quantum state relies on quantum feedback, which must overcome a fundamental difficulty: the sensor measurements cause a random back-action on the system. An optimal compromise uses weak measurements, providing partial information with minimal perturbation. The controller should include the effect of this perturbation in the computation of the actuator's operation, which brings the incrementally perturbed state closer to the target. Although some aspects of this scenario have been experimentally demonstrated for the control of quantum or classical micro-system variables, continuous feedback loop operations that permanently stabilize quantum systems around a target state have not yet been realized. Here we have implemented such a real-time stabilizing quantum feedback scheme following a method inspired by ref. 13. It prepares on demand photon number states (Fock states) of a microwave field in a superconducting cavity, and subsequently reverses the effects of decoherence-induced field quantum jumps. The sensor is a beam of atoms crossing the cavity, which repeatedly performs weak quantum non-demolition measurements of the photon number. The controller is implemented in a real-time computer commanding the actuator, which injects adjusted small classical fields into the cavity between measurements. The microwave field is a quantum oscillator usable as a quantum memory or as a quantum bus swapping information between atoms. Our experiment demonstrates that active control can generate non-classical states of this oscillator and combat their decoherence, and is a significant step towards the implementation of complex quantum information operations.     

Combining theoretical and experimental data to decipher CFTR 3D structures and functions

Cryo-electron microscopy (cryo-EM) has recently provided invaluable experimental data about the full-length cystic fibrosis transmembrane conductance regulator (CFTR) 3D structure. However, this experimental information deals with inactive states of the channel, either in an apo, quiescent conformation, in which nucleotide-binding domains (NBDs) are widely separated or in an ATP-bound, yet closed conformation. Here, we show that 3D structure models of the open and closed forms of the channel, now further supported by metadynamics simulations and by comparison with the cryo-EM data, could be used to gain some insights into critical features of the conformational transition toward active CFTR forms. These critical elements lie within membrane-spanning domains but also within NBD1 and the N-terminal extension, in which conformational plasticity is predicted to occur to help the interaction with filamin, one of the CFTR cellular partners.     

Molecular chaperones are nanomachines that catalytically unfold misfolded and alternatively folded proteins

By virtue of their general ability to bind (hold) translocating or unfolding polypeptides otherwise doomed to aggregate, molecular chaperones are commonly dubbed “holdases”. Yet, chaperones also carry physiological functions that do not necessitate prevention of aggregation, such as altering the native states of proteins, as in the disassembly of SNARE complexes and clathrin coats. To carry such physiological functions, major members of the Hsp70, Hsp110, Hsp100, and Hsp60/CCT chaperone families act as catalytic unfolding enzymes or unfoldases that drive iterative cycles of protein binding, unfolding/pulling, and release. One unfoldase chaperone may thus successively convert many misfolded or alternatively folded polypeptide substrates into transiently unfolded intermediates, which, once released, can spontaneously refold into low-affinity native products. Whereas during stress, a large excess of non-catalytic chaperones in holding mode may optimally prevent protein aggregation, after the stress, catalytic disaggregases and unfoldases may act as nanomachines that use the energy of ATP hydrolysis to repair proteins with compromised conformations. Thus, holding and catalytic unfolding chaperones can act as primary cellular defenses against the formation of early misfolded and aggregated proteotoxic conformers in order to avert or retard the onset of degenerative protein conformational diseases.     

Oligodendroglia metabolically support axons and contribute to neurodegeneration

Oligodendroglia support axon survival and function through mechanisms independent of myelination, and their dysfunction leads to axon degeneration in several diseases. The cause of this degeneration has not been determined, but lack of energy metabolites such as glucose or lactate has been proposed. Lactate is transported exclusively by monocarboxylate transporters, and changes to these transporters alter lactate production and use. Here we show that the most abundant lactate transporter in the central nervous system, monocarboxylate transporter 1 (MCT1, also known as SLC16A1), is highly enriched within oligodendroglia and that disruption of this transporter produces axon damage and neuron loss in animal and cell culture models. In addition, this same transporter is reduced in patients with, and in mouse models of, amyotrophic lateral sclerosis, suggesting a role for oligodendroglial MCT1 in pathogenesis. The role of oligodendroglia in axon function and neuron survival has been elusive; this study defines a new fundamental mechanism by which oligodendroglia support neurons and axons.     

Approximate analysis of variance of spatially autocorrelated regional data

The classical method for analysis of variance of data divided in geographic regions is impaired if the data are spatially autocorrelated within regions, because the condition of independence of the observations is not met. Positive autocorrelation reduces within-group variability, thus artificially increasing the relative amount of among-group variance. Negative autocorrelation may produce the opposite effect. This difficulty can be viewed as a loss of an unknown number of degrees of freedom. Such problems can be found in population genetics, in ecology and in other branches of biology, as well as in economics, epidemiology, geography, geology, marketing, political science, and sociology. A computer-intensive method has been developed to overcome this problem in certain cases. It is based on the computation of pooled within-group sums of squares for sampled permutations of internally connected areas on a map. The paper presents the theory, the algorithms, and results obtained using this method. A computer program, written in PASCAL, is available.This work was supported by NSERC grant no. A7738 to Pierre Legendre and by grant BSR 8614384 from the National Science Foundation to Robert R. Sokal. This is contribution No. 366 of the Groupe d'Ecologie des Eaux Douces, Université de Montréal, and contribution No. 727 in Ecology and Evolution from the State University of New York at Stony Brook.     

Increased survival time of leukemic mice following treatment with phytohemagglutinin

Résumé Des souris ayant subi un traitement journalier au PHA, entrepris 4 jours avant l'implantation de cellules leucémiques L1210 on survécu plus longtemps que celles qui furent traitées au sel. Le traitement journalier entrepris 24 h après l'inoculation de cellules leucémiques n'a pas eu d'effet sur la durée de survie. Par le traitement au PHA combiné à la 6-mercaptopurine, la durée de vie fut plus longue que par celui que l'on obtint avec d'autres agents employés isolément. Un mécanisme proposé pour l'effet antileucémique de PHA est discuté.

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This work was supported in part by Contract No. NIH-70-2001 from the Cancer Chemotherapy National Service Center, National Cancer Institute and by a grant from the Life Insurance Medical Research fund No. G-68-11.