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Building on previous work that identified a mutant avian H5 virus that is transmissible between ferrets, the authors present an algorithm to predict virus avidity from the affinity of single haemagglutinin (HA)–receptor interactions; these studies predict that the mutant has a 200-fold preference for the human over the avian receptor, and crystal structures of the mutant HA in complex with human and avian receptors shed light on the molecular basis for these altered binding properties. Receptor binding of transmissible flu virus The recent identification of an avian H5 haemagglutinin (HA) that can mediate aerosol transmission in ferrets when incorporated into a human influenza virus backbone has provided a model in which the nature of transmission of this type of virus can be closely examined. This new study goes further in demonstrating that this same transmissible-mutant virus has acquired a small increase in affinity for the human receptor, but a marked decrease in affinity for the avian receptor, leading to a 200-fold preference for binding human over avian receptors. The authors provide a crystal structure of this mutant HA in complex with human and avian receptor analogues, revealing something of the molecular basis for the altered binding properties. Cell-surface-receptor binding by influenza viruses is a key determinant of their transmissibility, both from avian and animal species to humans as well as from human to human. Highly pathogenic avian H5N1 viruses that are a threat to public health have been observed to acquire affinity for human receptors, and transmissible-mutant-selection experiments have identified a virus that is transmissible in ferrets 1 , 2 , 3 , the generally accepted experimental model for influenza in humans. Here, our quantitative biophysical measurements of the receptor-binding properties of haemagglutinin (HA) from the transmissible mutant indicate a small increase in affinity for human receptor and a marked decrease in affinity for avian receptor. From analysis of virus and HA binding data we have derived an algorithm that predicts virus avidity from the affinity of individual HA–receptor interactions. It reveals that the transmissible-mutant virus has a 200-fold preference for binding human over avian receptors. The crystal structure of the transmissible-mutant HA in complex with receptor analogues shows that it has acquired the ability to bind human receptor in the same folded-back conformation as seen for HA from the 1918, 1957 (ref. 4 ), 1968 (ref. 5 ) and 2009 (ref. 6 ) pandemic viruses. This binding mode is substantially different from that by which non-transmissible wild-type H5 virus HA binds human receptor. The structure of the complex also explains how the change in preference from avian to human receptors arises from the Gln226Leu substitution, which facilitates binding to human receptor but restricts binding to avian receptor. Both features probably contribute to the acquisition of transmissibility by this mutant virus.

Building on previous work that identified a mutant avian H5 virus that is transmissible between ferrets, the authors present an algorithm to predict virus avidity from the affinity of single haemagglutinin (HA)-receptor interactions; these studies predict that the mutant has a 200-fold preference for the human over the avian receptor, and crystal structures of the mutant HA in complex with human and avian receptors shed light on the molecular basis for these altered binding properties.

Both the yeast nascent polypeptide-associated complex (NAC) and the Hsp40/70-based chaperone system RAC-Ssb are systems tethered to the ribosome to assist cotranslational processes such as folding of nascent polypeptides. While loss of NAC does not cause phenotypic changes in yeast, the simultaneous deletion of genes coding for NAC and the chaperone Ssb (nacΔssbΔ) leads to strongly aggravated defects compared to cells lacking only Ssb, including impaired growth on plates containing L-canavanine or hygromycin B, aggregation of newly synthesized proteins and a reduced translational activity due to ribosome biogenesis defects. In this study, we dissected the functional properties of the individual NAC-subunits (α-NAC, β-NAC and β'-NAC) and of different NAC heterodimers found in yeast (αβ-NAC and αβ'-NAC) by analyzing their capability to complement the pleiotropic phenotype of nacΔssbΔ cells. We show that the abundant heterodimer αβ-NAC but not its paralogue αβ'-NAC is able to suppress all phenotypic defects of nacΔssbΔ cells including global protein aggregation as well as translation and growth deficiencies. This suggests that αβ-NAC and αβ'-NAC are functionally distinct from each other. The function of αβ-NAC strictly depends on its ribosome association and on its high level of expression. Expression of individual β-NAC, β'-NAC or α-NAC subunits as well as αβ'-NAC ameliorated protein aggregation in nacΔssbΔ cells to different extents while only β-NAC was able to restore growth defects suggesting chaperoning activities for β-NAC sufficient to decrease the sensitivity of nacΔssbΔ cells against L-canavanine or hygromycin B. Interestingly, deletion of the ubiquitin-associated (UBA)-domain of the α-NAC subunit strongly enhanced the aggregation preventing activity of αβ-NAC pointing to a negative regulatory role of this domain for the NAC chaperone activity in vivo.

Dairy cows mobilize large amounts of body fat during early lactation to overcome negative energy balance which typically arises in this period. As an adaptation process, adipose tissues of cows undergo extensive remodeling during late pregnancy and early lactation. The objective of the present study was to characterize this remodeling to get a better understanding of adaptation processes in adipose tissues, affected by changing metabolic conditions including lipid mobilization and refilling as a function of energy status. This was done by determining adipocyte size in histological sections of subcutaneous and retroperitoneal adipose tissue biopsy samples collected from German Holstein cows at 42 days prepartum, and 1, 21, and 100 days postpartum. Characterization of cell size changes was extended by the analysis of DNA, triacylglycerol, and protein content per gram tissue, and β-actin protein expression in the same samples. In both adipose tissue depots cell size was becoming smaller during the course of the study, suggesting a decrease in cellular triacylglycerol content. Results of DNA, triacylglycerol, and protein content, and β-actin protein expression could only partially explain the observed differences in cell size. The retroperitoneal adipose tissue exhibited a greater extent of time-related differences in cell size, DNA, and protein content, suggesting greater dynamics and metabolic flexibility for this abdominal depot compared to the investigated subcutaneous depot.

Both the yeast nascent polypeptide-associated complex (NAC) and the Hsp40/70-based chaperone system RAC-Ssb are systems tethered to the ribosome to assist cotranslational processes such as folding of nascent polypeptides. While loss of NAC does not cause phenotypic changes in yeast, the simultaneous deletion of genes coding for NAC and the chaperone Ssb (nac[delta]ssb[delta]) leads to strongly aggravated defects compared to cells lacking only Ssb, including impaired growth on plates containing L-canavanine or hygromycin B, aggregation of newly synthesized proteins and a reduced translational activity due to ribosome biogenesis defects. In this study, we dissected the functional properties of the individual NAC-subunits ([alpha] -NAC, [Beta]-NAC and [Beta]'-NAC) and of different NAC heterodimers found in yeast ([alpha] [Beta]-NAC and [alpha] [Beta]'-NAC) by analyzing their capability to complement the pleiotropic phenotype of nac[delta]ssb[delta] cells. We show that the abundant heterodimer [alpha] [Beta]-NAC but not its paralogue [alpha] [Beta]'-NAC is able to suppress all phenotypic defects of nac[delta]ssb[delta] cells including global protein aggregation as well as translation and growth deficiencies. This suggests that [alpha] [Beta]-NAC and [alpha] [Beta]'-NAC are functionally distinct from each other. The function of [alpha] [Beta]-NAC strictly depends on its ribosome association and on its high level of expression. Expression of individual [Beta]-NAC, [Beta]'-NAC or [alpha] -NAC subunits as well as [alpha] [Beta]'-NAC ameliorated protein aggregation in nac[delta]ssb[delta] cells to different extents while only [Beta]-NAC was able to restore growth defects suggesting chaperoning activities for [Beta]-NAC sufficient to decrease the sensitivity of nac[delta]ssb[delta] cells against L-canavanine or hygromycin B. Interestingly, deletion of the ubiquitin-associated (UBA)-domain of the [alpha] -NAC subunit strongly enhanced the aggregation preventing activity of [alpha] [Beta]-NAC pointing to a negative regulatory role of this domain for the NAC chaperone activity in vivo.