Interaction with Both Domain I and III of Albumin Is Required for Optimal pH-dependent Binding to the Neonatal Fc Receptor (FcRn)

Albumin is an abundant blood protein that acts as a transporter of a plethora of small molecules like fatty acids, hormones, toxins, and drugs. In addition, it has an unusual long serum half-life in humans of nearly 3 weeks, which is attributed to its interaction with the neonatal Fc receptor (FcRn). FcRn protects albumin from intracellular degradation via a pH-dependent cellular recycling mechanism. To understand how FcRn impacts the role of albumin as a distributor, it is of importance to unravel the structural mechanism that determines pH-dependent binding. Here, we show that although the C-terminal domain III (DIII) of human serum albumin (HSA) contains the principal binding site, the N-terminal domain I (DI) is important for optimal FcRn binding. Specifically, structural inspection of human FcRn (hFcRn) in complex with HSA revealed that two exposed loops of DI were in proximity with the receptor. To investigate to what extent these contacts affected hFcRn binding, we targeted selected amino acid residues of the loops by mutagenesis. Screening by in vitro interaction assays revealed that several of the engineered HSA variants showed decreased binding to hFcRn, which was also the case for two missense variants with mutations within these loops. In addition, four of the variants showed improved binding. Our findings demonstrate that both DI and DIII are required for optimal binding to FcRn, which has implications for our understanding of the FcRn-albumin relationship and how albumin acts as a distributor. Such knowledge may inspire development of novel HSA-based diagnostics and therapeutics.     

Lateral bias in feeding and brachiation inHylobates

Lateralized hand use in gibbons was assessed for both food reaching and leading limb in brachiation. Sex and age effects were found in hand preference for food reaching. Adult females were all very strongly right hand preferent, whereas adult males had no across group consistent preference. Within the female group there was a strong correlation between age and strength of right handedness. When compared in terms of absolute strength of hand preference, females were found to be more strongly lateralized than males. Leading limb preference in brachiation was scored into vocal and non-vocal categories. Three subjects had a shift in preferred leading limb from the non-vocal brachiation condition to the vocal brachiation condition. This shift may be influenced by the arousal effects of species typical vocalization. The results of this study underline the importance of consideration of such factors as sex and age when interpreting behavioral lateralization data. The exploration of laterality in many different response measures is important to the achievement of a complete understanding of behavioral lateralization in primates.     

The adaptive capacity of fishery management systems for confronting climate change impacts on marine populations

Global climate change will affect the abundance, distribution, and life history timing of many exploited marine populations, but specific changes are difficult to predict. Management systems in which harvest strategies and tactics are flexible in responding to unpredictable biological changes are more likely to succeed in maintaining productive populations. We explore the adaptability of fisheries management systems in relation to oceanic warming rates by asking how two important management characteristics vary with temperature changes for >500 stocks. (1) Harvest control rules, a framework for altering fishing pressure in response to changes in the abundance of targeted species (primarily due to fishing), may provide the capacity for harvest policies to change in response to climate-driven abundance declines also. (2) Seasonal openings with flexible dates that involve in-season monitoring may allow managers to better respond to possible changes in the timing of life-history periods like spawning to prevent fishing seasons falling out of sync with species’ phenology. Harvest control rules were widely used across industrialized fisheries including in regions that experienced relatively high oceanic warming rates, but after controlling for regional factors we found no association between ocean warming and the use of harvest control rules. Flexible-date seasonal openings were rare compared to fixed-date seasonal openings, but tended to occur in areas with the greatest warming rates while fisheries without seasonal closures tended to occur in areas with the least observed temperature changes. We found no consistent evidence of recent ocean warming effects on the current biomass or exploitation rates relative to management targets of 241 assessed marine populations. Together, these results suggest that the oceanic areas expected to have the greatest climate impacts on populations do at least tend to contain fisheries that demonstrate the potential for adaptability to unpredictable climate impacts.     

Psychometric Properties of the Problem Areas in Diabetes (PAID) Instrument in Singapore

Background

Emotional distress is an important dimension in diabetes, and several instruments have been developed to measure this aspect. The Problem Areas in Diabetes (PAID) scale is one such instrument which has demonstrated validity and reliability in Western populations, but its psychometric properties in Asian populations have not been examined.

Methods

This was a secondary analysis of data from patients with Type 2 diabetes mellitus recruited through convenience sampling from a diabetes specialist outpatient clinic in Singapore. The following psychometric properties were assessed: Construct validity through confirmatory factor analysis (CFA) and Rasch analysis, concurrent validity through correlation with related scales (Kessler Psychological Distress Scale, Diabetes Health Profile—psychological distress, Audit of Diabetes Dependent Quality of Life), reliability through assessment of internal consistency and floor and ceiling effects, and sensitivity by estimating effect sizes for known clinical and social functioning groups.

Results

203 patients with mean age of 45±12 years were analysed. None of the previously published model structures achieved a good fit on CFA. On Rasch analysis, four items showed poor fit and were removed. The abridged 16-item PAID mapped to a single latent trait, with a high degree of internal consistency (Cronbach ɑ 0.95), but significant floor effect (24.6% scoring at floor). Both 20-item and 16-item PAID scores were moderately correlated with scores of related scales, and sensitive to differences in clinical and social functioning groups, with large effect sizes for glycemic control and diabetes related complications, nephropathy and neuropathy.

Conclusion

The abridged 16-item PAID measures a single latent trait of emotional distress due to diabetes whereas the 20-item PAID appears to measures more than one latent trait. However, both the 16-item and 20-item PAID versions are valid, reliable and sensitive for use among Singaporean patients with diabetes.     

High-Level Resistance to Cobalt and Nickel but Probably No Transenvelope Efflux: Metal Resistance in the Cuban Serratia marcescens Strain C-1

Molecular mechanisms underlying inducible cobalt and nickel resistance of a bacterial strain isolated from a Cuban serpentine deposit were investigated. This strain C-1 was assigned to Serratia marcescens by 16S rDNA analysis and DNA/DNA hybridization. Genes involved in metal resistance were identified by transposon mutagenesis followed by selection for cobalt- and nickel-sensitive derivatives. The transposon insertion causing the highest decrease in metal resistance was located in the ncrABC determinant. The predicted NcrA product was a NreB ortholog of the major facilitator protein superfamily and central for cobalt/nickel resistance in S. marcescens strain C-1. NcrA also mediated metal resistance in Escherichia coli and caused decreased accumulation of Co(II) and Ni(II) in this heterologous host. NcrB may be a regulatory protein. NcrC was a protein of the nickel–cobalt transport (NiCoT) protein family and necessary for full metal resistance in E. coli, but only when NcrA was also present. Without NcrA, NcrC caused a slight decrease in metal resistance and mediated increased accumulation of Ni(II) and Co(II). Because the cytoplasmic metal concentration can be assumed to be the result of a flow equilibrium of uptake and efflux processes, this interplay between metal uptake system NcrC and metal efflux system NcrA may contribute to nickel and cobalt resistance in this bacterium.     

Strategies to minimize background autofluorescence in live mice during noninvasive fluorescence optical imaging

As small-animal fluorescence imaging becomes increasingly accessible to a broad spectrum of users, many lab animal researchers are just beginning to be exposed to its challenges. One setback to fluorescence imaging is background autofluorescence generated in animal tissue and in ingested food. The authors bring this issue into focus, and show how autofluorescence can be reduced in nude mice through selection of appropriate excitation wavelength and mouse diet.     

3,4-Dihydro-2H-benzoxazinones as dual-acting 5-HT1A receptor antagonists and serotonin reuptake inhibitors

Investigation of halogen substitution in lead compound 1 has led to the identification of analogues which combine high affinity for 5-HT(1A) receptors and potent serotonin reuptake inhibitory activity. Several compounds show an improved selectivity over 5-HT(1B) and 5-HT(1D) receptors and a superior pharmacokinetic profile in the rat.