Structure-based design of HSPA5 inhibitors: From peptide to small molecule inhibitors

We identified nine small-molecule hit compounds of Heat shock 70 kDa protein 5 (HSPA5) from cascade in silico screening based on the binding modes of the tetrapeptides derived from the peptide substrate or inhibitors of Escherichia coli HSP70. Two compounds exhibit promising inhibition activities from cancer cell viability and tumor inhibition assays. The binding modes of the hit compounds provide a platform for development of selective small molecule inhibitors of HSPA5.     

PEG conjugates of potent α4 integrin inhibitors,maintaining sustained levels and bioactivity in vivo,following subcutaneous administration

Mitsunobu reactions were employed to link t-butyl esters of α4 integrin inhibitors at each of the termini of a three-arm, 40 kDa, branched PEG. Cleavage of the t-butyl esters using HCO₂H provided easily isolated PEG derivatives, which are potent α4 integrin inhibitors, and which achieve sustained levels and bioactivity in vivo, following subcutaneous administration to rats.     

Population genetics of the American eel (Anguilla rostrata): FST = 0 and North Atlantic Oscillation effects on demographic fluctuations of a panmictic species

We performed population genetic analyses on the American eel (Anguilla rostrata) with three main objectives. First, we conducted the most comprehensive analysis of neutral genetic population structure to date to revisit the null hypothesis of panmixia in this species. Second, we used this data to provide the first estimates of contemporary effective population size (N_e) and to document temporal variation in effective number of breeders (N_b) in American eel. Third, we tested for statistical associations between temporal variation in the North Atlantic Oscillation (NAO), the effective number of breeders and two indices of recruit abundance. A total of 2142 eels from 32 sampling locations were genotyped with 18 microsatellite loci. All measures of differentiation were essentially zero, and no evidence for significant spatial or temporal genetic differentiation was found. The panmixia hypothesis should thus be accepted for this species. N_b estimates varied by a factor of 23 among 12 cohorts, from 473 to 10 999. The effective population size N_e was estimated at 10 532 (95% CI, 9312–11 752). This study also showed that genetically based demographic indices, namely N_b and allelic richness (Ar), can be used as surrogates for the abundance of breeders and recruits, which were both shown to be positively influenced by variation during high (positive) NAO phases. Thus, long‐term genetic monitoring of American glass eels at several sites along the North American Atlantic coast would represent a powerful and efficient complement to census monitoring to track demographic fluctuations and better understand their causes.     

Protein acyl thioesterases (Review)

Many proteins are S-acylated, affecting their localization and function. Dynamic S-acylation in response to various stimuli has been seen for several proteins in vivo. The regulation of S-acylation is beginning to be elucidated. Proteins can autoacylate or be S-acylated by protein acyl transferases (PATs). Deacylation, on the other hand, is an enzymatic process catalyzed by protein thioesterases (APT1 and PPT1) but only APT1 appears to be involved in the regulation of the reversible S-acylation of cytoplasmic proteins seen in vivo. PPT1, on the other hand, is involved in the lysosomal degradation of S-acylated proteins and PPT1 deficiency causes the disease infant neuronal ceroid lipofuscinosis.     

Epistasis in iron metabolism: complex interactions between Cp, Mon1a, and Slc40a1 loci and tissue iron in mice

Disorders of iron metabolism are among the most common acquired and constitutive diseases. Hemochromatosis has a solid genetic basis and in Northern European populations it is usually associated with homozygosity for the C282Y mutation in the HFE protein. However, the penetrance of this mutation is incomplete and the clinical presentation is highly variable. The rare and common variants identified so far as genetic modifiers of HFE-related hemochromatosis are unable to account for the phenotypic heterogeneity of this disorder. There are wide variations in the basal iron status of common inbred mouse strains, and this diversity may reflect the genetic background of the phenotypic diversity under pathological conditions. We therefore examined the genetic basis of iron homeostasis using quantitative trait loci mapping applied to the HcB-15 recombinant congenic strains for tissue and serum iron indices. Two highly significant QTL containing either the N374S Mon1a mutation or the Ferroportin locus were found to be major determinants in spleen and liver iron loading. Interestingly, when considering possible epistatic interactions, the effects of Mon1a on macrophage iron export are conditioned by the genotype at the Slc40a1 locus. Only mice that are C57BL/10ScSnA homozygous at both loci display a lower spleen iron burden. Furthermore, the liver-iron lowering effect of the N374S Mon1a mutation is observed only in mice that display a nonsense mutation in the Ceruloplasmin (Cp) gene. This study highlights the existence of genetic interactions between Cp, Mon1a, and the Slc40a1 locus in iron metabolism, suggesting that epistasis may be a crucial determinant of the variable biological and clinical presentations in iron disorders.     

Eumelanin‐based colouration reflects local survival of juvenile feral pigeons in an urban pigeon house

Urbanisation introduces deep changes in habitats, eventually creating new urban ecosystems where ecological functions are driven by human activities. The higher frequency of some phenotypes in urban vs rural/wild areas has led to the assumption that directional selection in urban habitats occurs, which may thereby favour some behavioural and physiological traits in urban animal populations compared to rural ones. However, empirical evidence of directional selection on phenotypic traits in urban areas remains scarce. In this study we tested whether eumelanin‐based colouration could be linked to survival in two urban populations of the feral pigeon Columba livia. A number of studies in different cities pointed out a higher frequency of darker individuals in more urbanised areas compared to rural ones. To investigate whether directional selection through survival on this highly heritable trait could explain such patterns, we conducted mark–recapture studies on two populations of feral pigeons in highly urbanized areas. We predicted that darker coloured individuals would exhibit higher survival and/or philopatry (integrated into ‘local survival’) than paler coloured ones. No difference in local survival was found between adults of different colouration intensities. However, on one site, we found that darker juveniles had a higher local survival probability than light ones. Juvenile local survival on that site was also negatively correlated with the number of chicks born. This suggests the existence of colour‐ and/or density‐dependent selection processes acting on juvenile feral pigeons in urban environments, acting through differential mortality and/or dispersal.     

Impact of DECISION + 2 on patient and physician assessment of shared decision making implementation in the context of antibiotics use for acute respiratory infections

Background

DECISION?+?2, a training program for physicians, is designed to implement shared decision making (SDM) in the context of antibiotics use for acute respiratory tract infections (ARTIs). We evaluated the impact of DECISION?+?2 on SDM implementation as assessed by patients and physicians, and on physicians’ intention to engage in SDM.

Methods

From 2010 to 2011, a multi-center, two-arm, parallel randomized clustered trial appraised the effects of DECISION?+?2 on the decision to use antibiotics for patients consulting for ARTIs. We randomized 12 family practice teaching units (FPTUs) to either DECISION?+?2 or usual care. After the consultation, both physicians and patients independently completed questionnaires based on the D-Option scale regarding SDM behaviors during the consultation. Patients also answered items assessing the role they assumed during the consultation (active/collaborative/passive). Before and after the intervention, physicians completed a questionnaire based on the Theory of Planned Behavior to measure their intention to engage in SDM. To account for the cluster design, we used generalized estimating equations and generalized linear mixed models to assess the impact of DECISION?+?2 on the outcomes of interest.

Results

A total of 270 physicians (66% women) participated in the study. After DECISION?+?2, patients’ D-Option scores were 80.1?±?1.1 out of 100 in the intervention group and 74.9?±?1.1 in the control group (p?=?0.001). Physicians’ D-Option scores were 79.7?±?1.8 in the intervention group and 76.3?±?1.9 in the control group (p?=?0.2). However, subgroup analyses showed that teacher physicians D-Option scores were 79.7?±?1.5 and 73.0?±?1.4 respectively (p?=?0.001). More patients reported assuming an active or collaborative role in the intervention group (67.1%), than in the control group (49.2%) (p?=?0.04). There was a significant relation between patients’ and physicians’ D-Option scores (p?<?0.01) and also between patient-reported assumed roles and both D-Option scores (as assessed by patients, p?<?0.01; and physicians, p?=?0.01). DECISION?+?2 had no impact on the intention of physicians to engage in SDM.

Conclusion

DECISION?+?2 positively influenced SDM behaviors as assessed by patients and teacher physicians. Physicians’ intention to engage in SDM was not affected by DECISION?+?2.

Trial registration

ClinicalTrials.gov trials register no. NCT01116076.