Structure-based design of Trifarotene (CD5789), a potent and selective RARγ agonist for the treatment of acne

Retinoids have a dominant role in topical acne therapy and to date, only RARβ and RARγ dual agonists have reached the market. Given the tissue distribution of RAR isoforms, it was hypothesized that developing RARγ -selective agonists could yield a new generation of topical acne treatments that would increase safety margins while maintaining the robust efficacy of previous drugs. Structural knowledge derived from the X-ray structure of known γ-selective CD437, suggested the design of a novel triaryl series of agonists which was optimized and ultimately led to the discovery of Trifarotene/CD5789.     

Nebulized Liposomal Amphotericin B for Treatment of Pulmonary Infection Caused by <Emphasis Type="Italic">Hormographiella aspergillata</Emphasis>: Case Report and Literature Review

Invasive fungal infection is a serious complication following allogeneic hematopoietic stem cell transplantation. Pulmonary infection due to Hormographiella aspergillata is an uncommon condition associated with a high mortality rate. The susceptibility of H. aspergillata to available antifungal agents is not well established. We report for the first time a case of H. aspergillata lung infection that responded poorly to conventional treatment with liposomal amphotericin B (LAmB; 3 mg kg^?1 of body weight per day) with renal damage at higher posology (5 mg kg^?1 of body weight per day), but improved rapidly after addition of nebulized LAmB to intravenous LAmB (3 mg kg^?1 of body weight per day). Successful treatment of our patient using nebulized LAmB would be worth evaluating in cases refractory to standard treatment or when the reference treatment may not be extended due to interaction or side effects.     

Analysis of relatedness and determination of the source of founders in the captive bearded vulture, Gypaetus barbatus, population

Genetic relatedness among founders is a vitalparameter in the management of captivepopulations as kin structure can have asignificant effect on subsequent populationstructure. Methods for inferring relatednessfrom microsatellite markers have all beendeveloped for natural populations; theirapplicability to captive populations withunknown founder origins needs thereforetesting. We used information derived from 14microsatellites in 177 individuals and Quellerand Goodnight's approach, to estimaterelatedness in the captive bearded vulturepopulation and to test the assumption ofunrelated founders. Mean relatedness of knownparent–offspring, full-sib and half-sib pairswithin the captive population were in agreementwith theoretical distributions. Pairwiserelatedness values among the founders had amean of –0.051 (SE ± 0.007) and theirdistribution did only differ marginally fromthe one found in the natural Pyreneanpopulation. A maximum likelihood approach wasused to determine the likelihood of founderpairs to be as closely related as full-sibs orparent–offspring. These results were combinedwith data from 268 bp mitochondrial DNA controlregion sequences and studbook information. Wecould exclude a close relationship among themajority of the 36 successfully reproducingfounders. Our study therefore removesmanagement concerns about hidden problems ofinbreeding and inbreeding depression. Itdemonstrates the applicability of relatednessestimates based on microsatellite allelefrequency data even in captive populations.Furthermore, we verified studbook informationon the origin of two founders from thePyrenees, and show the value of assignmenttests based on microsatellites for deducingfounder origins and their important role infuture monitoring projects.     

Enhancement of the microbial community biomass and diversity during air sparging bioremediation of a soil highly contaminated with kerosene and BTEX

In order to obtain insights in complexity shifts taking place in natural microbial communities under strong selective pressure, soils from a former air force base in the Czech Republic, highly contaminated with jet fuel and at different stages of a bioremediation air sparging treatment, were analyzed. By tracking phospholipid fatty acids and 16S rRNA genes, a detailed monitoring of the changes in quantities and composition of the microbial communities developed at different stages of the bioventing treatment progress was performed. Depending on the length of the air sparging treatment that led to a significant reduction in the contamination level, we observed a clear shift in the soil microbial community being dominated by Pseudomonads under the harsh conditions of high aromatic contamination to a status of low aromatic concentrations, increased biomass content, and a complex composition with diverse bacterial taxonomical branches. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. The online version of an erratum to this article can be found at http://dx.doi.org/. An erratum to this article can be found at     

Human ability to detect kinship in strangers' faces: effects of the degree of relatedness

The resemblance between human faces has been shown to be a possible cue in recognizing the relatedness between parents and children, and more recently, between siblings. However, the general inclusive fitness theory proposes that kin-selective behaviours are also relevant to more distant relatives, which requires the detection of larger kinship bonds. We conducted an experiment to explore the use of facial clues by ‘strangers’, i.e. evaluators from a different family, to associate humans of varying degrees of relatedness. We hypothesized that the visual capacity to detect relatedness should be weaker with lower degrees of relatedness. We showed that human adults are capable of (although not very efficient at) assessing the relatedness of unrelated individuals from photographs and that visible facial cues vary according to the degree of relatedness. This sensitivity exists even for kin pair members that are more than a generation apart and have never lived together. Collectively, our findings are in agreement with emerging knowledge on the role played by facial resemblance as a kinship cue. But we have progressed further to show how the capacity to distinguish between related and non-related pairs applies to situations relevant to indirect fitness.     

HCN Channels Are Not Required for Mechanotransduction in Sensory Hair Cells of the Mouse Inner Ear

The molecular composition of the hair cell transduction channel has not been identified. Here we explore the novel hypothesis that hair cell transduction channels include HCN subunits. The HCN family of ion channels includes four members, HCN1-4. They were orginally identified as the molecular correlates of the hyperpolarization-activated, cyclic nucleotide gated ion channels that carry currents known as I_f, I_Q or I_h. However, based on recent evidence it has been suggested that HCN subunits may also be components of the elusive hair cell transduction channel. To investigate this hypothesis we examined expression of mRNA that encodes HCN1-4 in sensory epithelia of the mouse inner ear, immunolocalization of HCN subunits 1, 2 and 4, uptake of the transduction channel permeable dye, FM1-43 and electrophysiological measurement of mechanotransduction current. Dye uptake and transduction current were assayed in cochlear and vestibular hair cells of wildtype mice exposed to HCN channel blockers or a dominant-negative form of HCN2 that contained a pore mutation and in mutant mice that lacked HCN1, HCN2 or both. We found robust expression of HCNs 1, 2 and 4 but little evidence that localized HCN subunits in hair bundles, the site of mechanotransduction. Although high concentrations of the HCN antagonist, ZD7288, blocked 50–70% of the transduction current, we found no reduction of transduction current in either cochlear or vestibular hair cells of HCN1- or HCN2- deficient mice relative to wild-type mice. Furthermore, mice that lacked both HCN1 and HCN2 also had normal transduction currents. Lastly, we found that mice exposed to the dominant-negative mutant form of HCN2 had normal transduction currents as well. Taken together, the evidence suggests that HCN subunits are not required for mechanotransduction in hair cells of the mouse inner ear.     

Neuropathological and Reelin Deficiencies in the Hippocampal Formation of Rats Exposed to MAM; Differences and Similarities with Schizophrenia

Background

Adult rats exposed to methylazoxymethanol (MAM) at embryonic day 17 (E17) consistently display behavioral characteristics similar to that observed in patients with schizophrenia and replicate neuropathological findings from the prefrontal cortex of psychotic individuals. However, a systematic neuropathological analysis of the hippocampal formation and the thalamus in these rats is lacking. It is also unclear if reelin, a protein consistently associated with schizophrenia and potentially involved in the mechanism of action of MAM, participates in the neuropathological effects of this compound. Therefore, a thorough assessment including cytoarchitectural and neuromorphometric measurements of eleven brain regions was conducted. Numbers of reelin positive cells and reelin expression and methylation levels were also studied.

Principal Findings

Compared to untreated rats, MAM-exposed animals showed a reduction in the volume of entorhinal cortex, hippocampus and mediodorsal thalamus associated with decreased neuronal soma. The entorhinal cortex also showed laminar disorganization and neuronal clusters. Reelin methylation in the hippocampus was decreased whereas reelin positive neurons and reelin expression were unchanged.

Conclusions

Our results indicate that E17-MAM exposure reproduces findings from the hippocampal formation and the mediodorsal thalamus of patients with schizophrenia while providing little support for reelin''s involvement. Moreover, these results strongly suggest MAM-treated animals have a diminished neuropil, which likely arises from abnormal neurite formation; this supports a recently proposed pathophysiological hypothesis for schizophrenia.     

Expected Relationship Between the Silent Substitution Rate and the GC Content: Implications for the Evolution of Isochores

The relationship between the silent substitution rate (K _s) and the GC content along the genome is a focal point of the debate about the origin of the isochore structure in vertebrates. Recent estimation of the silent substitution rate showed a positive correlation between K _s and GC content, in contradiction with the predictions of both the regional mutation bias model and the selection or biased gene conversion model. The aim of this paper is to help resolve this contradiction between theoretical studies and data. We analyzed the relationship between K _s and GC content under (1) uniform mutation bias, (2) a regional mutation bias, and (3) mutation bias and selection. We report that an increase in K _s with GC content is expected under mutation bias because of either nonequilibrium of the isochore structure or an increasing mutation rate from AT toward GC nucleotides in GC-richer isochores. We show by simulations that CpG deamination tends to increase the mutation rate with GC content in a regional mutation bias model. We also demonstrate that the relationship between K _s and GC under the selectionist or biased gene conversion model is positive under weak selection if the mutation selection equilibrium GC frequency is less than 0.5. Received: 28 March 2001 / Accepted: 16 May 2001     

Co-infection of Ticks: The Rule Rather Than the Exception

IntroductionTicks are the most common arthropod vectors of both human and animal diseases in Europe, and the Ixodes ricinus tick species is able to transmit a large number of bacteria, viruses and parasites. Ticks may also be co-infected with several pathogens, with a subsequent high likelihood of co-transmission to humans or animals. However few data exist regarding co-infection prevalences, and these studies only focus on certain well-known pathogens. In addition to pathogens, ticks also carry symbionts that may play important roles in tick biology, and could interfere with pathogen maintenance and transmission. In this study we evaluated the prevalence of 38 pathogens and four symbionts and their co-infection levels as well as possible interactions between pathogens, or between pathogens and symbionts.Conclusion/significanceOur study reveals high pathogen co-infection rates in ticks, raising questions about possible co-transmission of these agents to humans or animals, and their consequences to human and animal health. We also demonstrated high prevalence rates of symbionts co-existing with pathogens, opening new avenues of enquiry regarding their effects on pathogen transmission and vector competence.