Computational and experimental prediction of human C-type lectin receptor druggability

Mammalian C-type lectin receptors (CTLRS) are involved in many aspects of immune cell regulation such as pathogen recognition, clearance of apoptotic bodies, and lymphocyte homing. Despite a great interest in modulating CTLR recognition of carbohydrates, the number of specific molecular probes is limited. To this end, we predicted the druggability of a panel of 22 CTLRs using DoGSiteScorer. The computed druggability scores of most structures were low, characterizing this family as either challenging or even undruggable. To further explore these findings, we employed a fluorine-based nuclear magnetic resonance screening of fragment mixtures against DC-SIGN, a receptor of pharmacological interest. To our surprise, we found many fragment hits associated with the carbohydrate recognition site (hit rate = 13.5%). A surface plasmon resonance-based follow-up assay confirmed 18 of these fragments (47%) and equilibrium dissociation constants were determined. Encouraged by these findings we expanded our experimental druggability prediction to Langerin and MCL and found medium to high hit rates as well, being 15.7 and 10.0%, respectively. Our results highlight limitations of current in silico approaches to druggability assessment, in particular, with regard to carbohydrate-binding proteins. In sum, our data indicate that small molecule ligands for a larger panel of CTLRs can be developed

Algal MIPs, high diversity and conserved motifs

<p>Abstract</p> <p>Background</p> <p>Major intrinsic proteins (MIPs) also named aquaporins form channels facilitating the passive transport of water and other small polar molecules across membranes. MIPs are particularly abundant and diverse in terrestrial plants but little is known about their evolutionary history. In an attempt to investigate the origin of the plant MIP subfamilies, genomes of chlorophyte algae, the sister group of charophyte algae and land plants, were searched for MIP encoding genes.</p> <p>Results</p> <p>A total of 22 MIPs were identified in the nine analysed genomes and phylogenetic analyses classified them into seven subfamilies. Two of these, Plasma membrane Intrinsic Proteins (PIPs) and GlpF-like Intrinsic Proteins (GIPs), are also present in land plants and divergence dating support a common origin of these algal and land plant MIPs, predating the evolution of terrestrial plants. The subfamilies unique to algae were named MIPA to MIPE to facilitate the use of a common nomenclature for plant MIPs reflecting phylogenetically stable groups. All of the investigated genomes contained at least one <it>MIP </it>gene but only a few species encoded MIPs belonging to more than one subfamily.</p> <p>Conclusions</p> <p>Our results suggest that at least two of the seven subfamilies found in land plants were present already in an algal ancestor. The total variation of MIPs and the number of different subfamilies in chlorophyte algae is likely to be even higher than that found in land plants. Our analyses indicate that genetic exchanges between several of the algal subfamilies have occurred. The PIP1 and PIP2 groups and the Ca²⁺gating appear to be specific to land plants whereas the pH gating is a more ancient characteristic shared by all PIPs. Further studies are needed to discern the function of the algal specific subfamilies MIPA-E and to fully understand the evolutionary relationship of algal and terrestrial plant MIPs.</p

Factors influencing terrestriality in primates of the Americas and Madagascar

Among mammals, the order Primates is exceptional in having a high taxonomic richness in which the taxa are arboreal, semiterrestrial, or terrestrial. Although habitual terrestriality is pervasive among the apes and African and Asian monkeys (catarrhines), it is largely absent among monkeys of the Americas (platyrrhines), as well as galagos, lemurs, and lorises (strepsirrhines), which are mostly arboreal. Numerous ecological drivers and species-specific factors are suggested to set the conditions for an evolutionary shift from arboreality to terrestriality, and current environmental conditions may provide analogous scenarios to those transitional periods. Therefore, we investigated predominantly arboreal, diurnal primate genera from the Americas and Madagascar that lack fully terrestrial taxa, to determine whether ecological drivers (habitat canopy cover, predation risk, maximum temperature, precipitation, primate species richness, human population density, and distance to roads) or species-specific traits (bodymass, group size, and degree of frugivory) associate with increased terrestriality. We collated 150,961 observation hours across 2,227 months from 47 species at 20 sites in Madagascar and 48 sites in the Americas. Multiple factors were associated with ground use in these otherwise arboreal species, including increased temperature, a decrease in canopy cover, a dietary shift away from frugivory, and larger group size. These factors mostly explain intraspecific differences in terrestriality. As humanity modifies habitats and causes climate change, our results suggest that species already inhabiting hot, sparsely canopied sites, and exhibiting more generalized diets, are more likely to shift toward greater ground use

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Factors influencing terrestriality in primates of the Americas and Madagascar

Among mammals, the order Primates is exceptional in having a high taxonomic richness in which the taxa are arboreal, semiterrestrial, or terrestrial. Although habitual terrestriality is pervasive among the apes and African and Asian monkeys (catarrhines), it is largely absent among monkeys of the Americas (platyrrhines), as well as galagos, lemurs, and lorises (strepsirrhines), which are mostly arboreal. Numerous ecological drivers and species-specific factors are suggested to set the conditions for an evolutionary shift from arboreality to terrestriality, and current environmental conditions may provide analogous scenarios to those transitional periods. Therefore, we investigated predominantly arboreal, diurnal primate genera from the Americas and Madagascar that lack fully terrestrial taxa, to determine whether ecological drivers (habitat canopy cover, predation risk, maximum temperature, precipitation, primate species richness, human population density, and distance to roads) or species-specific traits (body mass, group size, and degree of frugivory) associate with increased terrestriality. We collated 150,961 observation hours across 2,227 months from 47 species at 20 sites in Madagascar and 48 sites in the Americas. Multiple factors were associated with ground use in these otherwise arboreal species, including increased temperature, a decrease in canopy cover, a dietary shift away from frugivory, and larger group size. These factors mostly explain intraspecific differences in terrestriality. As humanity modifies habitats and causes climate change, our results suggest that species already inhabiting hot, sparsely canopied sites, and exhibiting more generalized diets, are more likely to shift toward greater ground use

Biophysical characterization of chitin-binding beak proteins in dosidicus gigas

Carbohydrate-binding proteins (CBPs) are a versatile group of proteins occurring in almost every organism on earth. These proteins are imperative to various functions, ranging from enzymatic carbohydrate degradation and serve as templating scaffolds with load-bearing properties in the exoskeleton of crustaceans or insects. A large amount of data on how lectins bind highly specifically to carbohydrates exist, however, the actual binding mechanisms involved is unknown in most biological materials where they are found. Primary focus of the subsequent study is the determination of the structure of CBD-γ, a chitin-binding domain found in the Chitin-binding Beak Protein-3 (DgCBP-3) using NMR spectroscopy. DgCBP-3 is one of four unique chitin-binding proteins (DgCBPs) found in the beak structure of Dosidicus gigas and is believed to interact with chitin to form a net-like structure in which a second class of proteins, namely Histidine-binding Beak Proteins (DgHBPs) infiltrate to assemble the beak. Previous research has identified one chitin-binding motif, the extended Rebers and Riddiford” consensus (R&R), to play a critical step in the biogenesis and hardening process in exoskeletons of arthropods. However, till date no experimental tertiary structure of a protein containing an R&R Consensus has been reported and the mechanism how the R&R Consensus binds chitin remains unclear. The following study includes the structural determination of CBD-γ, which appears to be the first experimentally solved three-dimensional protein structure of a CBP containing the R&R Consensus. Further, solution state NMR spectroscopy has been used to elucidate the molecular interactions between CBD-γ and the soluble chitin derivative pentaacetyl-chitopentaose (PCP). The study shows that PCP triggers a folding of CBD-γ upon its interaction. The results of this study can be used as a template to understand in more details the role of the R&R motif and may inform other research conducted on other structural chitin-binding domains across species, including other cephalopods, crustaceans, and insects.Doctor of Philosoph

Technological infrastructure supporting the story network principle of the Atlas of Ageing Society

Atlases have a long tradition of showing and linking information for the exploration of various mostly spatially related topics. The Atlas of the Ageing Society is an interactive platform illustrating age related data. It enables individuals to explore facts and information related to age and the ageing society. To support content representation as well as a diverse audience, we developed the “story network principle”, which embeds annotated visualizations into a network of information in order to allow storytelling with data. Enabling the exploration of such a multifaceted and highly interconnected data landscape, however, posed some technical challenges. This paper describes and discusses a back-end implementation that meets the requirements of the story network principle from a technical perspective. We detail and exemplify the design and implementation of the atlas infrastructure to enable others to benefit from our developments and approaches to the challenges. The story network principle is potentially applicable to a range of applications such as other atlases or digital portfolios.21723

Micropapillary urothelial carcinoma: Cytologic features in a retrospective series of urine specimens

Background : The micropapillary variant of urothelial carcinoma (uPC) is a rare variant of urothelial carcinoma that carries a poor prognosis. Definitive surgery may represent optimal management of low stage tumors. Urine cytology is indispensable in the screening and follow-up of urinary tract cancer. However, cytopathological criteria for diagnosis of uPC and its differentiation from conventional urothelial carcinoma (CUC) are not well-defined. Materials and Methods : Twenty-five cases of histologically confirmed micropapillary uPC from 21 patients were compared to 25 cases of histologically confirmed high-grade CUC. Results : In uPC cases, cell clusters were identified in 13 of 25 specimens from 10 patients. Six of the 13 specimens containing cell clusters corresponded to surgical pathology specimens in which micropapillary carcinoma accounted for at least 50% of total carcinoma. In contrast, only 1 of the 12 urine specimens devoid of cell clusters corresponded to surgical specimens in which micropapillary carcinoma accounted for at least 50% of total carcinoma. Cytomorphologic features of urinary specimens from patients with histologically confirmed micropapillary carcinoma were generally similar to those from patients with high-grade CUC, making it difficult to distinguish these entities in exfoliative urine specimens. Conclusions and Summary : Further investigation of the core cytopathological characteristics of uPC is warranted to refine its diagnostic criteria by exfoliative urine cytology