Decay in survival motor neuron and plastin 3 levels during differentiation of iPSC-derived human motor neurons

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by mutations in Survival Motor Neuron 1 (SMN1), leading to degeneration of alpha motor neurons (MNs) but also affecting other cell types. Induced pluripotent stem cell (iPSC)-derived human MN models from severe SMA patients have shown relevant phenotypes. We have produced and fully characterized iPSCs from members of a discordant consanguineous family with chronic SMA. We differentiated the iPSC clones into ISL-1+/ChAT+ MNs and performed a comparative study during the differentiation process, observing significant differences in neurite length and number between family members. Analyses of samples from wild-type, severe SMA type I and the type IIIa/IV family showed a progressive decay in SMN protein levels during iPSC-MN differentiation, recapitulating previous observations in developmental studies. PLS3 underwent parallel reductions at both the transcriptional and translational levels. The underlying, progressive developmental decay in SMN and PLS3 levels may lead to the increased vulnerability of MNs in SMA disease. Measurements of SMN and PLS3 transcript and protein levels in iPSC-derived MNs show limited value as SMA biomarkers

The role of ligand efficiency metrics in drug discovery

The judicious application of ligand or binding efficiencies, which quantify the molecular properties required to gain binding affinity for a drug target, is gaining traction in the selection and optimisation of fragments, hits, and leads. Retrospective analysis of recently marketed oral drugs shows that they frequently have highly optimised ligand efficiency values for their target. Optimising ligand efficiencies based on both molecular size and lipophilicity, when set in the context of the specific target, has the potential to ameliorate the molecular inflation that pervades current practice in medicinal chemistry, and to increase the developability of drug candidates

Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCF^Slmb degron

Spinal muscular atrophy (SMA) is caused by homozygous mutations in human SMN1. Expression of a duplicate gene (SMN2) primarily results in skipping of exon 7 and production of an unstable protein isoform, SMNΔ7. Although SMN2 exon skipping is the principal contributor to SMA severity, mechanisms governing stability of survival motor neuron (SMN) isoforms are poorly understood. We used a Drosophila model system and label-free proteomics to identify the SCFSlmb ubiquitin E3 ligase complex as a novel SMN binding partner. SCFSlmb interacts with a phosphor degron embedded within the human and fruitfly SMN YG-box oligomerization domains. Substitution of a conserved serine (S270A) interferes with SCFSlmb binding and stabilizes SMNΔ7. SMA-causing missense mutations that block multimerization of full-length SMN are also stabilized in the degron mutant background. Overexpression of SMNΔ7S270A, but not wild-type (WT) SMNΔ7, provides a protective effect in SMA model mice and human motor neuron cell culture systems. Our findings support a model wherein the degron is exposed when SMN is monomeric and sequestered when SMN forms higher-order multimers

Dual-Phase PET-CT to Differentiate [F-18]Fluoromethylcholine Uptake in Reactive and Malignant Lymph Nodes in Patients with Prostate Cancer

PURPOSE: To investigate whether time-trends of enhanced [(18)F]Fluoromethylcholine ([(18)F]FCH) in lymph nodes (LN) of prostate cancer (PCa) patients can help to discriminate reactive from malignant ones, and whether single time point standardized uptake value (SUV) measurements also suffice. PROCEDURES: 25 PCa patients with inguinal (presumed benign) and enlarged pelvic LN (presumed malignant) showing enhanced [(18)F]FCH uptake at dual-phase PET-CT were analyzed. Associations between LN status (benign versus malignant) and SUV(max) and SUV(meanA50), determined at 2 min (early) and 30 min (late) post injection, were assessed. We considered two time-trends of [(18)F]FCH uptake: type A (SUV early > SUV late) and type B (SUV late ≥ SUV early). Histopathology and/or follow-up were used to confirm the assumption that LN with type A pattern are benign, and LN with type B pattern malignant. RESULTS: Analysis of 54 nodes showed that LN status, time-trends, and 'late' (30 min p.i.) SUV(max) and SUV(meanA50) parameters were strongly associated (P<0.0001). SUV(max) relative difference was the best LN status predictor. All but one inguinal LN showed a decreasing [(18)F]FCH uptake over time (pattern A), while 95% of the pelvic nodes presented a stable or increasing uptake (pattern B) type. CONCLUSIONS: Time-trends of enhanced [(18)F]FCH uptake can help to characterize lymph nodes in prostate cancer patients. Single time-point SUV measurements, 30 min p.i., may be a reasonable alternative for predicting benign versus malignant status of lymph nodes, but this remains to be validated in non-enlarged pelvic lymph nodes

Contribution to the study of plant communities dominated by Ailanthus altissima (Mill.) Swingle, in the Eastern Romania (Moldavia)

In this paper, we aimed to analyze the structure, ecology and syntaxonomy of the communities dominated by Ailanthus altissima, in the Eastern Romania (Moldavia). This study has been achieved during our research on alien plants, conducted in 2009-2010. A number of 20 vegetation relevés have been carried out according to the Braun-Blanquet's methodology, in the spontaneous communities of Ailanthus altissima. The investigations led to the description of a new plant association (Balloto nigrae- Ailanthetum altissimae ass. nova). It is subordinated to the alliance Balloto nigrae- Robinion Jurko ex Hadač & Sofron 1980, order Chelidonio-Robinietalia Jurko ex Hadač & Sofron 1980, class Robinietea Jurko ex Hadač & Sofron 1980. Recognition species are Ballota nigra and Ailanthus altissima. Besides these, among the characteristic species of higher syntaxa (alliance, order, class), the following species stand out: Bromus sterilis (constant), Urtica dioica and Galium aparine (sub-constant). The stands are found on sunny lands, on roadsides, railway embankments, railway stations, steep slopes, ravines, abandoned fields, abandoned orchards or vineyards on terraces, ruderal lands, sandy lands, degraded pastures, or on the edge of Robinia pseudacacia plantations. They are situated between 38 and 265 m a.s.l. In ecological terms, the association Balloto nigrae- Ailanthetum altissimae includes heliophilous (sub-heliophilous), moderate thermophilous, xero-mesophilous, neutrophilous and moderate nitrophilous phytocoenoses. The results are discussed against the background of similar investigations of anthropogenic woody plant communities carried out by others authors

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Bat community species richness and composition in a restinga protected area in Southeastern Brazil

In Brazil, restingas are under severe human-induced impacts resulting in habitat degradation and loss and remain one of the less frequently studied ecosystems. The main objectives of the present study are to describe the bat community in a restinga in Paulo Cesar Vinha State Park, Guarapari municipality, state of Espírito Santo, southeastern Brazil. Fieldwork was conducted twice a month from August 2004 to September 2005. A total sampling effort of 40,300 m²/h, represents the largest sampling effort for sampling bats in restingas to date. Bats were sampled in five different vegetational types in the area. Captured bats were processed recording information on species, sex, age, forearm length and weight. Shannon Diversity and Jaccard indexes were used to analyse diversity and similarity among habitats in the Park. A total of 554 captures belonging to 14 species and two families were obtained. Noctilio leporinus was recorded through direct observation and an ultra-sound detector also registered the presence of individuals from the family Molossidae, without being possible to distinguish it at specific level. Frugivores were the most representative guild. Richness was higher in Clusia shrubs (11 species) and Caraís lagoon (10 species). Shannon diversity index was estimated at H' = 1.43 for the overall sample, with Caraís lagoon representing the most diverse habitat (H' = 1.60). The greater similarity (J = 0.714) was observed for the two areas under high human influence