Development of a stability-indicating UPLC method for determination of isotretinoin in bulk drug

A highly sensitive and rapid stability indicating ultra-performance liquid chromatographic (UPLC) method was developed for the quantification and identification of isotretinoin in bulk. Chromatographic separation was developed using a gradient elution in a reversed-phase system at flow rate of 0.5 ml/min with 12 min run time. The mobile phase was a gradient mixture of mobile phase A (contained a 30:70:0.5 mixture solution of methanol/purified water/glacial acetic acid) and mobile phase B (contained a 70:25:4.5:0.5 mixture solution of methanol/acetonitrile/purified water/glacial acetic acid). Eluents were monitored at 355 nm. The analytical method was validated for accuracy, precision, robustness, linearity, and forced degradation in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) topic Q2 (R1) ‘Validation of Analytical Procedures: Text and Methodology’. The method was linear over a concentration range of (1–7 µg/ml) with correlation coefficient of (r2 > 0.9999). The accuracy was confirmed by calculating the % recovery which was found to be 100.0–101.6%. The RSD values obtained for repeatability and intermediate precision experiments were less than 2%. The limit of detection (LOD) was 0.12 µg/ml, while the limit of quantification (LOQ) was 0.38 µg/ml. The drug samples were exposed to different stressed conditions and the results showed that all degradation products were satisfactorily separated from each other and from the peak of the drug using the developed method. The proposed method can be used for the quantitative determination of isotretinoin with confidence

Microvertebrates preserved in mammal burrows from the Holocene of the Argentine Pampas: a taphonomic and paleoecological approach

Microvertebrates are a major component of many assemblages recovered from the Quaternary of the Argentine Pampas. The main goal of this paper is to analyse the taphonomic history of a Holocene microfossil bonebed, recovered from the infilling of a burrow. Evidences suggest the plains vizcacha Lagostomus maximus as the putative producer of the burrow. The assemblage includes individuals belonging to different taxa of mammals (marsupials and rodents) and reptiles (snakes). Taphonomic features suggest that the accumulation inside the burrow was related to flooding processes in the plain. The burrow was a natural trap that favoured the accumulation and preservation of remains corresponding to individuals from different sources. According to the taphonomic evidence, some individuals (Lagostomus maximus, Lestodelphys halli and Serpentes indet.) died inside the burrow, whereas others (Microcavia australis, Reithrodon auritus and Ctenomys sp.) died outside the burrow, and after a time of being exposed on the surface their remains were transported by surface run-offs into the burrow. The record of Lestodelphys halli and Serpentes indet. in the burrow produced by Lagostomus maximus could be related to a circumstantial use. Mammal burrows are a significant taphonomic mode for the late Cenozoic of the Argentine Pampas

The Great American Biotic Interchange: Dispersals, Tectonics, Climate, Sea Level and Holding Pens

The biotic and geologic dynamics of the Great American Biotic Interchange are reviewed and revised. Information on the Marine Isotope Stage chronology, sea level changes as well as Pliocene and Pleistocene vegetation changes in Central and northern South America add to a discussion of the role of climate in facilitating trans-isthmian exchanges. Trans-isthmian land mammal exchanges during the Pleistocene glacial intervals appear to have been promoted by the development of diverse non-tropical ecologies

†Kenyaichthyidae fam. nov and †Kenyaichthys gen. nov - First Record of a Fossil Aplocheiloid Killifish (Teleostei, Cyprinodontiformes)

The extant Cyprinodontiformes (killifishes) with their two suborders Cyprinodontoidei and Aplocheiloidei represent a diverse and well-studied group of fishes. However, their fossil record is comparatively sparse and has so far yielded members of the Cyprinodontoidei only. Here we report on cyprinodontiform fossils from the upper Miocene Lukeino Formation in the Tugen Hills of the Central Rift Valley of Kenya, which represent the first fossil record of an aplocheiloid killifish. A total of 169 specimens - mostly extraordinarily well preserved and a sample of ten extant cyprinodontiform species were studied on the basis of morphometrics, meristics and osteology. A phylogenetic analysis using PAUP was also conducted for the fossils. Both the osteological data and the phylogenetic analysis provide strong evidence for the assignment of the fossils to the Aplocheiloidei, and justify the definition of the new family dagger Kenyaichthyidae, the new genus dagger Kenyaichthys and the new species dagger K. kipkechi sp. nov. The phylogenetic analysis unexpectedly places dagger Kenyaichthys gen. nov. in a sister relationship to the Rivulidae (a purely Neotropical group),a probable explanation might be lack of available synapomorphies for the Rivulidae, Nothobranchiidae and Aplocheilidae. The specimens of dagger K. kipkechi sp. nov. show several polymorphic characters and large overlap in meristic traits, which justifies their interpretation as a species flock in statu nascendi. Patterns of variation in neural and haemal spine dimensions in the caudal vertebrae of dagger Kenyaichthys gen. nov. and the extant species studied indicate that some previously suggested synapomorphies of the Cyprinodontoidei and Aplocheiloidei need to be revised

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

One thousand DNA barcodes of piranhas and pacus reveal geographic structure and unrecognised diversity in the Amazon

Piranhas and pacus (Characiformes: Serrasalmidae) are a charismatic but understudied family of Neotropical fishes. Here, we analyse a DNA barcode dataset comprising 1,122 specimens, 69 species, 16 genera, 208 localities, and 34 major river drainages in order to make an inventory of diversity and to highlight taxa and biogeographic areas worthy of further sampling effort and conservation protection. Using four methods of species discovery - incorporating both tree and distance based techniques - we report between 76 and 99 species-like clusters, i.e. between 20% and 33% of a priori identified taxonomic species were represented by more than one mtDNA lineage. There was a high degree of congruence between clusters, with 60% supported by three or four methods. Pacus of the genus Myloplus exhibited the most intraspecific variation, with six of the 13 species sampled found to have multiple lineages. Conversely, piranhas of the Serrasalmus rhombeus group proved difficult to delimit with these methods due to genetic similarity and polyphyly. Overall, our results recognise substantially underestimated diversity in the serrasalmids, and emphasise the Guiana and Brazilian Shield rivers as biogeographically important areas with multiple cases of across-shield and within-shield diversifications. We additionally highlight the distinctiveness and complex phylogeographic history of rheophilic taxa in particular, and suggest multiple colonisations of these habitats by different serrasalmid lineages. © 2018 The Author(s)

Breast milk microRNAs: Potential players in oral tolerance development

Breast milk is an essential source of nutrition and hydration for the infant. In addition, this highly complex biological fluid contains numerous immunologically active factors such as microorganisms, immunoglobulins, cytokines and microRNAs (miRNAs). Here, we set out to predict the function of the top 10 expressed miRNAs in human breast milk, focusing on their relevance in oral tolerance development and allergy prevention in the infant. The top expressed miRNAs in human breast milk were identified on basis of previous peer-reviewed studies gathered from a recent systematic review and an updated literature search. The miRNAs with the highest expression levels in each study were used to identify the 10 most common miRNAs or miRNA families across studies and these were selected for subsequent target prediction. The predictions were performed using TargetScan in combination with the Database for Annotation, Visualization and Integrated Discovery. The ten top expressed miRNAs were: let-7-5p family, miR-148a-3p, miR-30-5p family, miR-200a-3p + miR-141-3p, miR-22-3p, miR-181-5p family, miR-146b-5p, miR-378a-3p, miR-29-3p family, miR-200b/c-3p and miR-429-3p. The target prediction identified 3,588 potential target genes and 127 Kyoto Encyclopedia of Genes and Genomes pathways; several connected to the immune system, including TGF-b and T cell receptor signaling and T-helper cell differentiation. This review highlights the role of breast milk miRNAs and their potential contribution to infant immune maturation. Indeed, breast milk miRNAs seem to be involved in several pathways that influence oral tolerance development