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Pseudoextinction analyses, which simulate extinction in extant taxa, use molecular phylogenetics to assess the accuracy of morphological phylogenetics. Previous pseudoextinction analyses have shown a failure of morphological phylogenetics to place some individual placental orders in the correct superordinal clade. Recent work suggests that the inclusion of hypothetical ancestors of extant placental clades, estimated by ancestral state reconstructions of morphological characters, may increase the accuracy of morphological phylogenetic analyses. However, these studies reconstructed direct hypothetical ancestors for each extant taxon based on a well-corroborated molecular phylogeny, which is not possible for extinct taxa that lack molecular data. It remains to be determined if pseudoextinct taxa, and by proxy extinct taxa, can be accurately placed when their immediate hypothetical ancestors are unknown. To investigate this, we employed molecular scaffolds with the largest available morphological data set for placental mammals. Each placental order was sequentially treated as pseudoextinct by exempting it from the molecular scaffold and recoding soft morphological characters as missing for all its constituent species. For each pseudoextinct data set, we omitted the pseudoextinct taxon and performed a parsimony ancestral state reconstruction to obtain hypothetical predicted ancestors. Each pseudoextinct order was then evaluated in seven parsimony analyses that employed combinations of fossil taxa, hypothetical predicted ancestors, and a molecular scaffold. In treatments that included fossils, hypothetical predicted ancestors, and a molecular scaffold, only 8 of 19 pseudoextinct placental orders (42%) retained the same interordinal placement as on the molecular scaffold. In treatments that included hypothetical predicted ancestors but not fossils or a scaffold, only four placental orders (21%) were recovered in positions that are congruent with the scaffold. These results indicate that hypothetical predicted ancestors do not increase the accuracy of pseudoextinct taxon placement when the immediate hypothetical ancestor of the taxon is unknown. Hypothetical predicted ancestors are not a panacea for morphological phylogenetics.

Multistate morphological characters are routinely used in phylogenetic analyses. Individual multistate characters may be treated as linearly ordered, partially ordered, or unordered. Each option implies a hypothesis of character evolution, and significant debate surrounds the appropriateness of ordering multistate characters. Several previous analyses support ordering multistate morphological characters when the character states form a morphocline. Here, we explore the effects of ordering a subset of characters in the largest morphological character matrix that is available for placental mammals. All multistate characters were assessed and were ordered only if the character states were meristic or hypothesized to form a morphocline. We then performed parsimony analyses, with and without molecular scaffolds, to examine the effects of ordering on placental mammal phylogeny. We also performed pseudoextinction analyses, which treated designated extant taxa as extinct by eliminating them from the molecular scaffold and scoring soft-tissue characters as missing, to determine if ordered or unordered characters would more accurately reconstruct the relationships of pseudoextinct placental orders. Character ordering affected the placement of a variety of taxa in non-scaffolded analyses, but the effects were less evident in scaffolded analyses. Nevertheless, one of the islands of most parsimonious trees with the ordered data set and a scaffold for extant taxa supported the inclusion of Leptictida, including the Late Cretaceous Gypsonictops , inside of crown Placentalia. Our analyses rarely supported the monophyly of Tamirtheria, the Late Cretaceous-Paleogene stem-based clade that is hypothesized to be the sister to Placentalia. Pseudoextinction analyses using ordered and unordered characters both reconstructed 12 of 19 pseudoextinct orders in positions that are incongruent with a well-supported molecular scaffold. These results suggest that the use of ordered multistate characters does not increase the proportion of well-supported molecular clades that are reconstructed with the largest available phenomic data set for placental mammals.

Glioblastoma multiforme (GBM) is the most malignant primary brain cancer affecting adults. Therapeutic options for GBM have remained the same for over a decade with no significant improvement. Many therapies that are successful in culture have failed in patients, likely due to the complex microenvironment in the brain, which has yet to be reproduced in any culture model. Furthermore, the high passage number of cultured cells and clonal selection fail to recapitulate the molecular and genomic signatures of GBM. We have established orthotopic patient-derived xenografts (PDX) from 37 GBM patients with human GBM. Of the 69 patient samples analyzed, we were successful in passaging 37 lines three or more generations (53.6%). After phenotypic characterization of the xenografted tumor tissue, two different growth patterns emerged highly invasive or localized. The phenotype was dependent on malignancy and previous treatment of the patient from which the xenograft was derived. Physiologically, mice exhibited symptoms more quickly with each subsequent passage, particularly in the localized tumors. Study of these physiologically relevant human xenografts in mice will enable therapeutic screenings in a microenvironment that more closely resembles GBM and may allow development of individualized patient models which may eventually be used for simulating treatment.

Introduction and hypothesis Understanding the clustering of pelvic floor disorders (PFDs) within families is important because it may suggest underlying risk factors that may be environmental, genetic or both. The objective of this study was to describe clinical characteristics observed in familial cases with PFDs and compare them with strictly defined controls. Methods Women evaluated and treated for PFDs were recruited as part of a larger genetic study. Here, we define familial cases as those with bothersome symptoms or treatment for a PFD (pelvic organ prolapse [POP], stress urinary incontinence [SUI], and overactive bladder [OAB]) and who had a first-degree relative with bothersome symptoms or treatment for the same pelvic floor defect. We assigned clinical characteristics to probands and their relatives using standardized symptom questions (PFDI), examination, and review of treatment records, if any. Results We identified 126 familial POP cases, 183 familial SUI cases, and 101 familial OAB cases. Familial cases were more likely to have bothersome symptoms for more than one PFD. Among familial POP cases, bothersome SUI (71 %), OAB (54 %), and a combination of all three disorders (48 %) were common. Among familial SUI cases, bothersome OAB (60 %), POP (59 %), and combinations of all disorders (40 %) were common. Among familial OAB cases, bothersome SUI (88 %), POP (66 %), and combinations of all three disorders (59 %) were common. Conclusions Familial cases of POP, SUI, and OAB are more likely to have more than one pelvic floor defect. It is likely that underlying genetic factors contribute to more than one pelvic floor defect.