A morphological intermediate between eosimiiform and simiiform primates from the late middle Eocene of Tunisia: Macroevolutionary and paleobiogeographic implications of early anthropoids.

Although advanced anthropoid primates (i.e., Simiiformes) are recorded at the end of the Eocene in North Africa (Proteopithecidae, Parapithecidae, and Oligopithecidae), the origin and emergence of this group has so far remained undocumented. The question as to whether these primates are the result of a monophyletic radiation of endemic anthropoids in Africa, or several Asian clades colonizing Africa, is a current focus of paleoprimatology. In this article, we report the discovery of a new anthropoid from Djebel el Kébar in central Tunisia, dating from the late middle Eocene (Bartonian). This taxon, Amamria tunisiensis, new genus and species, currently known by only one isolated upper molar, is among the most ancient anthropoids to be recorded in Africa thus far. Amamria displays a suite of dental features that are primarily observed in Eosimiiformes (stem Anthropoidea). However, it is not allocated to any known family of that group (i.e., Asian Eosimiidae and Afro-Asian Afrotarsiidae) inasmuch as it develops some dental traits that are unknown among eosimiiforms, but can be found in African simiiform anthropoids such as proteopithecids and oligopithecids. With such a mosaic of dental traits, Amamria appears to be a structural intermediate, and as such it could occupy a key position, close to the root of the African simiiforms. Given its antiquity and its apparent pivotal position, the possibility exists that Amamria could have evolved in Africa from Asian eosimiiform or Asian "proto"-simiiform ancestors, which would have entered Africa sometime during the middle Eocene. Amamria could then represent one of the earliest offshoots of the African simiiform radiation. This view would then be rather in favor of the hypothesis of a monophyletic radiation of endemic simiiform anthropoids in Africa. Finally, these new data suggest that there must have been at least two Asian anthropoid colonizers of Africa: the afrotarsiids and the ancestor of Amamria.

New insights into the ear region anatomy and cranial blood supply of advanced stem Strepsirhini: evidence from three primate petrosals from the Eocene of Chambi, Tunisia.

We report the discovery of three isolated primate petrosal fragments from the fossiliferous locality of Chambi (Tunisia), a primate-bearing locality dating from the late early to the early middle Eocene. These fossils display a suite of anatomical characteristics otherwise found only in strepsirhines, and as such might be attributed either to Djebelemur or/and cf. Algeripithecus, the two diminutive stem strepsirhine primates recorded from this locality. Although damaged, the petrosals provide substantial information regarding the ear anatomy of these advanced stem strepsirhines (or pre-tooth-combed primates), notably the patterns of the pathway of the arterial blood supply. Using µCT-scanning techniques and digital segmentation of the structures, we show that the transpromontorial and stapedial branches of the internal carotid artery (ICA) were present (presence of bony tubes), but seemingly too small to supply enough blood to the cranium alone. This suggests that the ICA was not the main cranial blood supply in stem strepsirhines, but that the pharyngeal or vertebral artery primitively ensured a great part of this role instead, an arterial pattern that is reminiscent of modern cheirogaleid, lepilemurid lemuriforms and lorisiforms. This could explain parallel loss of the ICA functionality among these families. Specific measurements made on the cochlea indicate that the small strepsirhine primate(s) from Chambi was (were) highly sensitive to high frequencies and poorly sensitive to low frequencies. Finally, variance from orthogonality of the plane of the semicircular canals (SCs) calculated on one petrosal (CBI-1-569) suggests that Djebelemur or cf. Algeripithecus likely moved (at least its head) in a way similar to that of modern mouse lemurs.

Machine learning identification of specific changes in myeloid cell phenotype during bloodstream infections.

The early identification of bacteremia is critical for ensuring appropriate treatment of nosocomial infections in intensive care unit (ICU) patients. The aim of this study was to use flow cytometric data of myeloid cells as a biomarker of bloodstream infection (BSI). An eight-color antibody panel was used to identify seven monocyte and two dendritic cell subsets. In the learning cohort, immunophenotyping was applied to (1) control subjects, (2) postoperative heart surgery patients, as a model of noninfectious inflammatory responses, and (3) blood culture-positive patients. Of the complex changes in the myeloid cell phenotype, a decrease in myeloid and plasmacytoid dendritic cell numbers, increase in CD14+CD16+ inflammatory monocyte numbers, and upregulation of neutrophils CD64 and CD123 expression were prominent in BSI patients. An extreme gradient boosting (XGBoost) algorithm called the "infection detection and ranging score" (iDAR), ranging from 0 to 100, was developed to identify infection-specific changes in 101 phenotypic variables related to neutrophils, monocytes and dendritic cells. The tenfold cross-validation achieved an area under the receiver operating characteristic (AUROC) of 0.988 (95% CI 0.985-1) for the detection of bacteremic patients. In an out-of-sample, in-house validation, iDAR achieved an AUROC of 0.85 (95% CI 0.71-0.98) in differentiating localized from bloodstream infection and 0.95 (95% CI 0.89-1) in discriminating infected from noninfected ICU patients. In conclusion, a machine learning approach was used to translate the changes in myeloid cell phenotype in response to infection into a score that could identify bacteremia with high specificity in ICU patients.

New features in the treatment of androgen-independent prostate cancer.

Prostate cancer develops from clones that are already present as early as thirty-five years of age, when circulating concentrations of androgens are high. The progression of the disease is low and the cancer is diagnosed at a more advanced age. Prostate cancer evolves from an androgen dependant stage to stage where it escapes from all anti-androgenic treatments. The patient usually dies within two years following the diagnosis of advanced cancer. Therefore, it is of great interest to develop new therapies for androgen independent prostate cancer. The androgen independent evolution of prostate cancer is a complex phenomenon at the cellular and molecular levels. It includes an increased sensitivity to growth factors, the control of proliferation pathways, apoptotic and survival pathways as well as the control of angiogenesis. Epidemiological studies have also suggested that certain vitamins or phyto-oestrogens could protect against prostate cancer development. The present review attempts to present an overview of the fundamental research in cellular signalling which could be interesting as target for the treatment of androgen independent prostate cancer. Also the potential interest of non-androgenic steroids was reviewed for the same goal.

Djebelemur, a tiny pre-tooth-combed primate from the Eocene of Tunisia: a glimpse into the origin of crown strepsirhines.

BACKGROUND: Molecular clock estimates of crown strepsirhine origins generally advocate an ancient antiquity for Malagasy lemuriforms and Afro-Asian lorisiforms, near the onset of the Tertiary but most often extending back to the Late Cretaceous. Despite their inferred early origin, the subsequent evolutionary histories of both groups (except for the Malagasy aye-aye lineage) exhibit a vacuum of lineage diversification during most part of the Eocene, followed by a relative acceleration in diversification from the late Middle Eocene. This early evolutionary stasis was tentatively explained by the possibility of unrecorded lineage extinctions during the early Tertiary. However, this prevailing molecular view regarding the ancient origin and early diversification of crown strepsirhines must be viewed with skepticism due to the new but still scarce paleontological evidence gathered in recent years. METHODOLOGICAL/PRINCIPAL FINDINGS: Here, we describe new fossils attributable to Djebelemur martinezi, a≈50 Ma primate from Tunisia (Djebel Chambi). This taxon was originally interpreted as a cercamoniine adapiform based on limited information from its lower dentition. The new fossils provide anatomical evidence demonstrating that Djebelemur was not an adapiform but clearly a distant relative of lemurs, lorises and galagos. Cranial, dental and postcranial remains indicate that this diminutive primate was likely nocturnal, predatory (primarily insectivorous), and engaged in a form of generalized arboreal quadrupedalism with frequent horizontal leaping. Djebelemur did not have an anterior lower dentition as specialized as that characterizing most crown strepsirhines (i.e., tooth-comb), but it clearly exhibited a transformed antemolar pattern representing an early stage of a crown strepsirhine-like adaptation ("pre-tooth-comb"). CONCLUSIONS/SIGNIFICANCE: These new fossil data suggest that the differentiation of the tooth-comb must postdate the djebelemurid divergence, a view which hence constrains the timing of crown strepsirhine origins to the Middle Eocene, and then precludes the existence of unrecorded lineage extinctions of tooth-combed primates during the earliest Tertiary.

Clusterin activates survival through the phosphatidylinositol 3-kinase/Akt pathway.

Clusterin is, in its major form, a secreted heterodimeric disulfide-linked glycoprotein (75-80 kDa). It was first linked to cell death in the rat ventral prostate after androgen deprivation. Recent studies have demonstrated that overexpression of clusterin in prostatic cells protects them against tumor necrosis factor-alpha (TNFalpha)-induced apoptosis. However the details of this survival mechanism remain undefined. Here, we investigate how clusterin prevents cells from undergoing TNFalpha-induced apoptosis. We established a double-stable prostatic cell line for inducible clusterin by using the Tet-On gene expression system. We demonstrated that 50% of the cells overexpressing clusterin escaped from TNFalpha- and actinomycin D-induced cell death. Moreover we demonstrated that the incubation of MLL cells with conditioned medium containing the secreted clusterin or the supplementation of purified clusterin in the extracellular medium decreased the TNFalpha-induced apoptosis significantly. This extracellular action implicates megalin, the putative membrane receptor for clusterin to mediate survival. Indeed clusterin overexpression up-regulated the expression of megalin and induced its phosphorylation in a dose-dependent manner. We interestingly showed that clusterin overexpression is associated with the up-regulation of the phosphorylation of Akt. Activated Akt induced the phosphorylation of Bad and caused a decrease of cytochrome c release. These results enable us to pinpoint one mechanism by which secreted clusterin favors survival in androgen-independent prostate cancer cells, implicating its receptor megalin and Akt survival pathway.