†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

miR-143 Overexpression Impairs Growth of Human Colon Carcinoma Xenografts in Mice with Induction of Apoptosis and Inhibition of Proliferation

BACKGROUND: MicroRNAs (miRNAs) are aberrantly expressed in human cancer and involved in the (dys)regulation of cell survival, proliferation, differentiation and death. Specifically, miRNA-143 (miR-143) is down-regulated in human colon cancer. In the present study, we evaluated the role of miR-143 overexpression on the growth of human colon carcinoma cells xenografted in nude mice (immunodeficient mouse strain: N: NIH(s) II-nu/nu). METHODOLOGY/PRINCIPAL FINDINGS: HCT116 cells with stable miR-143 overexpression (Over-143) and control (Empty) cells were subcutaneously injected into the flanks of nude mice, and tumor growth was evaluated over time. Tumors arose ∼ 14 days after tumor cell implantation, and the experiment was ended at 40 days after implantation. miR-143 was confirmed to be significantly overexpressed in Over-143 versus Empty xenografts, by TaqMan® Real-time PCR (p<0.05). Importantly, Over-143 xenografts displayed slower tumor growth compared to Empty xenografts from 23 until 40 days in vivo (p<0.05), with final volumes of 928±338 and 2512±387 mm(3), respectively. Evaluation of apoptotic proteins showed that Over-143 versus Empty xenografts displayed reduced Bcl-2 levels, and increased caspase-3 activation and PARP cleavage (p<0.05). In addition, the incidence of apoptotic tumor cells, assessed by TUNEL, was increased in Over-143 versus Empty xenografts (p<0.01). Finally, Over-143 versus Empty xenografts displayed significantly reduced NF-κB activation and ERK5 levels and activation (p<0.05), as well as reduced proliferative index, evaluated by Ki-67 immunohistochemistry (p<0.01). CONCLUSIONS: Our results suggest that reduced tumor volume in Over-143 versus Empty xenografts may result from increased apoptosis and decreased proliferation induced by miR-143. This reinforces the relevance of miR-143 in colon cancer, indicating an important role in the control of in vivo tumor progression, and suggesting that miR-143 may constitute a putative novel therapeutic tool for colon cancer treatment that warrants further investigation

Identification of Y-Box Binding Protein 1 As a Core Regulator of MEK/ERK Pathway-Dependent Gene Signatures in Colorectal Cancer Cells

Transcriptional signatures are an indispensible source of correlative information on disease-related molecular alterations on a genome-wide level. Numerous candidate genes involved in disease and in factors of predictive, as well as of prognostic, value have been deduced from such molecular portraits, e.g. in cancer. However, mechanistic insights into the regulatory principles governing global transcriptional changes are lagging behind extensive compilations of deregulated genes. To identify regulators of transcriptome alterations, we used an integrated approach combining transcriptional profiling of colorectal cancer cell lines treated with inhibitors targeting the receptor tyrosine kinase (RTK)/RAS/mitogen-activated protein kinase pathway, computational prediction of regulatory elements in promoters of co-regulated genes, chromatin-based and functional cellular assays. We identified commonly co-regulated, proliferation-associated target genes that respond to the MAPK pathway. We recognized E2F and NFY transcription factor binding sites as prevalent motifs in those pathway-responsive genes and confirmed the predicted regulatory role of Y-box binding protein 1 (YBX1) by reporter gene, gel shift, and chromatin immunoprecipitation assays. We also validated the MAPK-dependent gene signature in colorectal cancers and provided evidence for the association of YBX1 with poor prognosis in colorectal cancer patients. This suggests that MEK/ERK-dependent, YBX1-regulated target genes are involved in executing malignant properties

The skull of Epidolops ameghinoi from the early Eocene Itaboraí fauna, southeastern Brazil, and the affinities of the extinct marsupialiform order Polydolopimorphia

The skull of the polydolopimorphian marsupialiform Epidolops ameghinoi is described in detail for the first time, based on a single well-preserved cranium and associated left and right dentaries plus additional craniodental fragments, all from the early Eocene (53-50 million year old) Itaboraí fauna in southeastern Brazil. Notable craniodental features of E. ameghinoi include absence of a masseteric process, very small maxillopalatine fenestrae, a prominent pterygoid fossa enclosed laterally by a prominent ectopterygoid crest, an absent or tiny transverse canal foramen, a simple, planar glenoid fossa, and a postglenoid foramen that is immediately posterior to the postglenoid process. Most strikingly, the floor of the hypotympanic sinus was apparently unossified, a feature found in several stem marsupials but absent in all known crown marsupials. "Type II" marsupialiform petrosals previously described from Itaboraí plausibly belong to E. ameghinoi; in published phylogenetic analyses, these petrosals fell outside (crown-clade) Marsupialia. "IMG VII" tarsals previously referred to E. ameghinoi do not share obvious synapomorphies with any crown marsupial clade, nor do they resemble those of the only other putative polydolopimorphians represented by tarsal remains, namely the argyrolagids. Most studies have placed Polydolopimorphia within Marsupialia, related to either Paucituberculata, or to Microbiotheria and Diprotodontia. However, diprotodonty almost certainly evolved independently in polydolopimorphians, paucituberculatans and diprotodontians, and Epidolops does not share obvious synapomorphies with any marsupial order. Epidolops is dentally specialized, but several morphological features appear to be more plesiomorphic than any crown marsupial. It seems likely Epidolops that falls outside Marsupialia, as do morphologically similar forms such as Bonapartherium and polydolopids. Argyrolagids differ markedly in their known morphology from Epidolops but share some potential apomorphies with paucituberculatans. It is proposed that Polydolopimorphia as currently recognised is polyphyletic, and that argyrolagids (and possibly other taxa currently included in Argyrolagoidea, such as groeberiids and patagoniids) are members of Paucituberculata. This hypothesis is supported by Bayesian non-clock phylogenetic analyses of a total evidence matrix comprising DNA sequence data from five nuclear protein-coding genes, indels, retroposon insertions and morphological characters: Epidolops falls outside Marsupialia, whereas argyrolagids form a clade with the paucituberculatans Caenolestes and Palaeothentes, regardless of whether the Type II petrosals and IMG VII tarsals are used to score characters for Epidolops or not. There is no clear evidence for the presence of crown marsupials at Itaboraí, and it is possible that the origin and early evolution of Marsupialia was restricted to the "Austral Kingdom" (southern South America, Antarctica, and Australia)

Inhibition of Osteoclast Differentiation by 1. 25‐D

International audienceActive vitamin D analogs and calcimimetics are the main therapies used for treating secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD). Peripheral blood mononuclear cells of 19 pediatric patients with CKD1-5D and 6 healthy donors (HD) were differentiated into mature osteoclasts with receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). The effects of single or combined treatment with active vitamin D (1.25-D) and/or calcimimetic KP2326 were evaluated on osteoclastic differentiation and osteoclastic-mediated bone resorption. Although 1.25-D inhibited osteoclastic differentiation, a significant resistance to 1.25-D was observed when glomerular filtration rate decreased. A significant albeit less important inhibitory effect of KP2326 on osteoclastic differentiation was also found both in cells derived from HD and CKD patients, through a putative activation of the Erk pathway. This inhibitory effect was not modified by CKD stage. Combinatorial treatment with 1.25-D and KP2326 did not result in synergistic effects. Last, KP2326 significantly inhibited osteoclast-mediated bone resorption. Both 1.25-D and KP2326 inhibit osteoclastic differentiation, however, to a different extent. There is a progressive resistance to 1.25-D in advanced CKD that is not found with KP2326. KP2326 also inhibits bone resorption. Given that 1.25-D has no effect on osteoclastic resorption activity and that calcimimetics also have direct anabolic effects on osteoblasts, there is an experimental rationale that could favor the use of decreased doses of 1.25-D with low doses of calcimimetics in SHPT in dialysis to improve the underlying osteodystrophy. However, this last point deserves confirmatory clinical studies. © 2020 American Society for Bone and Mineral Research

The impact of waterfowl herbivory on plant standing crop: a meta-analysis

Waterfowl can cause substantial reductions in plant standing crop, which may have ecological and economic consequences. However, what determines the magnitude of these reductions is not well understood. Using data from published studies, we derived the relationship between waterfowl density and reduction in plant standing crop. When waterfowl density was estimated as individuals ha−1 no significant relationship with reduction in plant standing crop was detected. However, when waterfowl density was estimated as kg ha−1 a significant, positive, linear relationship with reduction in plant standing crop was found. Whilst many previous studies have considered waterfowl species as homologous, despite large differences in body mass, our results suggest that species body mass is a key determinant of waterfowl impact on plant standing crop. To examine relative impacts of waterfowl groups based on species body mass, a measure of plant biomass reduction (Rs) per bird per hectare was calculated for each group. Comparison of Rs values indicated some differences in impact between different waterfowl groups, with swans having a greater per capita impact than smaller-bodied waterfowl groups. We present evidence that this difference is linked to disparities in individual body size and associated differences in intake rates, diet composition and energy requirements. Future research priorities are proposed, particularly the need for experiments that quantify the importance of factors that determine the magnitude of waterfowl impacts on plant standing crop