A 37 kb region upstream of Brachyury comprising a notochord enhancer is essential for notochord and tail development

The node-streak border region comprising notochord progenitor cells (NPCs) at the posterior node and neuro-mesodermal progenitor cells (NMPs) in the adjacent epiblast is the prime organizing center for axial elongation in mouse embryos. The T-box transcription factor Brachyury (T) is essential for both, formation of the notochord and maintenance of NMPs, and thus is a key regulator of trunk and tail development. The T promoter controlling T expression in NMPs and nascent mesoderm has been characterized in detail. However, control elements for T expression in the notochord have not been identified yet. We have generated a series of deletion alleles by CRISPR/Cas9 genome editing in mESCs, and analyzed their effects in mutant mouse embryos. We identified a 37 kb region upstream of T essential for notochord function and tailbud outgrowth. Within that region we discovered a T binding enhancer required for notochord cell specification and differentiation. Our data reveal a complex regulatory landscape controlling cell type-specific expression and function of T in NMP/nascent mesoderm and node/notochord allowing proper trunk and tail development.

Chain claims reserving methods in non-life insurance

Considering that the reliability of reserves valuation directly influences the financial strength of an insurance company, the main aim of this paper is to present a claims reserving estimation for a Romanian non-life insurer based on the most popular chain methods which are typically used in practice for the estimation of outstanding claims reserves in general insurance industry: Standard Chain Ladder and Munich Chain Ladder both on the claims incurred data and claims paid data. The tail development factors have been estimated based on the curve-fitting methods. The obvious advantage of these methods is represented by its simplicity of the practicality application. The results of the research under two chain claims reserving models reveal significant differences between the Standard Chain Ladder and Munich Chain Ladder with respect to the claims reserves level. Probably the Standard Chain Ladder based on paid method underestimates the outstanding loss liabilities and Standard Chain Ladder based on Incurred method overestimates the claims reserves. The claims reserves predictions under the Paid Munich Chain Ladder and Incurred Munich Chain Ladder are between the two Standard Chain Ladder outstanding loss liabilities estimates. The results of the tail extrapolation shown that the incorporation of the tail factors can have a significant impact on claims predictions.

Loss-of-function mutations in SPEF2 cause multiple morphological abnormalities of the sperm flagella (MMAF)

BackgroundMultiple morphological abnormalities of the sperm flagella (MMAF) is a kind of severe teratozoospermia. Patients with the MMAF phenotype are infertile and present aberrant spermatozoa with absent, short, coiled, bent and/or irregular flagella. Mutations in several genes can explain approximately 30%–50% of MMAF cases and more genetic pathogenies need to be explored. SPEF2 was previously demonstrated to play an essential role in sperm tail development in mice and pig. Dysfunctional mutations in SPEF2 impair sperm motility and cause a short-tail phenotype in both animal models.ObjectiveBased on 42 patients with severe infertility and MMAF phenotype, we explored the new genetic cause of human MMAF phenotype.Methods and resultsBy screening gene variants in 42 patients with MMAF using whole exome sequencing, we identified the c. 12delC, c. 1745-2A > G, c. 4102 G > T and c. 4323dupA mutations in the SPEF2 gene from two patients. Both of these mutations are rare and potentially deleterious. Transmission electron microscope (TEM) analysis showed a disrupted axonemal structure with mitochondrial sheath defects in the patients’ spermatozoa. The SPEF2 protein level was significantly decreased in the spermatozoa of the patients revealed by Western blot (WB) and immunofluorescence (IF) analyses.ConclusionOur experimental findings indicate that loss-of-function mutations in the SPEF2 gene can cause the MMAF phenotype in human.

Identification of a regeneration-organizing cell in the Xenopus tail

Unlike mammals, Xenopus laevis tadpoles have a high regenerative potential. To characterize this regenerative response, we performed single-cell RNA sequencing after tail amputation. By comparing naturally occurring regeneration-competent and -incompetent tadpoles, we identified a previously unrecognized cell type, which we term the regeneration-organizing cell (ROC). ROCs are present in the epidermis during normal tail development and specifically relocalize to the amputation plane of regeneration-competent tadpoles, forming the wound epidermis. Genetic ablation or manual removal of ROCs blocks regeneration, whereas transplantation of ROC-containing grafts induces ectopic outgrowths in early embryos. Transcriptional profiling revealed that ROCs secrete ligands associated with key regenerative pathways, signaling to progenitors to reconstitute lost tissue. These findings reveal the cellular mechanism through which ROCs form the wound epidermis and ensure successful regeneration.

COHERENT INCURRED PAID (CIP) MODELS FOR CLAIMS RESERVING

In this paper, we first propose a statistical model, called the Coherent Incurred Paid model, to predict future claims, using simultaneously the information contained in incurred and paid claims. This model does not assume log-normality of the levels (or normality of the growth rates) and is semi-parametric since it only specifies the first and the second moments; however, in order to evaluate the impact of the normality assumption, we also propose a benchmark Gaussian version of our model. Correlations between growth rates of incurred and paid claims are allowed and the tail development period is estimated. We also provide methods for computing the Claim Development Results and their Values at Risk in the semi-parametric framework. Moreover, we show how to take into account the updating of the estimation in the computation of the Claim Development Results. An application highlights the practical importance of relaxing the normality assumption and of updating the estimation of the parameters.