During the first postnatal week of mouse development, radial glial cells lining the ventricles of the brain differentiate into ependymal cells, undergoing a morphological change from pseudostratified cuboidal cells to a flattened monolayer. Concomitant with this change, multiple motile cilia are generated and aligned on each nascent ependymal cell. Proper ependymal cell development is crucial to forming the brain tissue:CSF barrier, and to the establishment of ciliary CSF flow, but the mechanisms that regulate this differentiation event are poorly understood. The Jhy^lacZ mouse line carries an insertional mutation in the Jhy gene (formerly 4931429I11Rik), and homozygous Jhy^lacZ/lacZ mice develop a rapidly progressive juvenile hydrocephalus, with defects in ependymal cilia morphology and ultrastructure. Here we show that beyond just defective motile cilia, Jhy^lacZ/lacZ mice display abnormal ependymal cell differentiation. Ventricular ependyma in Jhy^lacZ/lacZ mice retain an unorganized and multi-layered morphology, representative of undifferentiated ependymal (radial glial) cells, and they show altered expression of differentiation markers. Most Jhy^lacZ/lacZ ependymal cells do eventually acquire some differentiated ependymal characteristics, suggesting a delay, rather than a block, in the differentiation process, but ciliogenesis remains perturbed. Jhy^lacZ/lacZ ependymal cells also manifest disruptions in adherens junction formation, with altered N-cadherin localization, and have defects in the polarized organization of the apical motile cilia that do form. Functional studies showed that cilia of Jhy^lacZ/lacZ mice have severely reduced motility, a potential cause for the development of hydrocephalus. This work shows that JHY does not only control ciliogenesis, but is a crucial component of the ependymal differentiation process, with ciliary defects likely a consequence of altered ependymal differentiation.

Much effort has focused recently on determining the mechanisms that control the allele-specific expression of genes subject to genomic imprinting, yet imprinting regulation is only one aspect of configuring appropriate expression of these genes. Imprinting control mechanisms must interact with those regulating the tissue-specific expression pattern of each imprinted gene in a cluster. Proper expression of the imprinted Delta-like 1 (Dlk1) - Maternally expressed gene 3 (Meg3) gene pair is required for normal fetal development in mammals, yet the mechanisms that control tissue-specific expression of these genes are unknown. We have used a combination of in vivo and in vitro expression assays to localize cis-regulatory elements that may regulate Dlk1 expression in the mouse embryo. A bacterial artificial chromosome transgene encompassing the Dlk1 gene and 77 kb of flanking sequence conferred expression in most endogenous Dlk1-expressing tissues. In combination with previous transgenic data, these experiments localize the majority of Dlk1 cis-regulatory elements to a 41 kb region upstream of the gene. Cross-species sequence conservation was used to further define potential regulatory elements, several of which functioned as enhancers in a luciferase expression assay. Two of these elements were able to drive expression of a lacZ reporter transgene in Dlk1-expressing tissues in the mouse embryo. The sequence proximal to Dlk1 therefore contains at least two discrete regions that may regulate tissue-specificity of Dlk1 expression.

Background and Aims: While irresectable pancreatic cancer has still a dismal overall prognosis, evidence about the optimal chemotherapy sequence is scarce. After treatment with FOLFIRINOX in first-line, gemcitabine monotherapy was established for years. As a potential treatment alternative after failure of FOLFIRINOX therapy, combination of gemcitabine and nab-paclitaxel is used. However, this combination has formally not yet been approved for second-line treatment and investigation of efficiency and treatment tolerance is the aim of this trial. Methods: Therefore, we investigated 225 patients with histologically confirmed local advanced or metastatic pancreatic cancer in this retrospective monocentre study (November 2010 – July 2019). Of this, 44 patients received FOLFIRINOX therapy and outcome was further analysed. The primary end point of this cohort was overall survival (OS), and secondary end points included progression-free survival (PFS), response rate, and safety. Results: In most of the patients, FOLFIRINOX as first-line treatment of irresectable pancreatic cancer resulted in temporary cancer control (partial response [PR]: 50% and stable disease [SD]: 18%), whereas tumour progression was observed in 23% of the patients. The median PFS time for FOLFIRINOX treatment was 7.3 months and median OS 10.3 months. Seven (16%) patients received additional local radio chemotherapy of the pancreatic tumour. During first-line therapy, in 8 (18%) patients, laparotomy was performed to proof resectability of the tumour. Hereby, in 3 patients R0- and in 3 patients R1 resection was achieved, whereas 2 patients stayed irresectable. Twenty-five of the 44 patients (57%) received second-line therapy, namely, 24 patients gemcitabine/nab-paclitaxel and 1 patient gemcitabine and erlotinib. Hereby, gemcitabine/nab-paclitaxel led again to temporary tumour control in 46% of the patients (PR: 21%, SD: 25%), while in 29% of the patients, disease progression was observed. Corresponding median PFS for gemcitabine and nab-paclitaxel treatment was 3.5 months. Patients who received second-line treatment with nab-paclitaxel and gemcitabine had a more favourable prognosis (median OS: 17 vs. 9.2 months; HR 0.32 [0.14–0.70], p < 0.001) than patients who were not eligible for second-line treatment. Moreover, in multivariate analyses association with patients’ survival and tumour response to chemotherapy in both therapeutic lines and µGT concentrations below 100 IU/L in first-line FOLFIRINOX chemotherapy were observed. Conclusion: These real-world data suggest that gemcitabine/nab-paclitaxel may be feasible after FOLFIRINOX therapy in patients with irresectable pancreatic cancer. However, prospective randomized data about the superiority to gemcitabine monotherapy are needed.

The bowmouth guitarfish (Rhina ancylostomus) is among the most endangered of marine vertebrates, and evidence of severe declines and localized extinctions has been reported. Yet its life history and ecology suffer from a lack of scientific attention due to the scarcity and unpredictable movements of the species. By collecting opportunistic records from 2015 to 2023 during diving activities, this study describes for the first time the occurrence of a predictable aggregation of R. ancylostomus in the Gulf of Tadjoura (Djibouti). These data provide a key record of this species in the area, whose presence is strongly associated with sandy seabeds and corals at approximately 35 m depth. Based on the opportunistic sightings of R. ancylostomus during diving activity, Ras Eiro and Ras Korali appear to be the currently known core habitats for this species and may serve as breeding or feeding grounds. Overall, our data show that the Gulf of Tadjoura is a globally important conservation hotspot, and therefore its protection should be prioritized.

A subadult leatherback turtle was documented in the Gulf of Goubet (Djibouti) during a research expedition. This sighting confirms for the first time previous anecdotal observations of the occurrence of the leatherback turtle, Dermochelys coriacea (Vandelli, 1761), in Djibouti waters. Coupled with observations from fishers, this finding underlines the urgent need to carry out research programs to evaluate the species habitat use within Djibouti waters, and to review the species distribution in the Gulf of Aden. Although marine turtles are protected in Djibouti, illegal harvest and entanglement in fishing gear pose a threat to their survival, and conservation measures should be implemented.