Early evolution of the ecdysozoan body plan.

Extant ecdysozoans (moulting animals) are represented by a great variety of soft-bodied or articulated organisms that may or may not have appendages. However, controversies remain about the vermiform nature (i.e. elongated and tubular) of their ancestral body plan. We describe here Beretella spinosa gen. et sp. nov. a tiny (maximal length 3 mm) ecdysozoan from the lowermost Cambrian, Yanjiahe Formation, South China, characterized by an unusual sack-like appearance, single opening, and spiny ornament. Beretella spinosa gen. et sp. nov has no equivalent among animals, except Saccorhytus coronarius, also from the basal Cambrian. Phylogenetic analyses resolve both fossil species as a sister group (Saccorhytida) to all known Ecdysozoa, thus suggesting that ancestral ecdysozoans may have been non-vermiform animals. Saccorhytids are likely to represent an early off-shot along the stem-line Ecdysozoa. Although it became extinct during the Cambrian, this animal lineage provides precious insight into the early evolution of Ecdysozoa and the nature of the earliest representatives of the group.

Molting in early Cambrian armored lobopodians.

Lobopodians represent a key step in the early history of ecdysozoans since they were the first animals to evolve legs within this clade. Their Cambrian representatives share a similar body plan with a typically cylindrical annulated trunk and a series of non-jointed legs. However, they do not form a monophyletic group and likely include ancestors of the three extant panarthropod lineages (Tardigrada, Onychophora, Euarthropoda). Some species display astonishing protective devices such as cuticular plates and spines. We describe here the armor and molting process of Microdictyon from the early Cambrian of China. Microdictyon secreted ovoid paired cuticular sclerites that were duplicated in a non-synchronous way along the animal's body. The reticulated pattern and cuticular architecture of these sclerites have similarities to extant armored tardigrades that recently served in hypothesizing that tardigrades are possibly miniaturized lobopodians. Ecdysis and hard cuticular protection are now well documented in the whole spectrum of early Cambrian ecdysozoans such as soft-bodied scalidophorans, lobopodians and fully articulated euarthropods. We hypothesize that the secretion of sclerotized cuticular elements periodically renewed via ecdysis was a key innovation that opened large-scale evolutionary opportunities to invertebrate animal life, specifically ecdysozoans, both in terms of anatomical functionalities and ecological success.

Glucocorticoids paradoxically promote steroid resistance in B cell acute lymphoblastic leukemia through CXCR4/PLC signaling.

Glucocorticoid (GC) resistance in childhood relapsed B-cell acute lymphoblastic leukemia (B-ALL) represents an important challenge. Despite decades of clinical use, the mechanisms underlying resistance remain poorly understood. Here, we report that in B-ALL, GC paradoxically induce their own resistance by activating a phospholipase C (PLC)-mediated cell survival pathway through the chemokine receptor, CXCR4. We identify PLC as aberrantly activated in GC-resistant B-ALL and its inhibition is able to induce cell death by compromising several transcriptional programs. Mechanistically, dexamethasone (Dex) provokes CXCR4 signaling, resulting in the activation of PLC-dependent Ca2+ and protein kinase C signaling pathways, which curtail anticancer activity. Treatment with a CXCR4 antagonist or a PLC inhibitor improves survival of Dex-treated NSG mice in vivo. CXCR4/PLC axis inhibition significantly reverses Dex resistance in B-ALL cell lines (in vitro and in vivo) and cells from Dex resistant ALL patients. Our study identifies how activation of the PLC signalosome in B-ALL by Dex limits the upfront efficacy of this chemotherapeutic agent.

Direct reprogramming of non-limb fibroblasts to cells with properties of limb progenitors.

The early limb bud consists of mesenchymal limb progenitors derived from the lateral plate mesoderm (LPM). The LPM also gives rise to the mesodermal components of the flank and neck. However, the cells at these other levels cannot produce the variety of cell types found in the limb. Taking advantage of a direct reprogramming approach, we find a set of factors (Prdm16, Zbtb16, and Lin28a) normally expressed in the early limb bud and capable of imparting limb progenitor-like properties to mouse non-limb fibroblasts. The reprogrammed cells show similar gene expression profiles and can differentiate into similar cell types as endogenous limb progenitors. The further addition of Lin41 potentiates the proliferation of the reprogrammed cells. These results suggest that these same four factors may play pivotal roles in the specification of endogenous limb progenitors.

Orai1 Ca2+ channel modulators as therapeutic tools for treating cancer: Emerging evidence!

In non-excitable cells, Orai proteins represent the main channel for Store-Operated Calcium Entry (SOCE), and also mediate various store-independent Calcium Entry (SICE) pathways. Deregulation of these pathways contribute to increased tumor cell proliferation, migration, metastasis, and angiogenesis. Among Orais, Orai1 is an attractive therapeutic target explaining the development of specific modulators. Therapeutic trials using Orai1 channel inhibitors have been evaluated for treating diverse diseases such as psoriasis and acute pancreatitis, and emerging data suggest that Orai1 channel modulators may be beneficial for cancer treatment. This review discusses herein the importance of Orai1 channel modulators as potential therapeutic tools and the added value of these modulators for treating cancer.

A New Chengjiang Worm Sheds Light on the Radiation and Disparity in Early Priapulida.

The vast majority of early Paleozoic ecdysozoan worms are often resolved as stem-group Priapulida based on resemblances with the rare modern representatives of the group, such as the structure of the introvert and the number and distribution of scalids (a spiny cuticular outgrowth) and pharyngeal teeth. In Priapulida, both scalids and teeth create symmetry patterns, and three major diagnostic features are generally used to define the group: 25 longitudinal rows of scalids (five-fold symmetry), 8 scalids around the first introvert circle and the pentagonal arrangement of pharyngeal teeth. Here we describe Ercaivermis sparios gen. et sp. nov., a new priapulid from the early Cambrian Chengjiang Lagerstätte, characterized by an annulated trunk lacking a sclerotized ornament, four pairs of anal hooks and 16 longitudinal rows of scalids along its introvert and eight scalids around each introvert circle, giving the animal an unusual octoradial symmetry. Cladistic analyses resolve Ercaivermis as a stem-group priapulid. Ercaivermis also suggests that several biradial symmetry patterns (e.g., pentagonal, octagonal) expressed in the cuticular ornament, may have co-existed among early Cambrian priapulids and that the pentaradial mode may have become rapidly dominant during the course of evolution, possibly via the standardization of patterning, i.e., the natural selection of one symmetry type over others.

Mouse HP1γ regulates TRF1 expression and telomere stability.

AIMS: Telomeric repeat-containing RNAs are long non-coding RNAs generated from the telomeres. TERRAs are essential for the establishment of heterochromatin marks at telomeres, which serve for the binding of members of the heterochromatin protein 1 (HP1) protein family of epigenetic modifiers involved with chromatin compaction and gene silencing. While HP1γ is enriched on gene bodies of actively transcribed human and mouse genes, it is unclear if its transcriptional role is important for HP1γ function in telomere cohesion and telomere maintenance. We aimed to study the effect of mouse HP1γ on the transcription of telomere factors and molecules that can affect telomere maintenance. MAIN METHODS: We investigated the telomere function of HP1γ by using HP1γ deficient mouse embryonic fibroblasts (MEFs). We used gene expression analysis of HP1γ deficient MEFs and validated the molecular and mechanistic consequences of HP1γ loss by telomere FISH, immunofluorescence, RT-qPCR and DNA-RNA immunoprecipitation (DRIP). KEY FINDINGS: Loss of HP1γ in primary MEFs led to a downregulation of various telomere and telomere-accessory transcripts, including the shelterin protein TRF1. Its downregulation is associated with increased telomere replication stress and DNA damage (γH2AX), effects more profound in females. We suggest that the source for the impaired telomere maintenance is a consequence of increased telomeric DNA-RNA hybrids and TERRAs arising at and from mouse chromosomes 18 and X. SIGNIFICANCE: Our results suggest an important transcriptional control by mouse HP1γ of various telomere factors including TRF1 protein and TERRAs that has profound consequences on telomere stability, with a potential sexually dimorphic nature.

Beyond Corticoresistance, A Paradoxical Corticosensitivity Induced by Corticosteroid Therapy in Pediatric Acute Lymphoblastic Leukemias.

Known as a key effector in relapse of acute lymphoblastic leukemia (ALL), resistance to drug-induced apoptosis, is tightly considered one of the main prognostic factors for the disease. ALL cells are constantly developing cellular strategies to survive and resist therapeutic drugs. Glucocorticoids (GCs) are one of the most important agents used in the treatment of ALL due to their ability to induce cell death. The mechanisms of GC resistance of ALL cells are largely unknown and intense research is currently focused on this topic. Such resistance can involve different cellular and molecular mechanisms, including the modulation of signaling pathways involved in the regulation of proliferation, apoptosis, autophagy, metabolism, epigenetic modifications and tumor suppressors. Recently, several studies point to the paradoxical role of GCs in many survival processes that may lead to therapy-induced resistance in ALL cells, which we called "paradoxical corticosensitivity". In this review, we aim to summarize all findings on cell survival pathways paradoxically activated by GCs with an emphasis on previous and current knowledge on gene expression and signaling pathways.

Interpreting fossilized nervous tissues.

Paleoneuranatomy is an emerging subfield of paleontological research with great potential for the study of evolution. However, the interpretation of fossilized nervous tissues is a difficult task and presently lacks a rigorous methodology. We critically review here cases of neural tissue preservation reported in Cambrian arthropods, following a set of fundamental paleontological criteria for their recognition. These criteria are based on a variety of taphonomic parameters and account for morphoanatomical complexity. Application of these criteria shows that firm evidence for fossilized nervous tissues is less abundant and detailed than previously reported, and we synthesize here evidence that has stronger support. We argue that the vascular system, and in particular its lacunae, may be central to the understanding of many of the fossilized peri-intestinal features known across Cambrian arthropods. In conclusion, our results suggest the need for caution in the interpretation of evidence for fossilized neural tissue, which will increase the accuracy of evolutionary scenarios. Also see the video abstract here: https://youtu.be/2_JlQepRTb0.