Alternative splicing plays a key role in posttranscriptional regulation of gene expression, allowing a single gene to encode multiple protein isoforms. As such, alternative splicing amplifies the coding capacity of the genome enormously, generates protein diversity, and alters protein function. More than 90% of human genes undergo alternative splicing, and alternative splicing is especially prevalent in the nervous and immune systems, tissues where cells need to react swiftly and adapt to changes in the environment through carefully regulated mechanisms of cell differentiation, migration, targeting, and activation. Given its prevalence and complexity, this highly regulated mode of gene expression is prone to be affected by disease. In the following review, we look at how alternative splicing of signaling molecules—cytokines and their receptors—changes in different pathological conditions, from chronic inflammation to neurologic disorders, providing means of functional interaction between the immune and neuroendocrine systems. Switches in alternative splicing patterns can be very dynamic and can produce signaling molecules with distinct or antagonistic functions and localization to different subcellular compartments. This newly discovered link expands our understanding of the biology of immune and neuroendocrine cells, and has the potential to open new windows of opportunity for treatment of neurodegenerative disorders.

No abstract

Background Parasitic nematodes, including large roundworms colloquially known as ascarids, affect the health and well-being of livestock animals worldwide. The equine ascarids, Parascaris spp., are important parasites of juvenile horses and the first ascarids to develop widespread anthelmintic resistance. The microbiota has been shown to be an important factor in the fitness of many organisms, including parasitic nematodes, where endosymbiotic Wolbachia have been exploited for treatment of filariasis in humans. Methods This study used short-read 16S rRNA sequences and Illumina sequencing to characterize and compare microbiota of whole worm small intestinal stages and microbiota of male and female intestines and gonads. Diversity metrics including alpha and beta diversity, and the differential abundance analyses DESeq2, ANCOM-BC, corncob, and metagenomeSeq were used for comparisons. Results Alpha and beta diversity of whole worm microbiota did not differ significantly between groups, but Simpson alpha diversity was significantly different between female intestine (FI) and male gonad (MG) (P= 0.0018), and Shannon alpha diversity was significantly different between female and male gonads (P = 0.0130), FI and horse jejunum (HJ) (P = 0.0383), and FI and MG (P= 0.0001). Beta diversity (Fig. 2B) was significantly different between female and male gonads (P = 0.0006), male intestine (MI) and FG (P = 0.0093), and MG and FI (P = 0.0041). When comparing organs, Veillonella was differentially abundant for DESeq2 and ANCOM-BC (p < 0.0001), corncob (P = 0.0008), and metagenomeSeq (P = 0.0118), and Sarcina was differentially abundant across four methods (P < 0.0001). Finally, the microbiota of all individual Parascaris spp. specimens were compared to establish shared microbiota between groups. Conclusions Overall, this study provided important information regarding the Parascaris spp. microbiota and provides a first step towards determining whether the microbiota may be a viable target for future parasite control options. Graphical abstract

High-risk neuroblastoma (NB) is a solid pediatric tumor that develops from the extracranial sympathetic nervous system. Despite recent advances in therapeutic regimens of dose-intensive chemotherapies, radiation, and surgery NB often relapses as a metastatic and drug-resistant tumor. These issues further mandate the identification and development of novel therapeutic approaches for NB treatment. Cell cycle regulators, Cdk1 in combination with cyclin B1, and Cdk2 with cyclin E regulate the G2/M checkpoint and G1/S checkpoint respectively, to obstruct the cells from proceeding into mitosis with genomic DNA damage. Wee1, a tyrosine kinase, regulates the phosphorylation of Cdk1 and Cdk2 at tyrosine residues in response to DNA damage, making them inactive. Previous studies have reported high expression of Wee1 in NB patients and associate Wee1 with an overall poor NB prognosis. Inhibition of Wee1 obstructs the Cdk1 and Cdk2 activation and is no more reliant on an intact G2/M checkpoint for survival. In the present study, we analyzed multiple NB patient datasets and found that Wee1 expression is strongly correlated with poor overall survival of NB patients. Further, we used a specific small molecule Wee1 inhibitor in NB cells and observed that Wee1 inhibition significantly and in a dose-dependent manner inhibits NB proliferation and colony formation capacity in both MYCN-amplified and MYCN non-amplified NB cells. Further, Wee1 inhibition significantly induces apoptosis up to 3-fold in different NB cells in contrast to control treatments. Additionally, we used NB 3D spheroid models that mimic in vivo NB tumor growth and found that Wee1 inhibition significantly and in a dose-dependent manner inhibits 3D spheroid growth and volume up to 2.3-fold in contrast to control treatments. Additionally, and as expected, inhibition of Wee1 significantly inhibits NB cell cycle progression by inhibiting cell cycle S phase and blocking G2/M checkpoint in different NB cell lines. Further, the Wee1 inhibition inhibits the gene expression levels of different cell cycle-related genes in NB cells such as CDK1, CDK2, CCNB1, CHK2, and BCL-2. Overall, our data suggest that inhibition of the cell cycle regulator Wee1 is an effective therapeutic approach for NB. Further combining Wee1 inhibitors with current therapies will pave the way for developing effective targeted therapeutic approaches for NB patients.