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Lysophospholipids are a class of bioactive lipid molecules that produce their effects through various G protein-coupled receptors (GPCRs). Sphingosine 1-phosphate (S1P) is perhaps the most studied lysophospholipid and has a role in a wide range of physiological and pathophysiological events, via signalling through five distinct GPCR subtypes, S1PR 1 to S1PR 5 . Previous and continuing investigation of the S1P pathway has led to the approval of three S1PR modulators, fingolimod, siponimod and ozanimod, as medicines for patients with multiple sclerosis (MS), as well as the identification of new S1PR modulators currently in clinical development, including ponesimod and etrasimod. S1PR modulators have complex effects on S1PRs, in some cases acting both as traditional agonists as well as agonists that produce functional antagonism. S1PR subtype specificity influences their downstream effects, including aspects of their benefit:risk profile. Some S1PR modulators are prodrugs, which require metabolic modification such as phosphorylation via sphingosine kinases, resulting in different pharmacokinetics and bioavailability, contrasting with others that are direct modulators of the receptors. The complex interplay of these characteristics dictates the clinical profile of S1PR modulators. This review focuses on the S1P pathway, the characteristics and S1PR binding profiles of S1PR modulators, the mechanisms of action of S1PR modulators with regard to immune cell trafficking and neuroprotection in MS, together with a summary of the clinical effectiveness of the S1PR modulators that are approved or in late-stage development for patients with MS. 9mFLdhkinC3ai_zBDFnYbZ Sphingosine 1-phosphate receptor modulator therapy for multiple sclerosis: differential downstream receptor signalling and clinical profile effects (MP4 65540 kb)

A heartrending yet hopeful play about two mens parallel desires to build a secure foundation for their families even as everything around them is falling apart. At first glance, Ryan and Keith are two men in Twin Falls, Idaho, who have nothing in common. Ryan, a factory worker in the throes of financial instability, seeks help from Keith, a mortgage broker, to secure a loan. The two bond over their love of their daughters, as well as a specific kind of sadness that lives in the gap between their dreams and realities. Affecting in its seeming simplicity, Hunters play ultimately affirms, if not the existence of God, then at least the possibility that something sacred can come from the connection between two people.

Fingolimod, a structural analog of sphingosine derived from fungal metabolites, is a functional antagonist of the G-protein-coupled sphingosine 1-phosphate (S1P) receptors S1P 1,3,4,5 . In the treatment of relapsing forms of multiple sclerosis (RMS), fingolimod acts by reversibly retaining central memory T cells and naïve T cells in lymph nodes, thereby reducing the recirculation of autoreactive lymphocytes to the central nervous system (CNS). Fingolimod also has differential effects on the trafficking and function of B-cell subtypes and natural killer (NK) cells in peripheral blood and the CNS. Fingolimod also crosses the blood–brain barrier (BBB) and accumulates in the CNS. Experimental evidence increasingly supports a direct action of fingolimod within the CNS on brain cells, providing protection against the neurodegenerative component of RMS. We review the direct influence of this compound on CNS pathogenesis in RMS, including the central effects of fingolimod in animal models of MS and on neural cell types that express S1P receptors, such as astrocytes, BBB endothelial cells, microglia, neurones, and oligodendrocytes, which are all involved in RMS pathology.

Using conservation of resources theory, we challenge traditional unity of command models of leadership and propose that a dual-leadership framework can serve as a potential solution to the inherent challenges of innovation. Leading for innovation demands are depicted as uniquely disparate from other forms of leadership, resulting in several types of conflict and resource depletion for individual leaders. We contend that this exploration–exploitation role conflict and the resulting need to manage incongruent role identities produce stress, strain, and resource depletion that in turn hamper innovative goal achievement for both a single leader directly and via subordinates more indirectly. We propose, however, that as an extension of the resource investment tenet of the conservation of resources theory, a dual-leadership approach may alleviate many of these challenges for innovation. Specifically, the addition of a second leader can add resources to innovation and in turn decrease the role conflict inherent in managing the generation and implementation of creative ideas. Limitations and areas for future research are offered.

The signaling molecule retinoic acid (RA) regulates rod and cone photoreceptor fate, differentiation, and survival. Here we elucidate the role of RA in differential regulation of the tandemly-duplicated long wavelength-sensitive (LWS) cone opsin genes. Zebrafish embryos were treated with RA from 48 hours post-fertilization (hpf) to 75 hpf, and RNA was isolated from eyes for microarray analysis. ~170 genes showed significantly altered expression, including several transcription factors and components of cellular signaling pathways. Of interest, the LWS1 opsin gene was strongly upregulated by RA. LWS1 is the upstream member of the tandemly duplicated LWS opsin array and is normally not expressed embryonically. Embryos treated with RA 48 hpf to 100 hpf or beyond showed significant reductions in LWS2-expressing cones in favor of LWS1-expressing cones. The LWS reporter line, LWS-PAC(H) provided evidence that individual LWS cones switched from LWS2 to LWS1 expression in response to RA. The RA signaling reporter line, RARE:YFP indicated that increased RA signaling in cones was associated with this opsin switch, and experimental reduction of RA signaling in larvae at the normal time of onset of LWS1 expression significantly inhibited LWS1 expression. A role for endogenous RA signaling in regulating differential expression of the LWS genes in postmitotic cones was further supported by the presence of an RA signaling domain in ventral retina of juvenile zebrafish that coincided with a ventral zone of LWS1 expression. This is the first evidence that an extracellular signal may regulate differential expression of opsin genes in a tandemly duplicated array.

Zebrafish have the remarkable capacity to regenerate retinal neurons following a variety of damage paradigms. Following initial tissue insult and a period of cell death, a proliferative phase ensues that generates neuronal progenitors, which ultimately regenerate damaged neurons. Recent work has revealed that Müller glia are the source of regenerated neurons in zebrafish. However, the roles of another important class of glia present in the retina, microglia, during this regenerative phase remain elusive. Here, we examine retinal tissue and perform QuantSeq. 3′mRNA sequencing/transcriptome analysis to reveal localization and putative functions, respectively, of mpeg1 expressing cells (microglia/macrophages) during Müller glia-mediated regeneration, corresponding to a time of progenitor proliferation and production of new neurons. Our results indicate that in this regenerative state, mpeg1 -expressing cells are located in regions containing regenerative Müller glia and are likely engaged in active vesicle trafficking. Further, mpeg1 + cells congregate at and around the optic nerve head. Our transcriptome analysis reveals several novel genes not previously described in microglia. This dataset represents the first report, to our knowledge, to use RNA sequencing to probe the microglial transcriptome in such context, and therefore provides a resource towards understanding microglia/macrophage function during successful retinal (and central nervous tissue) regeneration.

Killer toxins are extracellular antifungal proteins that are produced by a wide variety of fungi, including Saccharomyces yeasts. Although many Saccharomyces killer toxins have been previously identified, their evolutionary origins remain uncertain given that many of these genes have been mobilized by double-stranded RNA (dsRNA) viruses. A survey of yeasts from the Saccharomyces genus has identified a novel killer toxin with a unique spectrum of activity produced by Saccharomyces paradoxus . The expression of this killer toxin is associated with the presence of a dsRNA totivirus and a satellite dsRNA. Genetic sequencing of the satellite dsRNA confirmed that it encodes a killer toxin with homology to the canonical ionophoric K1 toxin from Saccharomyces cerevisiae and has been named K1-like (K1L). Genomic homologs of K1L were identified in six non- Saccharomyces yeast species of the Saccharomycotina subphylum, predominantly in subtelomeric regions of the genome. When ectopically expressed in S . cerevisiae from cloned cDNAs, both K1L and its homologs can inhibit the growth of competing yeast species, confirming the discovery of a family of biologically active K1-like killer toxins. The sporadic distribution of these genes supports their acquisition by horizontal gene transfer followed by diversification. The phylogenetic relationship between K1L and its genomic homologs suggests a common ancestry and gene flow via dsRNAs and DNAs across taxonomic divisions. This appears to enable the acquisition of a diverse arsenal of killer toxins by different yeast species for potential use in niche competition.

Background Advances in next-generation sequencing technologies have facilitated extensive analysis of B cell and T cell receptor (BCR/TCR, respectively) sequences from monoclonal hybridoma libraries, single B cells, and single T cells, generating vast amounts of important data pertaining to antigen recognition. However, existing workflows and bioinformatics tools often lack the flexibility and scalability needed to handle large clonal level datasets effectively. An initial system and hybridoma dependent version of this code was distributed as part of the NeuroMabSeq publication, but clonevdjseq aims to be a technical addendum for broader system compatibility and enhanced modeling. Results We present clonevdjseq, an integrated and accessible software solution leveraging nextflow and Django. Developed primarily for large hybridoma libraries, the workflow and pipeline is amenable to BCR/TCR sequence analysis of homogenous populations or clones of B and T cells, respectively. The clonevdjseq pipeline includes modules for read processing, amplicon denoising, and quality control of paired variable light/heavy chains of BCRs from B cells and hybridomas, or alpha(ɑ)/beta(β) and delta(δ)/gamma(γ) chains of TCRs in the case of T cell applications. The pipeline is built upon a robust, high-throughput library prep protocol, upon which processed data has been verified across thousands of monoclonal antibodies. The results of this effort has yielded sequences used to develop functional recombinant monoclonal antibodies and single chain variable fragments as a part of the NeuroMabSeq initiative where thousands of hybridoma samples were processed (Mitchell et al. in Sci Rep 13(1):16200, 2023) as well as provide additional modeling and extensibility to other modalities. The clonevdjseq software is accessible via Nextflow and also offers a database and web app as a final optional step in the processing for dissemination of results and data exploration. Conclusions clonevdjseq offers a comprehensive and scalable solution for the processing and analysis of large monoclonal and oligoclonal VDJ datasets. Its modular design, dynamic pipeline, and robust database integration facilitate efficient data management and analysis. The platform is publicly available and aims to support the research community by providing an accessible and flexible tool for archiving and dissemination of BCR sequences from hybridomas, with applicability for other applications such as TCR sequences from single-cell T cell populations.

The Neuroscience Monoclonal Antibody Sequencing Initiative (NeuroMabSeq) is a concerted effort to determine and make publicly available hybridoma-derived sequences of monoclonal antibodies (mAbs) valuable to neuroscience research. Over 30 years of research and development efforts including those at the UC Davis/NIH NeuroMab Facility have resulted in the generation of a large collection of mouse mAbs validated for neuroscience research. To enhance dissemination and increase the utility of this valuable resource, we applied a high-throughput DNA sequencing approach to determine immunoglobulin heavy and light chain variable domain sequences from source hybridoma cells. The resultant set of sequences was made publicly available as a searchable DNA sequence database (neuromabseq.ucdavis.edu) for sharing, analysis and use in downstream applications. We enhanced the utility, transparency, and reproducibility of the existing mAb collection by using these sequences to develop recombinant mAbs. This enabled their subsequent engineering into alternate forms with distinct utility, including alternate modes of detection in multiplexed labeling, and as miniaturized single chain variable fragments or scFvs. The NeuroMabSeq website and database and the corresponding recombinant antibody collection together serve as a public DNA sequence repository of mouse mAb heavy and light chain variable domain sequences and as an open resource for enhancing dissemination and utility of this valuable collection of validated mAbs.

The purpose of this article is to highlight and comment on the key findings emerging from the collective efforts of the special issue on leadership, ethics, and identity. Highlights include definitional advancements, processes comprising ethical leadership, as well as outcomes and moderating factors. In addition, I attempt to synthesize work across authors by identifying common themes as well as conflicting elements in the article. I conclude with a discussion on emerging areas in need of future research investigation in the leadership and ethics arena.