Molecular structure, expression, and the emerging role of Siglec-15 in skeletal biology and cancer.

Siglec-15, a Siglec family member and type-1 transmembrane protein, is expressed mainly in human macrophages and dendritic cells. It is comprised of a lysine-containing transmembrane domain, two extracellular immunoglobulin (Ig)-like domains and a short cytoplasmic domain. Siglec-15 is highly conserved in vertebrates and acts as an immunoreceptor. It exerts diverse functions on osteoclast physiology as well as the tumor microenvironment. Siglec-15 interacts with adapter protein DAP12 - Syk signaling pathway to regulate the RANKL/RANK-mediated PI3K, AKT, and ERK signaling pathways during osteoclast formation in vitro. Consistently, the lack of the Siglec-15 gene in mice leads to impaired osteoclast activity and osteopetrosis in vivo. In addition, Siglec-15 is expressed by tumor-associated macrophages (TAMs) and regulates the tumor microenvironment by activating the SYK/MAPK signaling pathway. Interestingly, Siglec-15 shares sequence homology to programmed death-ligand 1 (PD-L1) and has a potential immune-regulatory role in cancer immunology. Thus, Siglec-15 might also represent an alternative target for the treatment of cancers that do not respond to anti-PD-L1/PD-1 immunotherapy. Understanding the role of Siglec-15 in osteoclastogenesis and the tumor microenvironment will help us to develop new treatments for bone disorders and cancer.

Neurodevelopmental signature of a transcriptome-based polygenic risk score for depression.

Disentangling the molecular underpinnings of major depressive disorder (MDD) is necessary for identifying new treatment and prevention targets. The functional impact of depression-related transcriptomic changes on the brain remains relatively unexplored. We recently developed a novel transcriptome-based polygenic risk score (tPRS) composed of genes transcriptionally altered in MDD. Here, we sought to investigate effects of tPRS on brain structure in a developmental cohort (Adolescent Brain Cognitive Development study; n = 5124; 2387 female) at baseline (9-10 years) and 2-year follow-up (11-12 years). We tested associations between tPRS and Freesurfer-derived measures of cortical thickness, cortical surface area, and subcortical volume. Across the whole sample, higher tPRS was significantly associated with thicker left posterior cingulate cortex at both baseline and 2-year follow-up. In females only, tPRS was associated with lower right hippocampal volume at baseline and 2-year follow-up, and lower right pallidal volume at baseline. Furthermore, regional subcortical volume significantly mediated an indirect effect of tPRS on depressive symptoms in females at both timepoints. Conversely, tPRS did not have significant effects on cortical surface area. These findings suggest the existence of a sex-specific neurodevelopmental signature associated with shifts towards a more depression-like brain transcriptome, and highlight novel pathways of developmentally mediated MDD risk.

Identification of Differentially Expressed Genes and Molecular Pathways Involved in Osteoclastogenesis Using RNA-seq.

Osteoporosis is a disease that is characterised by reduced bone mineral density (BMD) and can be exacerbated by the excessive bone resorption of osteoclasts (OCs). Bioinformatic methods, including functional enrichment and network analysis, can provide information about the underlying molecular mechanisms that participate in the progression of osteoporosis. In this study, we harvested human OC-like cells differentiated in culture and their precursor peripheral blood mononuclear cells (PBMCs) and characterised the transcriptome of the two cell types using RNA-sequencing in order to identify differentially expressed genes. Differential gene expression analysis was performed in RStudio using the edgeR package. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to identify enriched GO terms and signalling pathways, with inter-connected regions characterised using protein-protein interaction analysis. In this study, we identified 3201 differentially expressed genes using a 5% false discovery rate; 1834 genes were upregulated, whereas 1367 genes were downregulated. We confirmed a significant upregulation of several well-established OC genes including CTSK, DCSTAMP, ACP5, MMP9, ITGB3, and ATP6V0D2. The GO analysis suggested that upregulated genes are involved in cell division, cell migration, and cell adhesion, while the KEGG pathway analysis highlighted oxidative phosphorylation, glycolysis and gluconeogenesis, lysosome, and focal adhesion pathways. This study provides new information about changes in gene expression and highlights key biological pathways involved in osteoclastogenesis.

Restless Genital Syndrome: Case Report of a Rare Disorder from Pakistan.

Restless genital syndrome (RGS) is a newly recognized syndrome characterized by difficult to describe genital sensations, including itching, tingling, contractions, and even pain. It can be a source of distress for the patient and may lead to social withdrawal and delayed diagnosis. Many pharmacologic and non-pharmacologic treatment options have been documented in the literature. Dopamine agonists have been shown to be the most effective in symptomatic relief. We present a case of an Asian female with symptoms suggestive of RGS for 11 years before she was diagnosed who responded well to ropinirole. We discuss the pathophysiology and reasons for the delayed diagnosis.