Sanford Burnham Prebys Medical Discovery Institute

Nucleoporins are increasingly recognized as tissue-specific regulators beyond their structural roles in the nuclear pore complex. Here, we identify nucleoporin Nup358 as a critical repressor of Wnt signaling required for intestinal epithelium integrity. Ablation of Nup358 in adult mice causes a catastrophic loss of crypt-villus architecture and disrupts the intestinal epithelial layer. Notably, while the intestinal stem cell (ISC) pool remains stable, the transit-amplifying (TA) progenitor compartment is depleted. Mechanistically, we show that the interaction of Nup358 with Dvl1 through its N-terminal domain inhibits Dvl1 spontaneous phase separation. In the absence of Nup358, Dvl1 biomolecular condensates promote Tankyrase-mediated degradation of Axin1, leading to the constitutive stabilization of β-catenin and ligand-independent Wnt activation, negatively impacting cell differentiation and TA progenitor survival. Our results demonstrate that Nup358 acts as a molecular safeguard that dampens Wnt signaling levels in intestinal crypts. By preventing Dvl1-mediated Wnt signal amplification, Nup358 allows ISCs to transition into the TA compartment and initiate the differentiation programs essential for intestinal homeostasis.

Patients with multiple myeloma (MM) often use cardiovascular medications due to their increased risk of cardiovascular diseases. This study investigated the associations of baseline use of these drugs with survival and adverse events in MM patients initiating daratumumab, lenalidomide, or bortezomib combination treatments. Data from Phase III trials (CASTOR, MAIA, and POLLUX) were analysed, focusing on beta-blockers, calcium channel blockers, ACE inhibitors (ACEI), angiotensin II receptor blockers (ARBs), diuretics, and statins. Cox proportional hazard analysis and logistic regression were used to assess associations with survival and grade ≥ 3 adverse events. Among 1804 patients, ACEI/ARBs were most common (31%), followed by beta-blockers (23%), statins (21%), calcium channel blockers (17%), and diuretics (16%). ACEI/ARBs was associated with better progression-free survival (adjusted hazard ratio (aHR) [95% CI] = 0.84 [0.71-0.99], P = 0.034) but also higher odds of grade ≥ 3 adverse events (adjusted odds ratio (aOR) = 1.45 [1.06-1.97], P = 0.019). Diuretics were similarly associated with grade ≥ 3 adverse events (aOR = 1.53 [1.01-2.34], P = 0.047). Other cardiovascular drugs showed no significant associations. While ACEI/ARBs may improve progression-free survival, they pose safety concerns. It is reassuring that other cardiovascular drugs were not significantly associated with MM treatment outcomes. Further research is essential to fully understand the implications of these medications.

Purpose: The study aims to assess the deterrents to quality financial reporting in corporate organizations and provide an acceptable solution to address the identified challenges. Methodology: The data were collected using self-administered questionnaires; the unit of analysis was corporate organizations based in Lira, Uganda, and the unit of inquiry was employees. The study assessed discriminant validity among the latent variables using the Heterotrait-Monotrait Ratio, and correlations among the latent variables were computed. To enhance validity and reliability, the study addressed common method bias. A structural equation model was also developed to assess its predictive value and the strength of relationships among the latent variables. Results: The study found that high-quality reporting is associated with good accounting standards. A positive change in financial reporting strategies improves the quality of financial reporting. It is also noted that the use of qualified staff and ICT would enhance the quality of financial reporting. Implications: Corporate organizations that apply sound accounting standards, integrate ICT, and empower boards to perform oversight roles in accordance with established policies will always grow faster. Originality: This study examined the often overlooked, yet significant aspects of quality financial reporting in most corporate organizations, whereas the existing literature focuses primarily on regulatory issues and compliance. The study focused on specificities and hindrances to accuracy and transparency in financial reporting.

Cardinium endosymbionts are obligate intracellular bacteria found in a wide range of invertebrate hosts. In this study, we generated ten new Cardinium genomes from plant-parasitic nematodes of the genera Amplimerlinius, Bursaphelenchus, Cactodera, Ditylenchus, Globodera, Meloidoderita, and Rotylenchus, revealing their broad ecological and phylogenetic distribution. Using an expanded set of genes, we clarified the relationship between previously defined Cardinium groups B and F from nematodes, showing that they are closely related and likely share a single evolutionary origin within nematode-associated Cardinium. Among the newly assembled Cardinium genomes obtained in this study, two genomes originating from strains associated with wood-inhabiting Bursaphelenchus species exhibited remarkable genome reduction, with estimated sizes of approximately 695 kb. Functional annotation of Cardinium genomes indicated an absence of or a reduction in several central metabolic pathways, including the biotin biosynthetic pathway. A complete biotin pathway was found only in D. weischeri, and this pathway is only partially encoded in Cactodera sp. The polA gene, which encodes DNA polymerase I, showed partial loss in several Cardinium strains. Phylogenetic and comparative genomic analyses provided strong evidence that several carbohydrate, glycerophospholipid, and biotin metabolism genes in these endosymbionts have been acquired through horizontal gene transfer. Future research that integrates high-quality genome assemblies with functional analyses of host–symbiont interactions will be essential to elucidate how metabolic dependency, genome reduction, and horizontal gene transfer collectively shape the evolution and ecological diversification of Cardinium across nematode hosts.

Extrachromosomal DNAs (ecDNAs) are circular DNA molecules prevalent in human cancers that drive tumor evolution and drug resistance. Their circular topology, which disrupts topological domains and rewires regulatory circuits, has typically been studied via pairwise interactions. Here we develop ec3D, a computational method for reconstructing three-dimensional ecDNA structures from Hi-C data. Given a candidate ecDNA sequence and whole-genome Hi-C data, ec3D reconstructs spatial structures by maximizing the Poisson likelihood of observed interactions. We validate ec3D using simulated structures, previously characterized cancer cell lines, and microscopy imaging. Our reconstructions reveal that ecDNAs occupy spherical configurations and mediate unique long-range regulatory interactions involved in gene regulation. Through algorithmic innovations, ec3D can resolve complex structures with duplicated segments, identify multi-way interactions, and identify potential intermolecular (trans) interactions. Our findings provide insights into how ecDNA’s spatial organization bypasses normal chromosomal constraints and contributes to increased oncogene expression.

Tissue-nonspecific alkaline phosphatase (TNALP) is a membrane-anchored glycoprotein with five N-linked glycosylation sites (N140, N230, N271, N303, N430) that is crucial for bone mineralization. TNALP is released into the bloodstream, serving as a biomarker for bone and mineral disorders. This study explores the role of N-linked glycosylation in the secretion, enzymatic activity, stability, and structure of TNALP. To eliminate the N-linked glycosylation site specifically, a soluble TNALP expression construct was created with the following substitution mutations N140Q, N230Q, N271Q, N303Q and N430D, and expressed in mouse osteoblasts. The effect of glycosylation was also studied by computational modeling (molecular dynamics simulations and the GlycoSHIELD tool). We observed that substituting glycosylation sites reduced TNALP secretion, particularly in the double-site mutations N140Q/N271Q and N230Q/N271Q, due to increased cellular retention. Mutations comprising site N271 (N271Q, N140Q/N271Q, N271Q/N303Q and N271Q/N430D) significantly impaired the enzymatic activity. The computational modeling indicated that N-glycans can stabilize regions of the protein, including the Ca2+-binding domain. Further, interactions between N-glycans can compensate for specific double-site glycan losses. Protein thermal stability analysis showed that, compared to WT, N271Q/N430D and N303Q/N430D had increased stability at 56°C. TNALP isoform analysis revealed no differences in isoform patterns for mutations with retained enzymatic activity. The study suggests that N-linked glycosylation, particularly the presence of glycans at N271, is vital for TNALP stability, secretion, and enzymatic function, offering insights into the structural and functional properties of TNALP.

In the original publication [...].

Hypoplastic left heart syndrome (HLHS) is the most lethal congenital heart disease (CHD) whose genetic basis remains elusive, likely due to oligogenic complexity. To identify regulators of cardiomyocyte (CM) proliferation relevant to HLHS, we performed a genome-wide siRNA screen in human iPSC-derived CMs, revealing ribosomal protein (RP) genes as the most prominent effectors of CM proliferation. Whole-genome sequencing of 25 HLHS proband-parent trios similarly showed enrichment of rare RP gene variants, including a damaging RPS15A promoter variant shared in a familial CHD case. Cross-species functional analyses demonstrated that perturbation of RP genes impairs cardiac growth: knockdown of RPS15A, RPS17, RPL26L1, RPL39, or RPS15 reduced CM proliferation, caused cardiac malformations in Drosophila, and produced hypoplastic or dysfunctional hearts in zebrafish. Genetic interactions between RP genes and key cardiac transcription factors (TBX5 and NKX2-7) further support their developmental role. Importantly, p53 suppression or Hippo activation partially rescued RP deficiency phenotypes. Together, these findings implicate RP genes as critical regulators of cardiogenesis and candidate contributors to HLHS.