Chromatin structure and 3D architecture define the differential functions of PU.1 regulatory elements in blood cell lineages.

The precise spatiotemporal expression of the hematopoietic ETS transcription factor PU.1, a key determinant of hematopoietic cell fates, is tightly regulated at the chromatin level. However, how chromatin signatures are linked to this dynamic expression pattern across different blood cell lineages remains uncharacterized.

Nanosphere pharmacodynamics improves safety of immunostimulatory cytokine therapy.

Systemic administration of interleukin (IL)-12 induces potent anti-tumor immune responses in preclinical cancer models through the systemic activation of effector immune cells and release of proinflammatory cytokines. IL-12-loaded PLGA nanospheres (IL12ns) are hypothesized to improve therapeutic efficacy and thwart unwanted side effects observed in previous human clinical trials. Through the investigation of peripheral blood and local tissue immune responses in healthy BALB/c mice, the immune-protective pharmacodynamics of IL12ns were suggested.

Addressing the Environmental Impact of Science Through a More Rigorous, Reproducible, and Sustainable Conduct of Research.

The pervasiveness of irreproducible research remains a thorny problem for the progress of scientific endeavor, spawning an abundance of opinion, investigation, and proposals for improvement. Irreproducible research has negative consequences beyond the obvious impact on achieving new scientific discoveries that can advance healthcare and enable new technologies. The conduct of science is resource intensive, resulting in a large environmental impact from even the smallest research programs.

Rigor, Reproducibility, and Transparency in Shared Research Resources: Follow-Up Survey and Recommendations for Improvements.

Rigor, reproducibility, and transparency (RR&T) are essential components of all scientific pursuits. Shared research resources, also known as core facilities, are on the frontlines of ensuring robust RR&T practices. The Association of Biomolecular Resource Facilities Committee on Core Rigor and Reproducibility conducted a follow-up survey 4 years after the initial 2017 survey to determine if core facilities have seen a positive impact of new RR&T initiatives (including guidance from the National Institutes of Health, new scientific journal requirements on transparency and data provenance, and educational tools from professional organizations).

Evidence for oligodendrocyte progenitor cell heterogeneity in the adult mouse brain.

Oligodendrocyte progenitor cells (OPCs) account for approximately 5% of the adult brain and have been historically studied for their role in myelination. In the adult brain, OPCs maintain their proliferative capacity and ability to differentiate into oligodendrocytes throughout adulthood, even though relatively few mature oligodendrocytes are produced post-developmental myelination. Recent work has begun to demonstrate that OPCs likely perform multiple functions in both homeostasis and disease and can significantly impact behavioral phenotypes such as food intake and depressive symptoms.

Single-nucleus chromatin accessibility profiling highlights regulatory mechanisms of coronary artery disease risk.

Coronary artery disease (CAD) is a complex inflammatory disease involving genetic influences across cell types. Genome-wide association studies have identified over 200 loci associated with CAD, where the majority of risk variants reside in noncoding DNA sequences impacting cis-regulatory elements. Here, we applied single-nucleus assay for transposase-accessible chromatin with sequencing to profile 28,316 nuclei across coronary artery segments from 41 patients with varying stages of CAD, which revealed 14 distinct cellular clusters.

Characterization and comparison of innate and adaptive immune responses at vaccine sites in melanoma vaccine clinical trials.

The strength and durability of systemic anti-tumor immune responses induced by cancer vaccines depends on adjuvants to support an immunogenic vaccine site microenvironment (VSME). Adjuvants include water-in-oil emulsions with incomplete Freund's adjuvant (IFA) and combinations of toll-like receptor (TLR) agonists, including a preparation containing TLR4 and TLR9 agonists with QS-21 (AS15). IFA-containing vaccines can promote immune cell accumulation at the VSME, whereas effects of AS15 are largely unexplored.

Incomplete Freund's adjuvant reduces arginase and enhances Th1 dominance, TLR signaling and CD40 ligand expression in the vaccine site microenvironment.

Background: Immunogenicity of cancer vaccines is impacted by adjuvants and schedule, but systematic assessments of their effects have not been performed. Montanide ISA-51, an incomplete Freund's adjuvant (IFA), is used in many vaccine trials, but concerns have been raised about negative effects in murine studies. We found in humans that IFA enhances systemic immune responses and that repeat vaccination at one site (same site vaccination (SSV)) creates tertiary lymphoid structures (TLS) in the vaccine site microenvironment (VSME).

A Review of the Scientific Rigor, Reproducibility, and Transparency Studies Conducted by the ABRF Research Groups.

Shared research resource facilities, also known as core laboratories (Cores), are responsible for generating a significant and growing portion of the research data in academic biomedical research institutions. Cores represent a central repository for institutional knowledge management, with deep expertise in the strengths and limitations of technology and its applications. They inherently support transparency and scientific reproducibility by protecting against cognitive bias in research design and data analysis, and they have institutional responsibility for the conduct of research (research ethics, regulatory compliance, and financial accountability) performed in their Cores.

Survey on Scientific Shared Resource Rigor and Reproducibility.

Shared scientific resources, also known as core facilities, support a significant portion of the research conducted at biomolecular research institutions. The Association of Biomolecular Resource Facilities (ABRF) established the Committee on Core Rigor and Reproducibility (CCoRRe) to further its mission of integrating advanced technologies, education, and communication in the operations of shared scientific resources in support of reproducible research. In order to first assess the needs of the scientific shared resource community, the CCoRRe solicited feedback from ABRF members a survey.

Cytotoxicity of Zardaverine in Embryonal Rhabdomyosarcoma from a Costello Syndrome Patient.

Costello syndrome (CS) patients suffer from a very high 10% incidence of embryonal rhabdomyosarcoma (ERMS). As tools to discover targeted therapeutic leads, we used a CS patient-derived ERMS cell line (CS242 ERMS) harboring a homozygous p.G12A mutation in , and a control cell line derived from the same patient comprising non-malignant CS242 fibroblasts with a heterozygous p.

Age-related differences in prevalence of autism spectrum disorder symptoms in children and adolescents with Costello syndrome.

Dysregulation of the mitogen activated protein kinase (MAPK) pathway in Costello syndrome (CS) may contribute to increased risk for autism-spectrum disorder (ASD). We examined prevalence of ASD symptoms in 14 individuals (six females) age 1-18 years with molecularly confirmed CS. Caregivers completed the Modified Checklist for Autism in Toddlers (M-CHAT) for ages 0-4 years (n = 7), and the Social Communication Questionnaire (SCQ) for ages 4 and older (n = 7).

Phenotypic spectrum of Costello syndrome individuals harboring the rare HRAS mutation p.Gly13Asp.

Costello syndrome is part of the RASopathies, a group of neurocardiofaciocutaneous syndromes caused by deregulation of the RAS mitogen-activated protein kinase pathway. Heterozygous mutations in HRAS are responsible for Costello syndrome, with more than 80% of the patients harboring the specific p.Gly12Ser variant.

Elucidation of -mediated Noonan syndrome with cardiac hypertrophy.

Noonan syndrome (NS; MIM 163950) is an autosomal dominant disorder and a member of a family of developmental disorders termed "RASopathies," which are caused mainly by gain-of-function mutations in genes encoding RAS/MAPK signaling pathway proteins. Whole exome sequencing (WES) and trio-based genomic triangulation of a 15-year-old female with a clinical diagnosis of NS and concomitant cardiac hypertrophy and her unaffected parents identified a de novo variant in -encoded RAS-related protein 3 as the cause of her disease. Mutation analysis using in silico mutation prediction tools and molecular dynamics simulations predicted the identified variant, p.

Establishing a reference dataset for the authentication of spinal muscular atrophy cell lines using STR profiling and digital PCR.

Fibroblasts and lymphoblastoid cell lines (LCLs) derived from individuals with spinal muscular atrophy (SMA) have been and continue to be essential for translational SMA research. Authentication of cell lines helps ensure reproducibility and rigor in biomedical research. This quality control measure identifies mislabeling or cross-contamination of cell lines and prevents misinterpretation of data.

Genomic copy number variation association study in Caucasian patients with nonsyndromic cryptorchidism.

Background: Copy number variation (CNV) is a potential contributing factor to many genetic diseases. Here we investigated the potential association of CNV with nonsyndromic cryptorchidism, the most common male congenital genitourinary defect, in a Caucasian population.

Methods: Genome wide genotyping were performed in 559 cases and 1772 controls (Group 1) using Illumina HumanHap550 v1, HumanHap550 v3 or Human610-Quad platforms and in 353 cases and 1149 controls (Group 2) using the Illumina Human OmniExpress 12v1 or Human OmniExpress 12v1-1.

Paternal uniparental disomy with segmental loss of heterozygosity of chromosome 11 are hallmark characteristics of syndromic and sporadic embryonal rhabdomyosarcoma.

Costello syndrome (CS) arises from a typically paternally derived germline mutation in the proto-oncogene HRAS, and is considered a rasopathy. CS results in failure-to-thrive, intellectual disabilities, short stature, coarse facial features, skeletal abnormalities, congenital heart disease, and a predisposition for cancer, most commonly embryonal rhabdomyosarcoma (ERMS). The goal of this study was to characterize CS ERMS at the molecular level and to determine how divergent it is from sporadic ERMS.

A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair.

Noonan syndrome is a rasopathy caused by mutations in multiple genes encoding components of the RAS/MAPK pathway. Despite its variable phenotype, limited genotype-phenotype correlations exist. Noonan syndrome with loose anagen hair (NS-LAH) is characterized by its distinctive hair anomalies, developmental differences, and structural brain abnormalities and is caused by a single recurrent missense SHOC2 mutation.

Paternal uniparental disomy 11p15.5 in the pancreatic nodule of an infant with Costello syndrome: Shared mechanism for hyperinsulinemic hypoglycemia in neonates with Costello and Beckwith-Wiedemann syndrome and somatic loss of heterozygosity in Costello syndrome driving clonal expansion.

Costello syndrome (CS) entails a cancer predisposition and is caused by activating HRAS mutations, typically arising de novo in the paternal germline. Hypoglycemia is common in CS neonates. A previously reported individual with the rare HRAS p.