Objectives/Goals: Diamond Blackfan anemia (DBA) is caused by loss of ribosomal proteins leading to death of red blood cell progenitors. We identified a novel heterozygous variant (c.167+769C>T) in RPL30 in a patient with DBA. We hypothesized that this variant, in a gene not previously studied in DBA, would demonstrate DBA phenotype and reveal early drivers of disease. Methods/Study Population: To study the role of our novel variant, we developed an induced pluripotent stem cell (iPSC) model, including wild type (WT) and CRISPR-edited RPL30 mutant clones. We differentiated the iPSC into hematopoietic stem cells, identified cell populations with flow cytometry, and applied single-cell RNA sequencing. We identified erythroid clusters for differential gene expression analysis, using R Studio DESeq followed by Gene Ontology (GO) enrichment analysis. We are differentiating cells into red blood cells for further comparison with flow cytometry, bulk RNA sequencing, protein analysis, and hemoglobin staining. Our approach has relied on multidisciplinary expertise in clinical hematology and genetics, basic science study of ribosomes, computational biology, stem cell, and hematopoietic biology. Results/Anticipated Results: Compared to WT hematopoietic stem cells, RPL30mutant cells had significantly decreased expression of RPL30. Analysis of top differentially expressed genes revealed downregulation of HSPA1A which encodes heat shock protein 70 (HSP70), chaperone of a critical red blood cell transcription factor. Loss of HSP70 protein has been implicated in RPL-mutated red blood cells previously as a potential modulator of severe DBA phenotype. Upon GO enrichment analysis of downregulated genes, biologic process terms GO:0042254 ribosome biogenesis, GO:1903708 positive regulation of hemopoiesis, and GO:0045646 regulation of erythrocyte differentiation were all highlighted as driver terms. We expect further differentiation to reveal early death of RPL30mutant cells with associated downregulated HSP70. Discussion/Significance of Impact: Our results support our hypothesis that the RPL30 variant downregulates erythropoiesis, with a potential early role of HSP70 protein. Upon completion of our study, we will demonstrate the role of RPL30in DBA pathogenesis as well as provide understanding of its drivers, which is critical for improved management of this disease.

Young stellar objects (YSOs) are protostars that exhibit bipolar outflows fed by accretion disks. Theories of the transition between disk and outflow often involve a complex magnetic field structure thought to be created by the disk coiling field lines at the jet base; however, due to limited resolution, these theories cannot be confirmed with observation and thus may benefit from laboratory astrophysics studies. We create a dynamically similar laboratory system by driving a $\sim$1 MA current pulse with a 200 ns rise through a $\approx$2 mm-tall Al cylindrical wire array mounted to a three-dimensional (3-D)-printed, stainless steel scaffolding. This system creates a plasma that converges on the centre axis and ejects cm-scale bipolar outflows. Depending on the chosen 3-D-printed load path, the system may be designed to push the ablated plasma flow radially inwards or off-axis to make rotation. In this paper, we present results from the simplest iteration of the load which generates radially converging streams that launch non-rotating jets. The temperature, velocity and density of the radial inflows and axial outflows are characterized using interferometry, gated optical and ultraviolet imaging, and Thomson scattering diagnostics. We show that experimental measurements of the Reynolds number and sonic Mach number in three different stages of the experiment scale favourably to the observed properties of YSO jets with $Re\sim 10^5\unicode{x2013}10^9$ and $M\sim 1\unicode{x2013}10$, while our magnetic Reynolds number of $Re_M\sim 1\unicode{x2013}15$ indicates that the magnetic field diffuses out of our plasma over multiple hydrodynamical time scales. We compare our results with 3-D numerical simulations in the PERSEUS extended magnetohydrodynamics code.

This review article explores the role of land-grant Extension amidst an escalating epistemic crisis, where misinformation and the contestation of knowledge severely impact public trust and policymaking. We delve into the historical mission of land-grant institutions to democratize education and extend knowledge through Cooperative Extension Services, highlighting their unique position to address contemporary challenges of information disorder and declining public confidence in higher education. Land-grant universities can reaffirm their relevance and leadership in disseminating reliable information by reasserting their foundational principles of unbiased, objective scholarship and deep engagement with diverse stakeholders. This reaffirmation comes at a critical time when societal trust in science and academia is waning, necessitating a recommitment to community engagement and producing knowledge for the public good. The article underscores the necessity for these institutions to adapt to the changing information landscape by fostering stakeholder-engaged scholarship and enhancing accessibility, thus reinforcing their vital role in upholding the integrity of public discourse and policy.

Medieval hospitals were founded to provide charity, but poverty and infirmity were broad and socially determined categories and little is known about the residents of these institutions and the pathways that led them there. Combining skeletal, isotopic and genetic data, the authors weave a collective biography of individuals buried at the Hospital of St John the Evangelist, Cambridge. By starting with the physical remains, rather than historical expectations, they demonstrate the varied life courses of those who were ultimately buried in the hospital's cemetery, illustrating the diverse faces of medieval poverty and institutional notions of charity. The findings highlight the value of collective osteobiography when reconstructing the social landscapes of the past.

Alcohol use is influenced by genetic and environmental factors. We examined the interactive effects between genome-wide polygenic risk scores for alcohol use (alc-PRS) and social support in relation to alcohol use among European American (EA) and African American (AA) adults across sex and developmental stages (emerging adulthood, young adulthood, and middle adulthood). Data were drawn from 4,011 EA and 1,274 AA adults from the Collaborative Study on the Genetics of Alcoholism who were between ages 18–65 and had ever used alcohol. Participants completed the Semi-Structured Assessment for the Genetics of Alcoholism and provided saliva or blood samples for genotyping. Results indicated that social support from friends, but not family, moderated the association between alc-PRS and alcohol use among EAs and AAs (only in middle adulthood for AAs); alc-PRS was associated with higher levels of alcohol use when friend support was low, but not when friend support was high. Associations were similar across sex but differed across developmental stages. Findings support the important role of social support from friends in buffering genetic risk for alcohol use among EA and AA adults and highlight the need to consider developmental changes in the role of social support in relation to alcohol use.

OBJECTIVES/GOALS: Microtubule poisons, like Taxol, are used to treat triple negative breast cancer (TNBC) and may induce lethal aneuploidy in cancer cells. Patients initially respond, but often develop drug resistance. New targeted drugs that cause aneuploidy may be a valuable approach to therapy. One potential target is the Kinesin 13 MCAK, which limits aneuploidy. METHODS/STUDY POPULATION: TCGA and GSE47561 databases were probed for MCAK expression, and data was stratified by subtype and survival statistics. Knockdown studies were performed to test whether MCAK knockdown sensitizes cells to taxanes for cell proliferation and for induction of aneuploidy. FRET and image-based screens were used to identify MCAK inhibitors from small molecule inhibitor libraries. Inhibitors were then tested for functional effects in multiple cell-based assays and for clonal growth in colony formation assays. RESULTS/ANTICIPATED RESULTS: MCAK expression is upregulated in TNBC and associated with reduced overall survival. Knockdown of MCAK caused a two-to-five-fold reduction of the IC50 for Taxol in cancer cell lines, with no change in normal cell lines. Taxol treatment or MCAK knockdown increased aneuploidy induction, with no additive effect between the two. Our small molecule screen identified three putative MCAK inhibitors, which induced aneuploidy in both taxane-sensitive and taxane-resistant cells. These inhibitors also reduced clonogenic growth, and the most potent inhibitor, C4, caused an approximate five-fold reduction in the IC50 for Taxol in cell proliferation assays. DISCUSSION/SIGNIFICANCE: MCAK can serve as a biomarker of breast cancer prognosis. MCAK knockdown or inhibition sensitizes cancer cells to Taxol without affecting normal cells, making it a potential target in combination therapy. MCAK inhibitors also reduce growth as single agents in taxane resistant lines, giving them potential use as therapies in resistant disease.

This article is a clinical guide which discusses the “state-of-the-art” usage of the classic monoamine oxidase inhibitor (MAOI) antidepressants (phenelzine, tranylcypromine, and isocarboxazid) in modern psychiatric practice. The guide is for all clinicians, including those who may not be experienced MAOI prescribers. It discusses indications, drug-drug interactions, side-effect management, and the safety of various augmentation strategies. There is a clear and broad consensus (more than 70 international expert endorsers), based on 6 decades of experience, for the recommendations herein exposited. They are based on empirical evidence and expert opinion—this guide is presented as a new specialist-consensus standard. The guide provides practical clinical advice, and is the basis for the rational use of these drugs, particularly because it improves and updates knowledge, and corrects the various misconceptions that have hitherto been prominent in the literature, partly due to insufficient knowledge of pharmacology. The guide suggests that MAOIs should always be considered in cases of treatment-resistant depression (including those melancholic in nature), and prior to electroconvulsive therapy—while taking into account of patient preference. In selected cases, they may be considered earlier in the treatment algorithm than has previously been customary, and should not be regarded as drugs of last resort; they may prove decisively effective when many other treatments have failed. The guide clarifies key points on the concomitant use of incorrectly proscribed drugs such as methylphenidate and some tricyclic antidepressants. It also illustrates the straightforward “bridging” methods that may be used to transition simply and safely from other antidepressants to MAOIs.

Background: Clostridioides difficile infection (CDI) is a major source of morbidity and mortality. Even after recovery, recurrent CDI (rCDI) occurs frequently, and concomitant antibiotic use for treatment of a concurrent non–C. difficile infection is a major risk factor. Treatment with fidaxomicin versus vancomycin is associated with similar rate of cure and lower recurrence risk. However, the comparative efficacy of these 2 agents remains unclear in those receiving concomitant antibiotics. Methods: We conducted a randomized, controlled, open-label trial at the University of Michigan and St. Joseph Mercy hospitals in Ann Arbor, Michigan. Patients provided written informed consent at enrollment. We included all hospitalized patients aged ≥18 years with a positive test for toxigenic C. difficile, >3 unformed stools per 24 hours, and ≥1 qualifying concomitant antibiotic with a planned treatment of an infection for ≥5 days after enrollment. We excluded patients with complicated CDI, allergy to vancomycin–fidaxomicin, planned adjunctive CDI treatments, CDI treatment for >24 hours prior to enrollment, concomitant laxative use, current or planned colostomy or ileostomy, and/or planned long-term (>12 weeks) concomitant antibiotic use. Clinical cure was defined as resolution of diarrhea for 2 consecutive days maintained until the end of therapy and for 2 days afterward. rCDI was defined as recurrent diarrhea with positive testing within 30 days of initial treatment. Patients were randomized (stratified by ICU status) to fidaxomicin 200 mg twice daily or vancomycin 125 mg orally 4 times daily for 10 days. If concomitant antibiotic treatment continued >10 days, the study drug continued until the concomitant antibiotic ended. Bivariable statistics included t tests and χ2 tests. Results: After screening 5,101 patients for eligibility (May 2017–May 2021), 144 were included and randomized (Fig. 1). Study characteristics and outcomes are noted in Table 1. Baseline characteristics were similar between groups. Most patients were aged <65 years, were on a proton-pump inhibitor (PPI), and were not in the ICU. The mean duration of concomitant antibiotic was 18.4 days. In the intention-to-treat population, clinical cure (73% vs 62.9%; P =.195), and rCDI (3.3% vs 4.0%; P >.99) were similar for fidaxomicin and vancomycin, respectively. Conclusions: In this study of patients with CDI receiving a concomitant antibiotic, a numerically higher proportion were cured with fidaxomicin versus vancomycin, but this result did not reach statistical significance. Overall recurrence was lower than anticipated in both arms compared to previous studies in which duration of CDI treatment was not extended during concomitant antibiotic treatment. Future studies are needed to ascertain whether clinical cure is higher with fidaxomicin than vancomycin during concomitant antibiotic exposure, and whether extending the duration of CDI treatment reduces recurrence.

Funding: Merck & Co.

Disclosures: None

Rapid Access Ice Drill is a new drilling technology capable of quickly accessing the glacial bed of Antarctic ice sheets, retrieving ice core and rock core samples, and providing boreholes for downhole logging of physical properties. Scientific goals include searching for old ice near the glacial bed and sampling subglacial bedrock. During field trials near McMurdo Station on a piedmont glacier at Minna Bluff in the 2019–20 austral summer, we successfully completed a ‘top-to-bottom’ operational sequence in three boreholes by (1) augering through firn, (2) creating a borehole packer seal in non-porous ice, (3) establishing fluid circulation, (4) quickly drilling a borehole in ice at penetration rates up to 1.2 m min−1, (5) acquiring a short ice core at depth, (6) penetrating the glacial bed at a depth of ~677 m, (7) recovering a 3.2 m core of ice, basal till and subglacial bedrock, (8) optically logging the borehole on wireline, (9) testing hydrofracture potential by overpressuring the borehole fluid and (10) operating in an environmentally benign yet rapid field mode. Minna Bluff testing, therefore, demonstrates the effectiveness of this integrated system to drill rapidly through thick ice and penetrate across the glacial bed to take cores of bedrock.

GRACE and ICESat Antarctic mass-balance differences are resolved utilizing their dependencies on corrections for changes in mass and volume of the same underlying mantle material forced by ice-loading changes. Modeled gravimetry corrections are 5.22 times altimetry corrections over East Antarctica (EA) and 4.51 times over West Antarctica (WA), with inferred mantle densities 4.75 and 4.11 g cm−3. Derived sensitivities (Sg, Sa) to bedrock motion enable calculation of motion (δB0) needed to equalize GRACE and ICESat mass changes during 2003–08. For EA, δB0 is −2.2 mm a−1 subsidence with mass matching at 150 Gt a−1, inland WA is −3.5 mm a−1 at 66 Gt a−1, and coastal WA is only −0.35 mm a−1 at −95 Gt a−1. WA subsidence is attributed to low mantle viscosity with faster responses to post-LGM deglaciation and to ice growth during Holocene grounding-line readvance. EA subsidence is attributed to Holocene dynamic thickening. With Antarctic Peninsula loss of −26 Gt a−1, the Antarctic total gain is 95 ± 25 Gt a−1 during 2003–08, compared to 144 ± 61 Gt a−1 from ERS1/2 during 1992–2001. Beginning in 2009, large increases in coastal WA dynamic losses overcame long-term EA and inland WA gains bringing Antarctica close to balance at −12 ± 64 Gt a−1 by 2012–16.

An intermediate-depth (1751 m) ice core was drilled at the South Pole between 2014 and 2016 using the newly designed US Intermediate Depth Drill. The South Pole ice core is the highest-resolution interior East Antarctic ice core record that extends into the glacial period. The methods used at the South Pole to handle and log the drilled ice, the procedures used to safely retrograde the ice back to the National Science Foundation Ice Core Facility (NSF-ICF), and the methods used to process and sample the ice at the NSF-ICF are described. The South Pole ice core exhibited minimal brittle ice, which was likely due to site characteristics and, to a lesser extent, to drill technology and core handling procedures.

We observed the 2 July 2019 total solar eclipse with a variety of imaging and spectroscopic instruments recording from three sites in mainland Chile: on the centerline at La Higuera, from the Cerro Tololo Inter-American Observatory, and from La Serena, as well as from a chartered flight at peak totality in mid-Pacific. Our spectroscopy monitored Fe X, Fe XIV, and Ar X lines, and we imaged Ar X with a Lyot filter adjusted from its original H-alpha bandpass. Our composite imaging has been compared with predictions based on modeling using magnetic-field measurements from the pre-eclipse month. Our time-differenced sites will be used to measure motions in coronal streamers.