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DNA replication stress (RS) is a widespread phenomenon in carcinogenesis, causing genomic instability and extensive chromatin alterations. DNA damage leads to activation of innate immune signaling, but little is known about transcriptional regulators mediating such signaling upon RS. Using a chemical screen, we identified protein arginine methyltransferase 5 (PRMT5) as a key mediator of RS-dependent induction of interferon-stimulated genes (ISGs). This response is also associated with reactivation of endogenous retroviruses (ERVs). Using quantitative mass spectrometry, we identify proteins with PRMT5-dependent symmetric dimethylarginine (SDMA) modification induced upon RS. Among these, we show that PRMT5 targets and modulates the activity of ZNF326, a zinc finger protein essential for ISG response. Our data demonstrate a role for PRMT5-mediated SDMA in the context of RS-induced transcriptional induction, affecting physiological homeostasis and cancer therapy.

Macrophages are abundant immune cells in the microenvironment of diffuse large B-cell lymphoma (DLBCL). Macrophage estimation by immunohistochemistry shows varying prognostic significance across studies in DLBCL, and does not provide a comprehensive analysis of macrophage subtypes. Here, using digital spatial profiling with whole transcriptome analysis of CD68+ cells, we characterize macrophages in distinct spatial niches of reactive lymphoid tissues (RLTs) and DLBCL. We reveal transcriptomic differences between macrophages within RLTs (light zone /dark zone, germinal center/ interfollicular), and between disease states (RLTs/ DLBCL), which we then use to generate six spatially-derived macrophage signatures (MacroSigs). We proceed to interrogate these MacroSigs in macrophage and DLBCL single-cell RNA-sequencing datasets, and in gene-expression data from multiple DLBCL cohorts. We show that specific MacroSigs are associated with cell-of-origin subtypes and overall survival in DLBCL. This study provides a spatially-resolved whole-transcriptome atlas of macrophages in reactive and malignant lymphoid tissues, showing biological and clinical significance.

The research described in this article focuses on determining the effectiveness of Bongo in promoting student retention of concepts in online learning. This study used both quantitative and qualitative measures to examine the effectiveness of student video presentation assignments on student retention of learning and perceptions of the assignment's contributions to learning. The quantitative methods compared the effects of three treatment conditions (independent reading, Bongo video presentation, and Bongo video presentation with Auto Analysis) on retention of concepts (quizzes administered two weeks after the presentation recordings). Qualitative analysis of student perceptions of the perceived value of Bongo in general, and specifically the Auto Analysis tool, were accomplished through video surveys, transcription, and analysis. Analysis of the data provided strong support for the use of Bongo to increase student retention of concepts, and also revealed that students held favorable perceptions of the value and utility of the tool.

Particle acceleration is a commonly observed phenomenon at dipolarization fronts. Many studies have attempted to determine the acceleration mechanism, with betatron acceleration being a major candidate. In previous work, we attempted to match the observed change in electron energy to the change predicted by betatron acceleration, but found that although this worked in some cases, overall betatron acceleration alone could not describe the observed energy spectrum changes. In this work, we attempted to study whether ion acceleration showed similar behavior and whether a quasi-adiabatic correction would be more accurate. On average the betatron acceleration equation overestimated the observed acceleration and the quasi-adiabatic correction did not account for the difference, although there are limitations to this study due to data fidelity. We then turned to study whether our assumptions about the source population having the same phase space density as the cold pre-existing background population in the plasma sheet are valid. We indirectly studied this by comparing the relative abundances of O+ and He++ as proxies for ionospheric and solar wind populations respectively. We found the betatron acceleration equation method performs slightly better when there is a stronger ionospheric component. This suggests that when more plasma containing O+ is present in the dipolarization front, it indicates that the source population is more local and therefore this method of using betatron acceleration is more valid.

Questions remain regarding the effect of baseline host and exposure factors on vaccine efficacy (VE) across pathogens and vaccine platforms. We report placebo-controlled data from four Phase 3 COVID-19 trials during the early period of the pandemic. This was a cross-protocol analysis of four randomized, placebo-controlled efficacy trials (Moderna/mRNA1273, AstraZeneca/AZD1222, Janssen/Ad26.COV2.S, and Novavax/NVX-CoV2373) using a harmonized design. Trials were conducted in the United States and international sites in adults ≥ 18 years of age. VE was assessed for symptomatic and severe COVID-19. We analyzed 114,480 participants from both placebo and vaccine arms, enrolled July 2020 to February 2021, with follow up through July 2021. VE against symptomatic COVID-19 showed little heterogeneity across baseline socio-demographic, clinical or exposure characteristics, in either univariate or multivariate analysis, regardless of vaccine platform. Similarly, VE against severe COVID-19 in the single trial (Janssen) with sufficient endpoints for analysis showed little evidence of heterogeneity. COVID-19 VE is not influenced by baseline host or exposure characteristics across efficacy trials of different vaccine platforms and countries when well matched to circulating virus strains. This supports use of these vaccines, regardless of platform type, as effective tools in the near term for reducing symptomatic and severe COVID-19, particularly for older individuals and those with common co-morbidities during major variant shifts. Clinical trial registration numbers: NCT04470427, NCT04516746, NCT04505722, and NCT04611802.

Understanding the evolutionary consequences of anthropogenic change is imperative for estimating long-term species resilience. While contemporary genomic data can provide us with important insights into recent demographic histories, investigating past change using present genomic data alone has limitations. In comparison, temporal genomics studies, defined herein as those that incorporate time series genomic data, utilize museum collections and repeated field sampling to directly examine evolutionary change. As temporal genomics is applied to more systems, species and questions, best practices can be helpful guides to make the most efficient use of limited resources. Here, we conduct a systematic literature review to synthesize the effects of temporal genomics methodology on our ability to detect evolutionary changes. We focus on studies investigating recent change within the past 200 years, highlighting evolutionary processes that have occurred during the past two centuries of accelerated anthropogenic pressure. We first identify the most frequently studied taxa, systems, questions and drivers, before highlighting overlooked areas where further temporal genomic studies may be particularly enlightening. Then, we provide guidelines for future study and sample designs while identifying key considerations that may influence statistical and analytical power. Our aim is to provide recommendations to a broad array of researchers interested in using temporal genomics in their work.

Background/Objectives: The identification of inflammatory mediators and the involvement of CD206 macrophages in anti-inflammatory responses, along with the synthesis of fibrotic mediators, are crucial for the diagnosis and treatment of Idiopathic Pulmonary Fibrosis (IPF). Methods: In this study, the assessment of 68Ga-labeled linear and cyclic forms of the RP832c peptide, which demonstrate a specific affinity for CD206 macrophages, was performed to evaluate efficacy for CD206 imaging through PET/CT, biodistribution studies, and CD206 staining in a bleomycin-induced lung injury mouse model (BLM). This model serves as a representative framework for inflammation and fibrosis. Results: The findings reveal significant peak PET/CT signals (SUV means), ID/gram values, and CD206 staining scores in lung tissues at one week post bleomycin instillation, likely due to the heightened expression of CD206 in the bleomycin-induced lung injury model. In contrast, the healthy mice exhibited no detectable CD206 staining, lower PET signals, and reduced radiopharmaceutical accumulation in lung tissues at the same timepoint. Conclusions: These findings suggest that both linear and cyclic [68Ga]Ga-RP832c may function as promising PET imaging agents for CD206 macrophages, and thereby a strategy to non-invasively explore the role of macrophages during fibrogenesis.

Two different models have been proposed to explain how the endpoints of chromatin looped domains (‘TADs’) in eukaryotic chromosomes are determined. In the first, a cohesin complex extrudes a loop until it encounters a boundary element roadblock, generating a stem-loop. In this model, boundaries are functionally autonomous: they have an intrinsic ability to halt the movement of incoming cohesin complexes that is independent of the properties of neighboring boundaries. In the second, loops are generated by boundary:boundary pairing. In this model, boundaries are functionally non-autonomous, and their ability to form a loop depends upon how well they match with their neighbors. Moreover, unlike the loop-extrusion model, pairing interactions can generate both stem-loops and circle-loops. We have used a combination of MicroC to analyze how TADs are organized, and experimental manipulations of the even skipped TAD boundary, homie, to test the predictions of the ‘loop-extrusion’ and the ‘boundary-pairing’ models. Our findings are incompatible with the loop-extrusion model, and instead suggest that the endpoints of TADs in flies are determined by a mechanism in which boundary elements physically pair with their partners, either head-to-head or head-to-tail, with varying degrees of specificity. Although our experiments do not address how partners find each other, the mechanism is unlikely to require loop extrusion.

The chromosomes in multicellular eukaryotes are organized into a series of topologically independent loops called TADs. In flies, TADs are formed by physical interactions between neighboring boundaries. Fly boundaries exhibit distinct partner preferences, and pairing interactions between boundaries are typically orientation-dependent. Pairing can be head-to-tail or head-to-head. The former generates a stem-loop TAD, while the latter gives a circle-loop TAD. The TAD that encompasses the Drosophila even skipped (eve) gene is formed by the head-to-tail pairing of the nhomie and homie boundaries. To explore the relationship between loop topology and the physical and regulatory landscape, we flanked the nhomie boundary region with two attP sites. The attP sites were then used to generate four boundary replacements: λ DNA, nhomie forward (WT orientation), nhomie reverse (opposite of WT orientation), and homie forward (same orientation as WT homie). The nhomie forward replacement restores the WT physical and regulatory landscape: in MicroC experiments, the eve TAD is a ‘volcano’ triangle topped by a plume, and the eve gene and its regulatory elements are sequestered from interactions with neighbors. The λ DNA replacement lacks boundary function: the endpoint of the ‘new’ eve TAD on the nhomie side is ill-defined, and eve stripe enhancers activate a nearby gene, eIF3j. While nhomie reverse and homie forward restore the eve TAD, the topology is a circle-loop, and this changes the local physical and regulatory landscape. In MicroC experiments, the eve TAD interacts with its neighbors, and the plume at the top of the eve triangle peak is converted to a pair of ‘clouds’ of contacts with the next-door TADs. Consistent with the loss of isolation afforded by the stem-loop topology, the eve enhancers weakly activate genes in the neighboring TADs. Conversely, eve function is partially disrupted.

The reprocessing of radiation belt electron flux measurements into phase space density (PSD) as a function of the adiabatic invariants is a widely-used method to address major questions regarding electron energization and loss in the outer radiation belt. In this reprocessing, flux measurements j (α, E) at local pitch angles α, energies E, and optionally magnetometer measurements B, are combined with a global magnetic field model to express the phase space density f (L*) in terms of the third invariant Φ ∝ 1/L* at fixed first and second invariants M and K. While the general framework of the calculation is agreed upon, implementation details vary amongst the literature, and the issue of magnetic field model dependence is rarely addressed. This work reviews the steps of the calculation with lists of commonly used implementation options. For the first time, analysis is presented to display the effect of doing the calculation with different implementation options and with different backing models (including both empirical and MHD-driven models). The results are summarized to inform evaluation of existing results and future efforts calculating and analyzing radiation belt electron phase space density. Three events are analyzed, and while differences are found, the primary structural interpretations of the phase space density analysis exhibit model independence.

Abstract Macrophages are abundant immune cells in the microenvironment of diffuse large B-cell lymphoma (DLBCL). Macrophage estimation by immunohistochemistry shows varying prognostic significance across studies in DLBCL, and does not provide a comprehensive analysis of macrophage subtypes. Here, using digital spatial profiling with whole transcriptome analysis of CD68+ cells, we characterize macrophages in distinct spatial niches of reactive lymphoid tissues (RLTs) and DLBCL. We reveal transcriptomic differences between macrophages within RLTs (light zone /dark zone, germinal center/ interfollicular), and between disease states (RLTs/ DLBCL), which we then use to generate six spatially-derived macrophage signatures (MacroSigs). We proceed to interrogate these MacroSigs in macrophage and DLBCL single-cell RNA-sequencing datasets, and in gene-expression data from multiple DLBCL cohorts. We show that specific MacroSigs are associated with cell-of-origin subtypes and overall survival in DLBCL. This study provides a spatially-resolved whole-transcriptome atlas of macrophages in reactive and malignant lymphoid tissues, showing biological and clinical significance.

As the state of Texas transitions its developmental programs to the corequisite model, the faculty at Angelo State University (ASU) are adjusting their corequisite model, which was implemented 5 years ago. This article traces the origin and development of the current model of corequisite learning at ASU, as well as illustrate best practices that are found in our university.

Early relapse after platinum chemotherapy in epithelial ovarian cancer (EOC) portends poor survival. A-priori identification of platinum resistance is therefore crucial to improve on standard first-line carboplatin-paclitaxel treatment. The DNA repair pathway homologous recombination (HR) repairs platinum-induced damage, and the HR recombinase RAD51 is overexpressed in cancer. We therefore designed a REMARK-compliant study of pre-treatment RAD51 expression in EOC, using fluorescent quantitative immunohistochemistry (qIHC) to overcome challenges in quantitation of protein expression in situ. In a discovery cohort (n = 284), RAD51-High tumours had shorter progression-free and overall survival compared to RAD51-Low cases in univariate and multivariate analyses. The association of RAD51 with relapse/survival was validated in a carboplatin monotherapy SCOTROC4 clinical trial cohort (n = 264) and was predominantly noted in HR-proficient cancers (Myriad HRDscore

Pulsating aurora, which consists of diffuse patches blinking on and off, is caused by pitch angle scattering of radiation belt electrons into the loss cone by lower-band chorus waves. Understanding the drivers of pulsating aurora is important as it is a long-lasting and widespread phenomenon, accounting for significant energy transfer from the solar wind into the ionosphere. Substorm injections, which transport electrons from the magnetotail into the inner magnetosphere, are one source of electrons in this region. Injections have been observed simultaneously with pulsating aurora during conjunctions between ground cameras and satellites. In addition, previous work has also shown that substorms can enhance chorus activity (the fundamental process that produces pulsating aurora), providing a mechanism linking substorms to pulsating aurora. To further study this connection, we used the Van Allen Probes and all-sky cameras to look at events where pulsating aurora and substorm injections were observed at different locations in Magnetic Local Time (MLT), rather than focusing only on conjunctions. To make this comparison, we calculated the drift rate of electrons originating from observed injections and projected their motion forward in time until their Magnetic Local Time was the same as the ground camera. When the electrons are located at the same MLT as the ground camera, the pulsating aurora they cause would most likely occur in the field of view of the camera. We compared the time drifting substorm-injected particles arrived at the MLT of the camera to when pulsating aurora was observed. We found several instances where the initiation or intensification of pulsating aurora was accompanied by the arrival of substorm-injected electrons. This observation gives further evidence that pulsating aurora can be enhanced by or occur after substorm injections.

Deregulation of the DNA damage response (DDR) plays a critical role in the pathogenesis and progression of many cancers. The dependency of certain cancers on DDR pathways has enabled exploitation of such through synthetically lethal relationships e.g., Poly ADP-Ribose Polymerase (PARP) inhibitors for BRCA deficient ovarian cancers. Though lagging behind that of solid cancers, DDR inhibitors (DDRi) are being clinically developed for haematological cancers. Furthermore, a high proliferative index characterize many such cancers, suggesting a rationale for combinatorial strategies targeting DDR and replicative stress. In this review, we summarize pre-clinical and clinical data on DDR inhibition in haematological malignancies and highlight distinct haematological cancer subtypes with activity of DDR agents as single agents or in combination with chemotherapeutics and targeted agents. We aim to provide a framework to guide the design of future clinical trials involving haematological cancers for this important class of drugs.

Heart failure (HF) with reduced ejection fraction (HFrEF) is a risk factor for drug-induced QT interval prolongation. It is unknown if HF with preserved ejection fraction (HFpEF) is also associated with an increased risk. Dofetilide and sotalol are potent QT interval-prolonging agents that are frequently used in patients with HFpEF, in whom atrial fibrillation is a common comorbidity. We tested the hypothesis that the risk of QT interval prolongation associated with dofetilide and sotalol is increased in patients with HFpEF. We conducted a retrospective cohort study conducted using electronic health records from the Indiana Network for Patient Care (January 31, 2010 -May 3, 2021). After removing patients with overlapping diagnoses of HFpEF and HFrEF, no diagnosis code, and absence of QT interval records, we identified patients taking dofetilide or sotalol among three groups: HFrEF (n = 138), HFpEF (n = 109), and no HF (n = 729). QT prolongation was defined as heart rate-corrected QT (QTc) > 500 ms during dofetilide/sotalol therapy. Unadjusted odds ratios (OR) for QT prolongation were determined by univariate analysis. Adjusted ORs were determined by generalized estimating equations (GEE) with logit link to account for an individual cluster with different times of hospitalization and covariates. QTc prolongation associated with dofetilide or sotalol occurred in 53.2%, 71.7% and 30.0% of patients with HFpEF, HFrEF, and patients with no HF, respectively. After adjusting for age, sex, race, serum potassium and magnesium concentrations, kidney function, concomitant drug therapy, and comorbid conditions, the adjusted odds of QTc prolongation were significantly higher in patients with HFpEF [OR = 1.98 (95% CI 1.17-3.33)], and in those with HFrEF [OR = 5.23, (3.15-8.67)], compared to those with no evidence of HF. The odds of QT prolongation among inpatients receiving dofetilide or sotalol were increased in patients with HFpEF and HFrEF compared to those who did not have HF.

Background: Transitioning to community living after long-term care requires multiple complex individualized interventions to prevent readmission. The current focus of home and community-based services (HCBS) is on increasing consumer engagement and individualizing care. Telehealth interventions provide additional services without the burden of face-to-face encounters and have yet to be evaluated for feasibility and acceptability in rural HCBS. Methods: West Virginia Bureau for Medical Services and West Virginia University implemented and evaluated a telehealth intervention with 26 Aged and Disabled Waiver or Traumatic Brain Injury Waiver participants who were transitioning back into their communities from a long-term care facility. Feasibility was assessed through recruitment process, fidelity to planned intervention, number of people eligible for participation, number of individuals enrolling in the intervention, enrollment process, completed enrollment, engagement in the intervention, number of weeks participating in the intervention, type of devices provided, attrition, and fidelity to original intervention. Satisfaction with services was used as a marker of acceptability for both participants and providers. Results: Half (n?=?12) of the enrolled population completed the full 24-week telehealth monitoring period and modification of the original intervention was necessary for most. Provider and participant satisfaction was high. Recruitment and enrollment may have been affected by COVID-19. Conclusion: Future implementation will continue to track recruitment and retention efforts. Individualized care plans, demonstration and practice with equipment, family or direct-care worker presence, and live technical support through the phone are needed. Primary care provider and in-home direct-care worker satisfaction workflow planning and evaluation are required.

Abstract We have identified for the first time an energy‐time dispersion of precipitating electron flux in a pulsating aurora patch, ranging from 6.7 to 580 keV, through simultaneous in‐situ observations of sub‐relativistic electrons of microburst precipitations and lower‐energy electrons using the Loss through Auroral Microburst Pulsation sounding rocket launched from the Poker Flat Research Range in Alaska. Our observations reveal that precipitating electrons with energies of 180–320 keV were observed first, followed by 250–580 keV electrons 0–30 ms later, and finally, after 500–1,000 ms, 6.7–14.6 keV electrons were observed. The identified energy‐time dispersion is consistent with the theoretical estimation that the relativistic electron microbursts are a high‐energy tail of pulsating aurora electrons, which are caused by chorus waves propagating along the field line.

Electron cyclotron harmonic (ECH) waves along with whistler mode waves are suggested to be responsible for causing the persistent diffuse aurora in Jupiter. In this work, for the first time we systematically analyze the ECH waves in the Jovian inner magnetosphere, which was surveyed by Juno during the later orbits (>25). We find that in the Jovian inner magnetosphere, ECH waves occur in two specific regions—one equatorial and the other off-equatorial, just outside the Io torus. Equatorial ECH waves have higher intensity compared to their off-equatorial counterpart. We also notice an overlap between the region of mid-latitude hot injections and the region of off-equatorial ECH wave occurrence. Finally, we show an event to describe the complex nature of ECH wave growth/damping varying with particle density structures of the injection region at mid-latitude.

Betatron acceleration is commonly cited as a primary accelerator of energetic electrons at dipolarization fronts, and many case studies compare observed energetic electrons measurements to a betatron model. In this work, we extend this to a statistical study. We identified 168 dipolarizations with an enhanced flux of energetic electrons at Magnetospheric Multiscale (MMS). We compared the observed flux of energetic electrons above 1 keV to a betatron acceleration model assuming a source population similar to the population in the quiet plasma sheet and found that, on average, the model slightly overestimated the observation, but there was a wide spread of errors. We then tested characteristics such as position, change in and strength of magnetic field, and wave power to determine if any of these characteristics affected the accuracy of the model; the only clear correlations were that the model was less accurate when the initial total magnetic field was smaller and when there was a higher Ey during the dipolarization. Since the betatron model did not explain our observations very well, we repeated with a full adiabatic model that included a Fermi acceleration component as well. We found that the adiabatic model slightly underestimated the observations, but with a smaller error than the betatron model under the same assumptions. Testing the same parameters, we found that the adiabatic model also did not strongly rely on any of the parameters except the initial magnetic field, and the anti-correlation with Ey was no longer present. The fact that neither model was generally applicable means that either adiabatic processes alone are not enough to explain electron acceleration at dipolarization fronts in general, or the common assumption we used, that the source population has the same phase space density as the cold pre-existing population, is not valid.

Abstract The burden of cardiovascular diseases is rising rapidly globally. Heart transplant is one of the most last resort medical option for patients with heart failure. Unfortunately, this surgical intervention is associated with several serious complications including heart transplant rejection (HTR) and Cardiac Allograft Vasculopathy (CAV) which can manifest just within few years' posttransplant. These complications affect significantly the prognosis and quality of life among postheart transplant patients. Several medications including immunosuppressant, antibiotics, antihypertensive, and statins have been used during posttransplant care so as to address such complications. Unfortunately, most of those drugs are expensive and pose a number of serious side effects to the patients enough to compromise patients' quality of life too. Several studies on Vitamin C are therapeutically suggestive that it can be used during postheart transplant care with more cost‐effective benefits with less and minimized side effects compared to the current drugs in place. It should be considered pharmacologically that Vitamin C has a great potential role clinically in prevention and control of HTR and CAV development. On the light of such findings as described above, we recommend more studies especially clinical trials and molecular studies to determine whether Vitamin C can be repositioned to replace or to be used along the current drug regimens used in postheart transplant care for prevention and control of HTR and CAV.

Nitrate-N losses from artificially drained agricultural fields lead to an acceleration of eutrophication and hypoxia in aquatic ecosystems. Adoption of conservation practices, such as cover crops and woodchip bioreactors, can significantly reduce nitrate losses and improve water quality. However, the long-term performance of these conservation practices and their effect on water quality has not been sufficiently quantified. A replicated plot experiment was initiated to quantify the long-term effectiveness of such conservation practices on nitrate-N removal rates from subsurface tile drains. Maize (Zea mays L.) and soybean (Glycine max L. Merr.) were grown with three different treatments: 1) Control: no-till crop production, 2) no-till with a winter rye (Secale cereale L.) cover crop (RC), and 3) no-till with an in-situ woodchip denitrification wall (DW) where trenches were excavated parallel to the tile on both sides and filled with woodchips to serve as additional carbon sources to increase denitrification. During a period of 19 years (2002–2020), all three treatments received the same annual N fertilization in maize years with rates ranging from 168 to 247 kg N/ha, depending on the production year. Averaged across the 19 years, the RC and DW treatments reduced N leaching by 59% and 58%, respectively, compared with the Control. Both conservation practices were effective for the duration of the study, and both were affected by annual rainfall. Effectiveness of RC increased in dry years, while effectiveness of DW increased in wet years. Overall, treatment and annual precipitation had the greatest effects on annual N loss in drainage. This suggests that the unpredictability of rainfall may make it difficult to consistently reduce nitrate losses in drainage, but it does not diminish the effectiveness of conservation practices. Minimal or no yield penalty was observed following adoption of cover crop or in-situ woodchip bioreactor conservation practices, which is important for their wider acceptance by the agriculture community.