University of Alabama at Birmingham

Symbiotic mutualisms are essential to ecosystems and numerous species across the tree of life. For reef-building corals, the benefits of their association with endosymbiotic dinoflagellates differ within and across taxa, and nutrient exchange between these partners is influenced by environmental conditions. Furthermore, it is widely assumed that corals associated with symbionts in the genus Durusdinium tolerate high thermal stress at the expense of lower nutrient exchange to support coral growth. We traced both inorganic carbon (H¹³CO3–) and nitrate (¹⁵NO3–) uptake by divergent symbiont species and quantified nutrient transfer to the host coral under normal temperatures as well as in colonies exposed to high thermal stress. Colonies representative of diverse coral taxa associated with Durusdinium trenchii or Cladocopium spp. exhibited similar nutrient exchange under ambient conditions. By contrast, heat-exposed colonies with D. trenchii experienced less physiological stress than conspecifics with Cladocopium spp. while high carbon assimilation and nutrient transfer to the host was maintained. This discovery differs from the prevailing notion that these mutualisms inevitably suffer trade-offs in physiological performance. These findings emphasize that many host–symbiont combinations adapted to high-temperature equatorial environments are high-functioning mutualisms; and why their increased prevalence is likely to be important to the future productivity and stability of coral reef ecosystems.

In this commentary, I raise a few questions about Schmidt’s argument against (R-E): whether facts about incoherence are directly reasons for suspension on particular propositions, as opposed to reasons against sets of attitudes; whether (R-E) should really be formulated in terms of a broad category of “doxastic attitudes” that includes transitional attitudes like suspension; and whether incoherence-based reasons really must fit into the category of “epistemic reasons,” as opposed to be a more general category of right-kind reasons. Though my questions reflect some skepticism about the specifics of Schmidt’s argument, I conclude that it succeeds in what I take to be its broader aim.

Accurate lipid annotation is crucial for understanding the role of lipids in health and disease and identifying therapeutic targets. However, annotating the wide variety of lipid species in biological samples remains challenging in untargeted lipidomic studies. In this work, we present an optimized lipid annotation workflow based on the combination of LC-MS and MS/MS strategies, four bioinformatic tools, and a decision-tree-based approach to support the accurate annotation and semi-quantification of the lipid species present in lung tissue from control mice. The developed workflow allowed us to generate a lipid lung-based ATLAS (LiLA), which was then employed to unveil the lipidomic signatures of the Mycobacterium tuberculosis (Mtb) infection at two different time points for a deeper understanding of the disease progression. This workflow, combined with manual inspection strategies of MS/MS data, can enhance the annotation process for lipidomic studies and guide the generation of sample-specific lipidome maps. LiLA serves as a freely available data resource that can be employed in future studies to address lipidomic alterations in mice lung tissue.

Post-COVID conditions (PCCs) are common and have significant morbidity. Risk factors for PCC include advancing age, female sex, obesity, and diabetes mellitus. Little is known about treatment, inflammation, and PCC. Among 882 individuals with confirmed SARS-CoV-2 infection participating in a randomized trial of COVID-19 convalescent plasma (CCP) vs control plasma with available biospecimens and symptom data, the association between early CCP treatment, cytokine levels, and PCC was evaluated. Cytokine and chemokine levels were assessed at baseline, day 14, and day 90 using a multiplexed sandwich immunoassay (Meso Scale Discovery). Presence of any self-reported PCC symptoms was assessed at day 90. Associations between CCP treatment, cytokine levels, and PCC were examined using multivariate logistic regression models. One third of the 882 participants had day 90 PCC symptoms, with fatigue (14.5%) and anosmia (14.5%) being most common. Cytokine levels decreased from baseline to day 90. In a multivariable analysis, female sex (adjusted odds ratio [AOR] = 2.69 [1.93–3.81]), older age (AOR = 1.32 [1.17–1.50]), and elevated baseline levels of IL-6 (AOR = 1.59 [1.02–2.47]) were independently associated with development of PCC. Those who received early CCP treatment (≤5 days after symptom onset) compared to late CCP treatment had statistically significant lower odds of PCC. IMPORTANCE Approximately 20% of individuals infected with SARS-CoV-2 experienced long-term health effects, as defined PCC. However, it is unknown if there are any early biomarkers associated with PCC or whether early intervention treatments may decrease the risk of PCC. In a secondary analysis of a randomized clinical trial, this study demonstrates that among outpatients with SARS-CoV-2, increased IL-6 at time of infection is associated with increased odds of PCC. In addition, among individuals treated early, within 5 days of symptom onset, with COVID-19 convalescent plasma, there was a trend for decreased odds of PCC after adjusting for other demographic and clinical characteristics. Future treatment studies should be considered to evaluate the effect of early treatment and anti-IL-6 therapies on PCC development.

Objective This study aimed to evaluate whether there are genetic variants associated with adverse neurodevelopmental outcomes in extremely low birth weight (ELBW) infants. Study Design We conducted a candidate gene association study in two well-defined cohorts of ELBW infants (<1,000 g). One cohort was for discovery and the other for replication. The discovery case–control analysis utilized anonymized DNA samples and evaluated 1,614 single-nucleotide polymorphisms (SNPs) in 145 genes concentrated in inflammation, angiogenesis, brain development, and oxidation pathways. Cases were children who died by age one or who were diagnosed with cerebral palsy (CP) or neurodevelopmental delay (Bayley II mental developmental index [MDI] or psychomotor developmental index [PDI] < 70) by 18 to 22 months. Controls were survivors with normal neurodevelopment. We assessed significant epidemiological variables and SNPs associated with the combined outcome of CP or death, CP, mental delay (MDI < 70) and motor delay (PDI < 70). Multivariable analyses adjusted for gestational age at birth, small for gestational age, sex, antenatal corticosteroids, multiple gestation, racial admixture, and multiple comparisons. SNPs associated with adverse neurodevelopmental outcomes with p < 0.01 were selected for validation in the replication cohort. Successful replication was defined as p < 0.05 in the replication cohort. Results Of 1,013 infants analyzed (452 cases, 561 controls) in the discovery cohort, 917 were successfully genotyped for >90% of SNPs and passed quality metrics. After adjusting for covariates, 26 SNPs with p < 0.01 for one or more outcomes were selected for replication cohort validation, which included 362 infants (170 cases and 192 controls). A variant in SERPINE1, which encodes plasminogen activator inhibitor (PAI1), was associated with the combined outcome of CP or death in the discovery analysis (p = 4.1 × 10−4) and was significantly associated with CP or death in the replication cohort (adjusted odd ratio: 0.4; 95% confidence interval: 0.2–1.0; p = 0.039). Conclusion A genetic variant in SERPINE1, involved in inflammation and coagulation, is associated with CP or death among ELBW infants. Key Points

Background Pediatric heart transplant patients are at greatest risk of allograft loss in the first year. We assessed whether machine learning could improve 1‐year risk assessment using the Pediatric Heart Transplant Society database. Methods Patients transplanted from 2010 to 2019 were included. The primary outcome was 1‐year graft loss free survival. We developed a prediction model using cross‐validation, by comparing Cox regression, gradient boosting, and random forests. The modeling strategy with the best discrimination and calibration was applied to fit a final prediction model. We used Shapley additive explanation (SHAP) values to perform variable selection and to estimate effect sizes and importance of individual variables when interpreting the final prediction model. Results Cumulative incidence of graft loss or mortality was 7.6%. Random forests had favorable discrimination and calibration compared to Cox proportional hazards with a C‐statistic (95% confidence interval [CI]) of 0.74 (0.72, 0.76) versus 0.71 (0.69, 0.73), and closer alignment between predicted and observed risk. SHAP values computed using the final prediction model indicated that the diagnosis of congenital heart disease (CHD) increased 1 year predicted risk of graft loss by 1.7 (i.e., from 7.6% to 9.3%), need for mechanical circulatory support increased predicted risk by 2, and single ventricle CHD increased predicted risk by 1.9. These three predictors, respectively, were also estimated to be the most important among the 15 predictors in the final model. Conclusions Risk prediction models used to facilitate patient selection for pediatric heart transplant can be improved without loss of interpretability using machine learning.

The great transferability of DNNs has induced a popular paradigm of “pre-training & fine-tuning”, by which a data-scarce task can be performed much more easily. However, compared to the existing efforts made in the context of supervised transfer learning, fewer explorations have been made on effectively fine-tuning pre-trained Generative Adversarial Networks (GANs). As reported in recent empirical studies, fine-tuning GANs faces the similar challenge of catastrophic forgetting as in supervised transfer learning. This causes a severe capacity loss of the pre-trained model when adapting it to downstream datasets. While most existing approaches suggest to directly interfere parameter updating, this paper introduces novel schemes from another perspective, i.e. inputs and features, thus essentially focuses on data aspect. Firstly, we adopt a trust-region method to smooth the adaptation dynamics by progressively adjusting input distributions, aiming to avoid dramatic parameter changes, especially when the pre-trained GAN has no information of target data. Secondly, we aim to avoid the loss of the diversity of the generated results of the fine-tuned GAN. This is achieved by explicitly encouraging generated images to encompass diversified spectral components in their deep features. We theoretically study the rationale of the proposed schemes, and conduct extensive experiments on popular transfer learning benchmarks to demonstrate the superiority of the schemes. The code and corresponding supplemental materials are available at https://github.com/zezeze97/Transfer-Pretrained-Gan.

The unfolded protein response (UPR) is a cellular mechanism that protects cells during stress conditions in which there is an accumulation of misfolded proteins in the endoplasmic reticulum (ER). UPR activates three signaling pathways that function to alleviate stress conditions and promote cellular homeostasis and cell survival. During unmitigated stress conditions, however, UPR activation signaling changes to promote cell death through apoptosis. Interestingly, cancer cells take advantage of this pathway to facilitate survival and avoid apoptosis even during prolonged cell stress conditions. Here, we discuss different signaling pathways associated with UPR and focus specifically on one of the ER signaling pathways activated during UPR, inositol-requiring enzyme 1α (IRE1). The rationale is that the IRE1 pathway is associated with cell fate decisions and recognized as a promising target for cancer therapeutics. Here we discuss IRE1 inhibitors and how they might prove to be an effective cancer therapeutic. Graphical abstract

Background The short physical performance battery (SPPB) is an easy-to-use tool for fall risk prediction, but its predictive value for falls and fall-induced injuries among community dwellers has not been examined through a large-sample longitudinal study. Methods We analyzed five-round follow-up data (2, 3, 4, 5, 7 years) of the China Health and Retirement Longitudinal Study (CHARLS) (2011–2018). Data concerning falls and fall-induced injuries during multi-round follow-ups were collected through participant self-report. The Cochran-Armitage trend test examined trends in fall incidence rate across SPPB performance levels. Multivariable logistic regression and negative binomial regression models examined associations between SPPB performance and subsequent fall and fall-induced injury. The goodness-of-fit and area under the receiver operating curve (AUC) were used together to quantify the value of the SPPB in predicting fall and fall-induced injury among community-dwelling older adults. Results The CHARLS study included 9279, 6153, 4142, 4148, and 3583 eligible adults aged 60 years and older in the five included follow-up time periods. SPPB performance was associated with fall and fall-induced injury in two and three of the five follow-up time periods, respectively (P < 0.05). The goodness-of-fit for all predictive models was poor, with both Cox-Snell R² and Nagelkerke R² under 0.10 and AUCs of 0.53–0.57 when using only SPPB as a predictor and with both Cox-Snell R² and Nagelkerke R² lower than 0.12 and AUCs of 0.61–0.67 when using SPPB, demographic variables, and self-reported health conditions as predictors together. Sex and age-specific analyses displayed highly similar results. Conclusions Neither use of SPPB alone nor SPPB together with demographic variables and self-reported health conditions appears to offer good predictive performance for falls or fall-induced injuries among community-dwelling older Chinese adults.

Background There are persistent racial and ethnic health disparities in end-of-life health outcomes in the United States. African American patients are less likely than White patients to access palliative care, enroll in hospice care, have documented goals of care discussions with their healthcare providers, receive adequate symptom control, or die at home. We developed Community Health Worker Intervention for Disparities in Palliative Care (DeCIDE PC) to address these disparities. DeCIDE PC is an integrated community health worker (CHW) palliative care intervention that uses community health workers (CHWs) as care team members to enhance the receipt of palliative care for African Americans with advanced cancer. The overall objectives of this study are to (1) assess the effectiveness of the DeCIDE PC intervention in improving palliative care outcomes amongst African American patients with advanced solid organ malignancy and their informal caregivers, and (2) develop generalizable knowledge on how contextual factors influence implementation to facilitate dissemination, uptake, and sustainability of the intervention. Methods We will conduct a multicenter, randomized, assessor-blind, parallel-group, pragmatic, hybrid type 1 effectiveness-implementation trial at three cancer centers across the United States. The DeCIDE PC intervention will be delivered over 6 months with CHW support tailored to the individual needs of the patient and caregiver. The primary outcome will be advance care planning. The treatment effect will be modeled using logistic regression. The secondary outcomes are quality of life, quality of communication, hospice care utilization, and patient symptoms. Discussion We expect the DeCIDE PC intervention to improve integration of palliative care, reduce multilevel barriers to care, enhance clinic and patient linkage to resources, and ultimately improve palliative care outcomes for African American patients with advanced cancer. If found to be effective, the DeCIDE PC intervention may be a transformative model with the potential to guide large-scale adoption of promising strategies to improve palliative care use and decrease disparities in end-of-life care for African American patients with advanced cancer in the United States. Trial registration Registered on ClinicalTrials.gov (NCT05407844). First posted on June 7, 2022.

Body composition assessment is a valuable tool for clinical assessment and research that has implications for long‐term health. Unlike traditional measurements such as anthropometrics or body mass index, body composition assessments provide more accurate measures of body fatness and lean mass. Moreover, depending on the technique, they can offer insight into regional body composition, bone mineral density, and brown adipose tissue. Various methods of body composition assessment exist, including air displacement plethysmography, dual‐energy x‐ray absorptiometry, bioelectrical impedance, magnetic resonance imaging, D3 creatine, ultrasound, and skinfold thickness, each with its own strengths and limitations. In infants, several feeding practices and nutrition factors are associated with body composition outcomes, such as breast milk vs formula feeding, protein intake, breast milk composition, and postdischarge formulas for preterm infants. Longitudinal studies suggest that body composition in infancy predicts later body composition, obesity, and other cardiometabolic outcomes in childhood, making it a useful early marker of cardiometabolic health in both term and preterm infants. Emerging evidence also suggests that body composition during infancy predicts neurodevelopmental outcomes, particularly in preterm infants at high risk of neurodevelopmental impairment. The purpose of this narrative review is to provide clinicians and researchers with a comprehensive overview of body composition assessment techniques, summarize the links between specific nutrition practices and body composition in infancy, and describe the neurodevelopmental and cardiometabolic outcomes associated with body composition patterns in term and preterm infants.

The cellular protein GBF1, an activator of Arf GTPases (ArfGEF: Arf guanine nucleotide exchange factor), is recruited to the replication organelles of enteroviruses through interaction with the viral protein 3A, and its ArfGEF activity is required for viral replication, however how GBF1-dependent Arf activation supports the infection remains enigmatic. Here, we investigated the development of resistance of poliovirus, a prototype enterovirus, to increasing concentrations of brefeldin A (BFA), an inhibitor of GBF1. High level of resistance required a gradual accumulation of multiple mutations in the viral protein 2C. The 2C mutations conferred BFA resistance even in the context of a 3A mutant previously shown to be defective in the recruitment of GBF1 to replication organelles, and in cells depleted of GBF1, suggesting a GBF1-independent replication mechanism. Still, activated Arfs accumulated on the replication organelles of this mutant even in the presence of BFA, its replication was inhibited by a pan-ArfGEF inhibitor LM11, and the BFA-resistant phenotype was compromised in Arf1-knockout cells. Importantly, the mutations strongly increased the interaction of 2C with the activated form of Arf1. Analysis of other enteroviruses revealed a particularly strong interaction of 2C of human rhinovirus 1A with activated Arf1. Accordingly, the replication of this virus was significantly less sensitive to BFA than that of poliovirus. Thus, our data demonstrate that enterovirus 2Cs may behave like Arf1 effector proteins and that GBF1 but not Arf activation can be dispensable for enterovirus replication. These findings have important implications for the development of host-targeted anti-viral therapeutics.

PURPOSE The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) is a phase II platform trial that uses response adaptive randomization and genomic profiling to efficiently identify novel therapies for phase III testing. Three initial experimental arms (abemaciclib [a cyclin-dependent kinase [CDK]4/6 inhibitor], neratinib [an epidermal growth factor receptor [EGFR]/human epidermal growth factor receptor 2 inhibitor], and CC-115 [a deoxyribonucleic acid–dependent protein kinase/mammalian target of rapamycin inhibitor]) were simultaneously evaluated against a common control arm. We report the results for each arm and examine the feasibility and conduct of the adaptive platform design. PATIENTS AND METHODS Patients with newly diagnosed O ⁶ -methylguanine–DNA methyltransferase-unmethylated glioblastoma were eligible if they had tumor genotyping to identify prespecified biomarker subpopulations of dominant glioblastoma signaling pathways (EGFR, phosphatidylinositol 3-kinase, and CDK). Initial random assignment was 1:1:1:1 between control (radiation therapy and temozolomide) and the experimental arms. Subsequent Bayesian adaptive randomization was incorporated on the basis of biomarker-specific progression-free survival (PFS) data. The primary end point was overall survival (OS), and one-sided P values are reported. The trial is registered with ClinicalTrials.gov identifier: NCT02977780 . RESULTS Two hundred thirty-seven patients were treated (71 control; 73 abemaciclib; 81 neratinib; 12 CC-115) in years 2017-2021. Abemaciclib and neratinib were well tolerated, but CC-115 was associated with ≥ grade 3 treatment-related toxicity in 58% of patients. PFS was significantly longer with abemaciclib (hazard ratio [HR], 0.72; 95% CI, 0.49 to 1.06; one-sided P = .046) and neratinib (HR, 0.72; 95% CI, 0.50 to 1.02; one-sided P = .033) relative to the control arm but there was no PFS benefit with CC-115 (one-sided P = .523). None of the experimental therapies demonstrated a significant OS benefit ( P > .05). CONCLUSION The INSIGhT design enabled efficient simultaneous testing of three experimental agents using a shared control arm and adaptive randomization. Two investigational arms had superior PFS compared with the control arm, but none demonstrated an OS benefit. The INSIGhT design may promote improved and more efficient therapeutic discovery in glioblastoma. New arms have been added to the trial.

We used conjoint analysis—a method that assesses complex decision making—to quantify patients’ choices when selecting an osteoporosis therapy. While 60% of people prioritized medication efficacy when deciding among treatments, the remaining 40% highly valued factors other than efficacy, suggesting the need for personalized shared decision-making tools. In this study, we aimed to examine patient decision-making surrounding osteoporosis medications using conjoint analysis. We enrolled osteoporosis patients at an academic medical center to complete an online conjoint exercise which calculated each patient’s relative importance score of 6 osteoporosis medication attributes (higher = greater relative importance in decision-making). We used latent class analysis to identify distinct segments of patients with similar choice patterns and then used logistic regression to determine if demographics and osteoporosis disease features were associated with latent class assignment. Overall, 304 participants completed the survey. The rank order of medication attributes by importance score was the following: efficacy at preventing hip fractures (accounted for 31.0% of decision making), mode of administration (17.5%); risk of serious side effects (16.6%); dose frequency (13.9%); efficacy at preventing spine fractures (12.5%); risk of non-serious side effects (8.4%). We found that 60.9% of the cohort prioritized medication efficacy as their top factor when selecting among the therapies. Being a college graduate, having stronger beliefs on the necessity of using medications for osteoporosis, and never having used osteoporosis medicines were the only factors associated with prioritizing medication efficacy for fracture prevention over the other factors in the decision-making process. While about 60% of patients prioritized efficacy when selecting an osteoporosis therapy, the remaining 40% valued other factors more highly. Furthermore, individual patient characteristics and clinical factors did not reliably predict patient decision making, suggesting that development and implementation of shared decision-making tools is warranted.

Importance Published data about the impact of poststroke seizures (PSSs) on the outcomes of patients with stroke are inconsistent and have not been systematically evaluated, to the authors’ knowledge. Objective To investigate outcomes in people with PSS compared with people without PSS. Data Sources MEDLINE, Embase, PsycInfo, Cochrane, LILACS, LIPECS, and Web of Science, with years searched from 1951 to January 30, 2023. Study Selection Observational studies that reported PSS outcomes. Data Extraction and Synthesis The Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist was used for abstracting data, and the Joanna Briggs Institute tool was used for risk-of-bias assessment. Data were reported as odds ratio (OR) and standardized mean difference (SMD) with a 95% CI using a random-effects meta-analysis. Publication bias was assessed using funnel plots and the Egger test. Outlier and meta-regression analyses were performed to explore the source of heterogeneity. Data were analyzed from November 2022 to January 2023. Main Outcomes and Measures Measured outcomes were mortality, poor functional outcome (modified Rankin scale [mRS] score 3-6), disability (mean mRS score), recurrent stroke, and dementia at patient follow-up. Results The search yielded 71 eligible articles, including 20 110 patients with PSS and 1 166 085 patients without PSS. Of the participants with PSS, 1967 (9.8%) had early seizures, and 10 605 (52.7%) had late seizures. The risk of bias was high in 5 studies (7.0%), moderate in 35 (49.3%), and low in 31 (43.7%). PSSs were associated with mortality risk (OR, 2.1; 95% CI, 1.8-2.4), poor functional outcome (OR, 2.2; 95% CI, 1.8-2.8), greater disability (SMD, 0.6; 95% CI, 0.4-0.7), and increased dementia risk (OR, 3.1; 95% CI, 1.3-7.7) compared with patients without PSS. In subgroup analyses, early seizures but not late seizures were associated with mortality (OR, 2.4; 95% CI, 1.9-2.9 vs OR, 1.2; 95% CI, 0.8-2.0) and both ischemic and hemorrhagic stroke subtypes were associated with mortality (OR, 2.2; 95% CI, 1.8-2.7 vs OR, 1.4; 95% CI, 1.0-1.8). In addition, early and late seizures (OR, 2.4; 95% CI, 1.6-3.4 vs OR, 2.7; 95% CI, 1.8-4.1) and stroke subtypes were associated with poor outcomes (OR, 2.6; 95% CI, 1.9-3.7 vs OR, 1.9; 95% CI, 1.0-3.6). Conclusions and Relevance Results of this systematic review and meta-analysis suggest that PSSs were associated with significantly increased mortality and severe disability in patients with history of stroke. Unraveling these associations is a high clinical and research priority. Trials of interventions to prevent seizures may be warranted.

Environmental legislation promotes citizen participation in the environmental review process through public hearings, community meetings, and advisory groups. However, environmental justice literature advocates higher levels of grassroots citizen empowerment through education and involvement in the decision-making process. Numerous research studies indicated that although the federal government supports community involvement in environmental restoration projects, such involvement has never been implemented to its fullest potential. This case study examines citizen participation and empowerment in the environmental review process in the redevelopment of three brownfields in underserved neighborhoods in downtown Birmingham, Alabama. This study quantifies empowerment leveraging Arnstein's ladder of participation in a novel approach. Utilizing a survey questionnaire, this analysis was conducted in three ways: a comparison of actual citizen participation methods used in the process with those providing a higher level of empowerment; compilation of open-ended responses of citizen dissatisfaction with the environmental review process; and utilizing Arnstein's Ladder to measure perceived levels of empowerment of citizen, public official, and developer stakeholders. Findings suggest that the types of participation methods used were at lower levels of citizen empowerment removed from decision-making; in responses to open-ended questions, citizens expressed shortcomings in the participatory process compared with their opinion on how it should be conducted, and perceived levels of empowerment differed among the categories of stakeholders. Citizens reported perceptions of empowerment at levels of tokenism removed from decision-making, while developers and public officials reported higher levels of empowerment. This study concludes that more innovative citizen participation techniques, university/community partnerships, and collaborative compact models are needed for more equitable participation. Statement of Problem—The purpose of this case study is to analyze how well citizen participation in the environmental review process as specified by legislation corresponds to normative guidelines prescribed in the environmental justice literature.

Aging is the consequence of intra- and extracellular events that promote cellular senescence. Dyskeratosis congenita (DC) is an example of a premature aging disorder caused by underlying telomere/telomerase-related mutations. Cells from these patients offer an opportunity to study telomere-related aging and senescence. Our previous work has found that telomere shortening stimulates DNA damage responses (DDR) and increases reactive oxygen species (ROS), thereby promoting entry into senescence. This work also found that telomere elongation via TERT expression, the catalytic component of the telomere-elongating enzyme telomerase, or p53 shRNA could decrease ROS by disrupting this telomere-DDR-ROS pathway. To further characterize this pathway, we performed a CRISPR/Cas9 knockout screen to identify genes that extend lifespan in DC cells. Of the cellular clones isolated due to increased lifespan, 34% had a guide RNA (gRNA) targeting CEBPB while gRNAs targeting WSB1, MED28 and p73 were observed multiple times. CEBPB is a transcription factor associated with activation of proinflammatory response genes suggesting that inflammation may be present in DC cells. The inflammatory response was investigated using RNA-Seq to compare DC and control cells. Expression of inflammatory genes were found to be significantly elevated (p < 0.0001) in addition to a key subset of these inflammation-related genes (IL1B, IL6, IL8, IL12A, CXCL1 (GROa), CXCL2 (GROb), and CXCL5) which are regulated by CEBPB. Exogenous TERT expression led to downregulation of RNA/protein CEBPB expression and the inflammatory response genes suggesting a telomere-length dependent mechanism to regulate CEBPB. Furthermore, unlike exogenous TERT and p53 shRNA, CEBPB shRNA did not significantly decrease ROS suggesting that CEBPB’s contribution in DC cells’ senescence is ROS-independent. Our findings demonstrate a key role for CEBPB in engaging senescence by mobilizing an inflammatory response within DC cells.

Youth who grow up in disadvantaged neighborhoods experience poorer health later in life, but little is known about the biological mechanisms underlying these effects and socioenvironmental factors that may protect youth from the biological embedding of neighborhood adversity. This study tests whether supportive and consistent parenting buffers associations between neighborhood disadvantage in early adolescence and epigenetic aging in adulthood. A community sample from Birmingham, Alabama, USA (N = 343; 57% female; 81% Black, 19% White) was assessed in early adolescence (T1; ages 11 and 13) and adulthood (T2; age 27). At T1, neighborhood poverty was derived from census data and neighborhood disorder was reported by caregivers. Both youth and parents reported on parental discipline and nurturance. At T2, methylation of salivary DNA was used to derive a mortality risk index and Hannum, Horvath, PhenoAge, and GrimAge epigenetic age estimators. Regression analyses revealed that neighborhood disadvantage was associated with accelerated epigenetic aging and/or mortality risk only when combined with high levels of harsh and inconsistent discipline and low child-reported parental nurturance. These findings identify epigenetic aging and mortality risk as relevant mechanisms through which neighborhood adversity experienced in adolescence may affect later health; they also point to the importance of supportive and consistent parenting for reducing the biological embedding of neighborhood adversity in early adolescence.

Rodents are the largest and most diverse group of mammals. Covering a wide range of structural and functional adaptations, rodents successfully occupy virtually every terrestrial habitat, and they are often found in close association with humans, domestic animals, and wildlife. Although a significant amount of research has focused on rodents’ prominence as known reservoirs of zoonotic viruses, there has been less emphasis on the viral ecology of rodents in general. Here, we utilized a viral metagenomics approach to investigate polyomaviruses in wild rodents from the Baja California peninsula, Mexico, using fecal samples. We identified a novel polyomavirus in fecal samples from two rodent species, a spiny pocket mouse (Chaetodipus spinatus) and a Dulzura kangaroo rat (Dipodomys simulans). These two polyomaviruses represent a new species in the genus Betapolyomavirus. Sequences of this polyomavirus cluster phylogenetically with those of other rodent polyomaviruses and two other non-rodent polyomaviruses (WU and KI) that have been identified in the human respiratory tract. Through our continued work on seven species of rodents, we endeavor to explore the viral diversity associated with wild rodents on the Baja California peninsula and expand on current knowledge of rodent viral ecology and evolution.