Epigenetic therapy potentiates transposable element transcription to create tumor-enriched antigens in glioblastoma cells.

Inhibiting epigenetic modulators can transcriptionally reactivate transposable elements (TEs). These TE transcripts often generate unique peptides that can serve as immunogenic antigens for immunotherapy. Here, we ask whether TEs activated by epigenetic therapy could appreciably increase the antigen repertoire in glioblastoma, an aggressive brain cancer with low mutation and neoantigen burden. We treated patient-derived primary glioblastoma stem cell lines, an astrocyte cell line and primary fibroblast cell lines with epigenetic drugs, and identified treatment-induced, TE-derived transcripts that are preferentially expressed in cancer cells. We verified that these transcripts could produce human leukocyte antigen class I-presented antigens using liquid chromatography with tandem mass spectrometry pulldown experiments. Importantly, many TEs were also transcribed, even in proliferating nontumor cell lines, after epigenetic therapy, which suggests that targeted strategies like CRISPR-mediated activation could minimize potential side effects of activating unwanted genomic regions. The results highlight both the need for caution and the promise of future translational efforts in harnessing treatment-induced TE-derived antigens for targeted immunotherapy.

Relationships of mitochondrial DNA mutations and select clinical diagnoses in perinatally HIV- and ART-exposed uninfected children.

The prevalence of pathogenic mutations within mitochondrial (mt) DNA of youth who were perinatally exposed to HIV and ART but remained uninfected (YHEU) were assessed relative to phenotypic clinical indicators of mitochondrial dysfunction (MtD). This was a cross-sectional, nested case-control study. A total of 144 cases met at least one clinical MtD definition and were matched with up to two controls each (n = 287). At least one risk mutation was present in nearly all YHEU (97 %). No differences in mutation frequencies were observed between metabolic or neurodevelopmental cases and respective controls; however, higher frequencies were found in controls versus respective neurologic or growth cases.

Reprint of: Impact of a pharmacist-driven COPD clinic on outcomes related to COPD in a federally qualified health center.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) affects many patients across the United States. Morbidity related to COPD can lead to increased financial strain to health care system. The United States is also shifting toward value-based payments, which rely on satisfying quality measures. Pharmacists are equipped with knowledge in adjusting medications based on symptom burden and guideline recommendations in COPD and are equipped with the proper knowledge to address quality measures. OBJECTIVE: This project aimed to determine the impact of a clinical pharmacy service centered around inhaler education and optimization on COPD morbidity and Uniform Data System (UDS) quality measure satisfaction in a federally qualified health center. METHODS: This quality improvement project consisted of patient referrals by and reports from a population health software for the pharmacy service from November 2022 to March 2023. The outcomes in this study included symptom change measured by follow-up modified Medical Research Council (mMRC) Dyspnea Scale in addition to changes in compliance with UDS quality measures. At follow-up, patients were administered another mMRC to evaluate treatment effect and determine quality measure satisfaction. RESULTS: Thirteen patient visits were conducted. Most patients were female (84.6%) with an exacerbation in the previous year (46.1%). All patients received an adjustment in their pharmacotherapy along with inhaler education. The average baseline mMRC score decreased from 2.1 to 0.6, indicating a decrease in overall COPD symptoms. Five quality measures of 13 were satisfied during the follow-up period. CONCLUSION: The COPD clinical pharmacy service led to an increase in guideline-driven pharmacotherapy regimens for patients with COPD while having an overall decrease in morbidity. Quality measures were also addressed and satisfied after the appointment. Continuation of this quality improvement service will ensure proper assessment of COPD along with addressing UDS quality measures.

Severe trauma leads to sustained muscle loss, induced frailty, and distinct temporal changes in myokine and chemokine profiles of older patients.

INTRODUCTION: Sarcopenia is a known risk factor for adverse outcomes across multiple disease states, including severe trauma. Factors such as age, hyperinflammation, prolonged immobilization, and critical illness may not only exacerbate progression of this disease but may also contribute to the development of induced sarcopenia, or sarcopenia secondary to hospitalization. This study seeks to (1) determine the effects of severe traumatic injury on changes in skeletal muscle mass in older adults; (2) test whether changes in skeletal muscle mass are associated with clinical frailty, physical performance, and health-related quality of life; and (3) examine trauma-induced frailty and temporal changes in myokine and chemokine profiles. METHODS: A prospective, longitudinal cohort study of 47 critically ill, older (≥45 years) adults presenting after severe blunt trauma was conducted. Repeated measures of computed tomography-based skeletal muscle index, frailty, and quality of life were obtained in addition to selected plasma biomarkers over 6 months. RESULTS: Severe trauma was associated with significant losses in skeletal muscle mass and increased incidence of sarcopenia from 36% at baseline to 60% at 6 months. Severe trauma also was associated with a transient worsening of induced frailty and reduced quality of life irrespective of sarcopenia status, which returned to baseline by 6 months after injury. Admission biomarker levels were not associated with skeletal muscle index at the time points studied but demonstrated distinct temporal changes across our entire cohort. CONCLUSIONS: Severe blunt trauma in older adults is associated with increased incidence of induced sarcopenia and reversible induced frailty. Despite muscle wasting, functional decline is transient, with a return to baseline by 6 months, suggesting a need for holistic definitions of sarcopenia and further investigation into long-term functional outcomes in this population.

Examining Audiences' Psychological Reactance to Christian-Sourced Excessive Alcohol Consumption Messages in the United States.

This study experimentally investigated the effect of dogmatic and suggestive language in Christian-sourced excessive alcohol consumption messages among college-aged participants who identify as Christians or non-Christians, as well as the role of perceived similarity with the message source, on their self-reported freedom-threat, psychological reactance, and behavioral intentions to consume alcohol. The results from this study support psychological reactance theory and demonstrate the various message strategies to effectively communicate the negative health effects of excessive alcohol consumption to individuals who identify either as Christians or non-Christians.

Sexual Minority Identity and Risky Alcohol Use: the Moderating Role of Aggressive Behavior.

Adolescent alcohol use has significant consequences for concurrent and longitudinal health and wellbeing, with sexual minority youth consistently reporting higher levels of alcohol use than their heterosexual peers. Understanding how individual-difference variables like aggressive behavior are associated with variability in sexual minority adolescents' higher levels of alcohol use offers novel theoretical insight into this vulnerability. The 81,509 participants were drawn from the Profiles of Student life: Attitudes and Behavior Study. They were ages 14-17 years (M = 15.38, SD = 1.09) and 50.1% were cisgender girls. For sexual identity, 88% were heterosexual, 5% were mostly heterosexual, were 4% bisexual, were 1% mostly gay or lesbian, and were 1% being gay or lesbian. Participants reported on alcohol use, aggressive behavior, and sexual identity. Gay/lesbian and mostly gay/lesbian adolescents who reported higher aggressive behavior had higher levels of alcohol use than their heterosexual peers who also reported higher aggressive behavior. The way in which aggressive behavior amplified the link between mostly gay/lesbian and gay/lesbian identities and alcohol use suggests the need for more research examining how this trait may heighten both exposure and reaction to minority stressors among some subgroups of sexual minority youth.

Hepatic transcript profiling in beef cattle: Effects of feeding endophyte-infected tall fescue seeds.

The objective of our study was to evaluate the effect of endophyte-infected tall fescue (E+) seeds intake on liver tissue transcriptome in growing Angus × Simmental steers and heifers through RNA-seq analysis. Normal weaned calves (~8 months old) received either endophyte-free tall fescue (E-; n = 3) or infected tall fescue (E+; n = 6) seeds for a 30-d period. The diet offered was ad libitum bermudagrass (Cynodon dactylon) hay combined with a nutritional supplement of 1.61 kg (DM basis) of E+ or E- tall fescue seeds, and 1.61 kg (DM basis) of energy/protein supplement pellets for a 30-d period. Dietary E+ tall fescue seeds were included in a rate of 20 µg of ergovaline/kg BW/day. Liver tissue was individually obtained through biopsy at d 30. After preparation and processing of the liver samples for RNA sequencing, we detected that several metabolic pathways were activated (i.e., upregulated) by the consumption of E+ tall fescue. Among them, oxidative phosphorylation, ribosome biogenesis, protein processing in endoplasmic reticulum and apoptosis, suggesting an active mechanism to cope against impairment in normal liver function. Interestingly, hepatic protein synthesis might increase due to E+ consumption. In addition, there was upregulation of "thermogenesis" KEGG pathway, showing a possible increase in energy expenditure in liver tissue due to consumption of E+ diet. Therefore, results from our study expand the current knowledge related to liver metabolism of growing beef cattle under tall fescue toxicosis.

Radical hope in parents of transgender and gender diverse youth in the United States.

Parental support is crucial in the well-being of transgender and gender diverse (TGD) youth. Research shows that parents of TGD youth often experience stigma and negative mental health outcomes as a result of being exposed to cissexist settings as they advocate and seek services for their child. Yet, there is a lack of research on the experiences of parents of TGD youth in the United States. This study explores the reported hopes of 990 parents (Mage = 48.6 years; SD = 6.7; 88.1% White; 67.3% heterosexual; 89.4% cisgender women) of TGD youth for their children (youth ages 3-18 years) in the United States. Radical hope framework is applied to unpack narratives of hopes by parents of TGD youth as a critical component of resistance and motivation toward healing from oppression. For this study, the following open-ended question was analyzed using thematic analysis: What is your greatest hope for your child? Four main themes and 11 subthemes of parental hopes emerged: (1) living authentically (freely expressing themselves, developing self-love, living a happy and normal life), (2) interpersonal connections (finding community, building social networks and friendships, developing romantic relationships, building their own family, and loved by others), (3) meeting life milestones (career and employment, achieving goals and dreams, and becoming an advocate), and (4) acceptance by society. We provide clinical recommendations grounded on the tenets of radical hope such as collective ways in which parents of TGD youth can engage in both resisting systemic oppression and building strong loving relationships with their child. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Design principles and therapeutic applications of novel synthetic WNT signaling agonists.

Wingless-related integration site or Wingless and Int-1 or Wingless-Int (WNT) signaling is crucial for embryonic development, and adult tissue homeostasis and regeneration, through its essential roles in cell fate, patterning, and stem cell regulation. The biophysical characteristics of WNT ligands have hindered efforts to interrogate ligand activity in vivo and prevented their development as therapeutics. Recent breakthroughs have enabled the generation of synthetic WNT signaling molecules that possess characteristics of natural ligands and potently activate the pathway, while also providing distinct advantages for therapeutic development and manufacturing. This review provides a detailed discussion of the protein engineering of these molecular platforms for WNT signaling agonism. We discuss the importance of WNT signaling in several organs and share insights from the initial application of these new classes of molecules in vitro and in vivo. These molecules offer a unique opportunity to enhance our understanding of how WNT signaling agonism promotes tissue repair, enabling targeted development of tailored therapeutics.

First-trimester exposure to newer antiretroviral agents and congenital anomalies in a US cohort.

OBJECTIVE: To characterize associations of exposure to newer antiretroviral medications in the first trimester with congenital anomalies among infants born to persons with HIV in the United States. DESIGN: Longitudinal cohort of infants born 2012-2022 to pregnant persons with HIV enrolled in the Surveillance Monitoring for ART Toxicities (SMARTT) study. METHODS: First-trimester exposures to newer antiretrovirals (ARVs) were abstracted from maternal medical records. Trained site staff conducted physical exams and abstracted congenital anomalies from infant medical records. Investigators classified anomalies using the Metropolitan Atlanta Congenital Defects Program classification system. The prevalence of major congenital anomalies identified by age one year was estimated for infants exposed and unexposed to each ARV. Generalized estimating equation models were used to estimate the odds ratio (OR) of major congenital anomalies for each ARV exposure, adjusting for potential confounders. RESULTS: Of 2034 infants, major congenital anomalies were identified in 135 [6.6%; 95% confidence interval (CI): 5.6-7.8%]. Cardiovascular ( n  = 43) and musculoskeletal ( n  = 37) anomalies were the most common. Adjusted ORs (95% CI) of congenital anomalies were 1.03 (0.62-1.72) for darunavir, 0.91 (0.46-1.81) for raltegravir, 1.04 (0.58-1.85) for rilpivirine, 1.31 (0.71-2.41) for elvitegravir, 0.76 (0.37-1.57) for dolutegravir, and 0.34 (0.05-2.51) for bictegravir, compared to those unexposed to each specific ARV. Findings were similar after adjustment for nucleoside/nucleotide backbones. CONCLUSIONS: The odds of congenital anomalies among infants with first-trimester exposure to newer ARVs did not differ substantially from those unexposed to these specific ARVs, which is reassuring. Continued evaluation of these ARVs with larger studies will be needed to confirm these findings.

Recombinant inbred line panels inform the genetic architecture and interactions of adaptive traits in Drosophila melanogaster.

The distribution of allelic effects on traits, along with their gene-by-gene and gene-by-environment interactions, contributes to the phenotypes available for selection and the trajectories of adaptive variants. Nonetheless, uncertainty persists regarding the effect sizes underlying adaptations and the importance of genetic interactions. Herein, we aimed to investigate the genetic architecture and the epistatic and environmental interactions involving loci that contribute to multiple adaptive traits using two new panels of Drosophila melanogaster recombinant inbred lines (RILs). To better fit our data, we re-implemented functions from R/qtl (Broman et al. 2003) using additive genetic models. We found 14 quantitative trait loci (QTL) underlying melanism, wing size, song pattern, and ethanol resistance. By combining our mapping results with population genetic statistics, we identified potential new genes related to these traits. None of the detected QTLs showed clear evidence of epistasis, and our power analysis indicated that we should have seen at least one significant interaction if sign epistasis or strong positive epistasis played a pervasive role in trait evolution. In contrast, we did find roles for gene-by-environment interactions involving pigmentation traits. Overall, our data suggest that the genetic architecture of adaptive traits often involves alleles of detectable effect, that strong epistasis does not always play a role in adaptation, and that environmental interactions can modulate the effect size of adaptive alleles.

Phosphaturia in HIV-Exposed Uninfected Neonates Associated with Maternal Use of Tenofovir Disoproxil Fumarate in Late Pregnancy.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) is often used in treating pregnant women living with HIV. Third-trimester TDF exposure is associated with a 12% reduction in bone mineral content in HIV-exposed uninfected (HEU) neonates. The potential mechanisms underlying this observation are unknown. METHODS: The TDF study enrolled newborns of gestational age ≥36 weeks from the Surveillance Monitoring for Antiretroviral Therapy and Toxicities study based on in utero TDF exposure (TDF use ≥8 weeks in the third trimester vs none). Blood and urine samples were collected cross-sectionally within 30 days of birth to assess renal function (serum creatinine, serum phosphate, eGFR, percent tubular reabsorption of phosphate [PTRP]), and bone turnover (serum parathyroid hormone, 25-OH vitamin D [25(OH)D], and urinary cross-linked N-telopeptide of type 1 collagen). For each biomarker, a LOESS plot was fit using values at age at specimen collection; regression lines over age were fit among samples collected from 4 to 30 days, to compare slopes by TDF exposure. RESULTS: Among 141 neonates, 77 were TDF-exposed and 64 TDF-unexposed. Between age 4 and 30 days, PTRP decreased more rapidly in the TDF-exposed compared to the unexposed group with slopes of -0.58 vs -0.08/day (difference -0.50/day [95% CI -0.88, -0.11]). Slopes for 25(OH)D were similar in both groups, but serum levels were lower in TDF-exposed neonates (median [IQR]: 22 [19, 29] vs 26 [22, 37] ng/mL). No differences were observed for other biomarkers. CONCLUSIONS: Third-trimester in utero exposure to TDF is associated with increased urinary loss of phosphate and lower serum concentrations of 25(OH)D in HEU neonates.

Patient-derived response estimates from zero-passage organoids of luminal breast cancer.

Background: Primary luminal breast cancer cells lose their identity rapidly in standard tissue culture, which is problematic for testing hormone interventions and molecular pathways specific to the luminal subtype. Breast cancer organoids are thought to retain tumor characteristics better, but long-term viability of luminal-subtype cases is a persistent challenge. Our goal was to adapt short-term organoids of luminal breast cancer for parallel testing of genetic and pharmacologic perturbations. Methods: We freshly isolated patient-derived cells from luminal tumor scrapes, miniaturized the organoid format into 5 µl replicates for increased throughput, and set an endpoint of 14 days to minimize drift. Therapeutic hormone targeting was mimicked in these "zero-passage" organoids by withdrawing ß-estradiol and adding 4-hydroxytamoxifen. We also examined sulforaphane as an electrophilic stress and commercial neutraceutical with reported anti-cancer properties. Downstream mechanisms were tested genetically by lentiviral transduction of two complementary sgRNAs and Cas9 stabilization for the first week of organoid culture. Transcriptional changes were measured by RT-qPCR or RNA sequencing, and organoid phenotypes were quantified by serial brightfield imaging, digital image segmentation, and regression modeling of cellular doubling times. Results: We achieved >50% success in initiating luminal breast cancer organoids from tumor scrapes and maintaining them to the 14-day zero-passage endpoint. Success was mostly independent of clinical parameters, supporting general applicability of the approach. Abundance of ESR1 and PGR in zero-passage organoids consistently remained within the range of patient variability at the endpoint. However, responsiveness to hormone withdrawal and blockade was highly variable among luminal breast cancer cases tested. Combining sulforaphane with knockout of NQO1 (a phase II antioxidant response gene and downstream effector of sulforaphane) also yielded a breadth of organoid growth phenotypes, including growth inhibition with sulforaphane, growth promotion with NQO1 knockout, and growth antagonism when combined. Conclusions: Zero-passage organoids are a rapid and scalable way to interrogate properties of luminal breast cancer cells from patient-derived material. This includes testing drug mechanisms of action in different clinical cohorts. A future goal is to relate inter-patient variability of zero-passage organoids to long-term outcomes.

On an electromagnetic calculation of ionospheric conductance that seems to override the field line integrated conductivity.

The ionospheric conductance is the major quantity that determines the interaction of the magnetosphere with the ionosphere, where the magnetosphere is the large region of space affected by Earth's geomagnetic field, and the ionosphere is its electrically conducting inner boundary, lying right on the edge of the atmosphere. Storms and substorms in space dissipate their energy through ionospheric currents, which heat the atmosphere and disrupt satellite orbits. The ionospheric conductance has, heretofore, been estimated using the staticized physics known as electrostatic theory, which finds that it can be computed by integrating the zero-frequency conductivity along the lines of Earth's geomagnetic field. In this work we test this supposition by deriving an electromagnetic solution for collisional plasma, and applying it to obtain a first-ever fully-electromagnetic calculation of ionospheric conductance. We compare the results to the field line integrated conductivity, and find significant differences on all scales investigated. We find short-wavelength, mode-mixing, and wave-admittance effects that were completely unexpected. When this theoretical result is matched with recent observational findings for the scale of the magnetosphere-ionosphere coupling-interaction, there results a situation where small- to intermediate-scale effects really may contribute to global modeling of the Sun-Earth system.

A WNT mimetic with broad spectrum FZD-specificity decreases fibrosis and improves function in a pulmonary damage model.

BACKGROUND: Wnt/ß-catenin signaling is critical for lung development and AT2 stem cell maintenance in adults, but excessive pathway activation has been associated with pulmonary fibrosis, both in animal models and human diseases such as idiopathic pulmonary fibrosis (IPF). IPF is a detrimental interstitial lung disease, and although two approved drugs limit functional decline, transplantation is the only treatment that extends survival, highlighting the need for regenerative therapies. METHODS: Using our antibody-based platform of Wnt/ß-catenin modulators, we investigated the ability of a pathway antagonist and pathway activators to reduce pulmonary fibrosis in the acute bleomycin model, and we tested the ability of a WNT mimetic to affect alveolar organoid cultures. RESULTS: A WNT mimetic agonist with broad FZD-binding specificity (FZD1,2,5,7,8) potently expanded alveolar organoids. Upon therapeutic dosing, a broad FZD-binding specific Wnt mimetic decreased pulmonary inflammation and fibrosis and increased lung function in the bleomycin model, and it impacted multiple lung cell types in vivo. CONCLUSIONS: Our results highlight the unexpected capacity of a WNT mimetic to effect tissue repair after lung damage and support the continued development of Wnt/ß-catenin pathway modulation for the treatment of pulmonary fibrosis.

Are Instagram Gym Advertisements Working Out? An Experimental Study of Model Body-Size and Slogan-Type.

Previous health communication research has demonstrated the negative psychological and health effects of depicting thin-sized models in mass media advertisements including on social media sites such as Instagram. However, gym advertisements are one common source for the presentation of lean and thin-sized models on Instagram. Therefore, the current study guided by social comparison theory and signaling theory aimed to experimentally examine the effect of thin-sized models relative to plus-sized models as well as slogan-type (health and wellness versus physique-based) on women's appearance comparison, body satisfaction, perceived gym fit, and intentions to join the gym. A sample of 217 undergraduate students who identified as women were randomly assigned to one of four Instagram gym advertisement conditions varying in model body-size and slogan-type. Appearance comparisons, perceived gym fit, and intentions to join the gym were measured post advertisement exposure and body satisfaction was measured pre-and-post advertisement exposure. As expected, exposure to Instagram gym advertisements featuring thin-sized models resulted in greater appearance comparisons and lower body satisfaction than exposure to Instagram gym advertisements featuring plus-sized models. Moreover, the combination of plus-sized models with health and wellness slogans in Instagram gym advertisements resulted in greater gym fit perceptions although there was no effect of model body-size and slogan-type on intentions to join the gym. This study supports social comparison theory, signaling theory, and practically the findings indicate that Instagram gym advertisements that depict plus-sized models (versus thin) with health-and-wellness slogans (versus physique) generate fewer body image concerns and lead to greater gym fit perceptions.

Climate change drives migratory range shift via individual plasticity in shearwaters.

How individual animals respond to climate change is key to whether populations will persist or go extinct. Yet, few studies investigate how changes in individual behavior underpin these population-level phenomena. Shifts in the distributions of migratory animals can occur through adaptation in migratory behaviors, but there is little understanding of how selection and plasticity contribute to population range shift. Here, we use long-term geolocator tracking of Balearic shearwaters (Puffinus mauretanicus) to investigate how year-to-year changes in individual birds' migrations underpin a range shift in the post-breeding migration. We demonstrate a northward shift in the post-breeding range and show that this is brought about by individual plasticity in migratory destination, with individuals migrating further north in response to changes in sea-surface temperature. Furthermore, we find that when individuals migrate further, they return faster, perhaps minimizing delays in return to the breeding area. Birds apparently judge the increased distance that they will need to migrate via memory of the migration route, suggesting that spatial cognitive mechanisms may contribute to this plasticity and the resulting range shift. Our study exemplifies the role that individual behavior plays in populations' responses to environmental change and highlights some of the behavioral mechanisms that might be key to understanding and predicting species persistence in response to climate change.

Racing Performance and Sale Result in 145 Thoroughbreds after Arthroscopic Removal of Osteochondral Fragments from the Lateral Femoral Trochlear Ridge as a Yearling (2012-2015).

OBJECTIVES: The lateral trochlear ridge (LTR) of the femur is the most common predilection site for osteochondritis dissecans (OCD) in the equine stifle. The objective was to investigate the relationship between lesion size, racing performance, and sale result of Thoroughbreds with LTR OCD following arthroscopic removal as a yearling. METHODS: In this retrospective study, medical records of 145 Thoroughbreds from one equine hospital that underwent surgery for LTR OCD were reviewed; the length and depth of the lesions were measured on preoperative radiographs. Horses were allocated to group S if they were presented to a public yearling sale post-surgery, and horses in group NS were not. Each horse from group S was matched with two control horses from the same sale (group C). Influence of lesion size on racing performance and sale result was analyzed. Racing performance and sale results were compared between different categories of OCD lesion sizes and between the groups. RESULTS: Lesion length and depth did not affect racing performance and did not differ between group S and group NS. However, group S did perform significantly better than group NS. When comparing groups S and C, there were no significant differences in racing performance and sale result. CONCLUSION: Thoroughbreds that had arthroscopic surgery for LTR OCD as a yearling and were presented on a public yearling sale performed comparable to Thoroughbreds that showed similar potential as a yearling. Sale result is not significantly affected in our study.