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Although immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, many patients do not respond or develop resistance to ICB. N⁶-methylation of adenosine (m⁶A) in RNA regulates many pathophysiological processes. Here, we show that deletion of the m⁶A demethylase Alkbh5 sensitized tumors to cancer immunotherapy. Alkbh5 has effects on m⁶A density and splicing events in tumors during ICB. Alkbh5 modulates Mct4/Slc16a3 expression and lactate content of the tumor microenvironment and the composition of tumor-infiltrating Treg and myeloid-derived suppressor cells. Importantly, a small-molecule Alkbh5 inhibitor enhanced the efficacy of cancer immunotherapy. Notably, the ALKBH5 gene mutation and expression status of melanoma patients correlate with their response to immunotherapy. Our results suggest that m⁶A demethylases in tumor cells contribute to the efficacy of immunotherapy and identify ALKBH5 as a potential therapeutic target to enhance immunotherapy outcome in melanoma, colorectal, and potentially other cancers.

Background The marginal and internal fit of full-coverage crowns is essential for their long-term clinical success. Computer-aided design and manufacturing (CAD/CAM) technologies have enhanced the precision of restorations. However, the performance of emerging three-dimensional (3D) printing systems, such as the Midas system based on digital press stereolithography (DPS), requires further investigation. Methods This in vitro study evaluated and compared the marginal, cervical, axial, and occlusal gaps of crowns fabricated using five different materials. A total of forty crowns were fabricated using subtractive milling (Empress CAD, Vita Enamic, Cerasmart, and zirconia; n  = 10 each), and ten crowns were fabricated using additive 3D printing with the Midas DPS system. A standardized molar preparation was scanned and used to produce fifty resin dies. Crowns were designed using dedicated software, cemented on the dies, and subjected to thermocycling (5000 cycles between 5 °C and 55 °C). Each specimen was sectioned and examined under 40× magnification using a stereomicroscope. A total of 160 gap measurements were recorded for each crown across four anatomical regions. Statistical analysis was performed using the Shapiro–Wilk, Kruskal–Wallis, and Mann–Whitney U tests with a significance level set at 0.05. Results All groups exhibited gap values within clinically acceptable ranges. Zirconia crowns demonstrated the lowest mean gaps and variability, especially in the cervical (66.0 micrometers, coefficient of variation: 6.1%) and axial (122.7 micrometers, coefficient of variation: 2.9%) regions. The Midas 3D-printed group presented greater variability, particularly in the occlusal region (211.9 micrometers, coefficient of variation: 52.1%). Statistically significant differences were found in cervical gap values among the materials tested. Conclusions Crowns fabricated using the Midas DPS 3D printing system exhibited acceptable adaptation, although with greater variability compared to those produced via subtractive methods. Zirconia demonstrated superior dimensional consistency, supporting its continued use as a reference material. These findings indicate that the Midas system holds promise as a clinically viable alternative, warranting further validation through clinical studies.

The aim of the present study was to evaluated hemoglobin A1c (HbA1c), the hemoglobin glycation index (HGI), and triglyceride and glucose (TG) index as predictive indicators for low feed intake in lactating sows due to glucose intolerance. Cactus ( Opuntia ficus-indica ) was included in sow diets as a modulating factor of glucose. Thirty-six sows were separated into three groups (Gs). Although the three groups received a conventional diet during gestation and lactation, 2.0 kg per sow per day of steam-cooked cactus (G1) and fresh cactus (G2) were added to the lactation diet as a glycemic modulating factor, with G3 serving as the control group. Glycemia was assessed via glucometer (blood glucose concentrations), HbA1c and HGI. For each indicator of glycemia the triglycerides and glucose (TG) index was evaluated. The highest blood glucose concentration was observed on day 3 of lactation (88.2 mg/dL). The average glycemic concentrations obtained from HbA1c on farrowing day (61.6 mg/dL) and day 21 of lactation (65.6 mg/dL) were lower (p<0.05) than those measured by a glucometer on the same days (71.8 and 77.7 mg/dL for farrowing day and day 21 of lactation, respectively). At farrowing, the TG index obtained from the HGI indicated that 83.0% of sows were glucose intolerant, compared to 100% according to the TG index obtained from a glucometer. At weaning, 50% of G2 did not show glucose intolerance when the TG index was calculated using the HGI, compared to 54% when it was calculated with blood glucose concentrations measured by a glucometer. All G3 sows presented glucose intolerance, regardless of the test used. The HbA1c, HGI, and TG index tests are viable alternatives to predict low feed intake due to glucose intolerance in lactating sows.

Patients harboring CRLF2-rearranged B-lineage acute lymphocytic leukemia (B-ALL) face a 5-year survival rate as low as 20%. While significant gains have been made to position targeted therapies for B-ALL treatment, continued efforts are needed to develop therapeutic options with improved duration of response. Here, first we have demonstrated that patients with CRLF2-rearranged Ph-like ALL harbor elevated thymic stromal lymphopoietin receptor (TSLPR) expression, which is comparable with CD19. Then we present and evaluate the anti-tumor characteristics of 1B7/CD3, a novel CD3-redirecting bispecific antibody (BsAb) that co-targets TSLPR. In vitro, 1B7/CD3 exhibits optimal binding to both human and cynomolgus CD3 and TSLPR. Further, 1B7/CD3 was shown to induce potent T cell activation and tumor lytic activity in both cell lines and primary B-ALL patient samples. Using humanized cell- or patient-derived xenograft models, 1B7/CD3 treatment was shown to trigger dose-dependent tumor remission or growth inhibition across donors as well as induce T cell activation and expansion. Pharmacokinetic studies in murine models revealed 1B7/CD3 to exhibit a prolonged half-life. Finally, toxicology studies using cynomolgus monkeys found that the maximum tolerated dose of 1B7/CD3 was ≤1 mg/kg. Overall, our preclinical data provide the framework for the clinical evaluation of 1B7/CD3 in patients with CRLF2-rearranged B-ALL.

N 6 ,2′- O -dimethyladenosine (m 6 Am) is an abundant RNA modification located adjacent to the 5′-end of the mRNA 7-methylguanosine (m 7 G) cap structure. m 6 A methylation on 2′- O -methylated A at the 5′-ends of mRNAs is catalyzed by the methyltransferase Phosphorylated CTD Interacting Factor 1 (PCIF1). The role of m 6 Am and the function of PCIF1 in regulating host–pathogens interactions are unknown. Here, we investigate the dynamics and reprogramming of the host m 6 Am RNA methylome during HIV infection. We show that HIV infection induces a dramatic decrease in m 6 Am of cellular mRNAs. By using PCIF1 depleted T cells, we identify 2237 m 6 Am genes and 854 are affected by HIV infection. Strikingly, we find that PCIF1 methyltransferase function restricts HIV replication. Further mechanism studies show that HIV viral protein R (Vpr) interacts with PCIF1 and induces PCIF1 ubiquitination and degradation. Among the m 6 Am genes, we find that PCIF1 inhibits HIV infection by enhancing a transcription factor ETS1 (ETS Proto-Oncogene 1, transcription factor) stability that binds HIV promoter to regulate viral transcription. Altogether, our study discovers the role of PCIF1 in HIV–host interactions, identifies m 6 Am modified genes in T cells which are affected by viral infection, and reveals how HIV regulates host RNA epitranscriptomics through PCIF1 degradation. m6Am is a modification of the 5′ end of mRNAs catalyzed by PCIF1. Here, Zhang et al. show that HIV infection induces a decrease in m6Am of cellular mRNAs through Vpr-mediated PCIF1 ubiquitination and degradation, resulting in increased HIV replication through regulation of host transcription factors.

[FOXP3.sup.+] Tregs are expanded within the inflamed intestine of human Crohn's disease, yet FOXP3-mediated gene repression within these cells is lost. The polycomb repressive complexes play a role in FOXP3 target gene regulation, but deeper mechanistic insight is incomplete. We have now specifically identified the polycomb-repressive complex 1 (PRC1) family member, BMI1 in the regulation of a proinflammatory enhancer network in both human and murine Tregs. Using human Tregs and lamina propria T cells, we inferred PRC1 to regulate Crohn's associated gene networks through assays of chromatin accessibility. Conditional deletion of BMI1 in murine [FOXP3.sup.+] cells led to systemic inflammation. BMI1- deficient Tregs beared a TH1/TH17-like phenotype as assessed by assays of genome wide transcription, chromatin accessibility and proteomic techniques. Finally, BMI1 mutant [FOXP3.sup.+] cells did not suppress colitis in the adoptive transfer model of human inflammatory bowel disease. We propose that BMI1 plays an important role in enforcing Treg identity in vitro and in vivo. Loss of Treg identity via genetic or transient BMI1 depletion perturbs the epigenome and converts Tregs into Th1/Th17- like proinflammatory cells, a transition relevant to human Crohn's disease associated [CD4.sup.+] T cells.

This mixed-methods study primarily explored how elementary educators exhibited TPACK in their virtual literacy instruction and the challenges they faced during the early months of the COVID-19 pandemic. Nine elementary-level educators participated in the study serving in the role of either general educator, special educator, or reading specialist. Data sources included a survey, email interviews, and teacher instructional materials. A hybrid thematic data analysis approach was utilized for the qualitative data, and basic descriptive statistical analysis was used for the survey data. TPACK and TPK were the most frequently coded domain among participants. TPACK was apparent across all areas of literacy instruction but less complex in the participants’ phonics instruction. The greatest relationship between perceived ability and demonstration of TPACK occurred in the TPACK domain. Through the lens of TPACK, identified challenges of virtual literacy instruction were student technology access and skills, student motivation and engagement, and student learning and accountability; identified successes addressed student emotional well-being, educator collaboration, and new learning.

The colonial history of the Caribbean created a context in which many religions, from indigenous to African-based to Christian, intermingled with one another, creating a rich diversity of religious life. Caribbean Religious History offers the first comprehensive religious history of the region. Ennis B. Edmonds and Michelle A. Gonzalez begin their exploration with the religious traditions of the Amerindians who flourished prior to contact with European colonizers, then detail the transplantation of Catholic and Protestant Christianity and their centuries of struggles to become integral to the Caribbean's religious ethos, and trace the twentieth century penetration of American Evangelical Christianity, particularly in its Pentecostal and Holiness iterations. Caribbean Religious History also illuminates the influence of Africans and their descendants on the shaping of such religious traditions as Vodou, Santeria, Revival Zion, Spiritual Baptists, and Rastafari, and the success of Indian indentured laborers and their descendants in reconstituting Hindu and Islamic practices in their new environment. Paying careful attention to the region's social and political history, Edmonds and Gonzalez present a one-volume panoramic introduction to this religiously vibrant part of the world.