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Novel binary gene expression tools like the LexA-LexAop system could powerfully enhance studies of metabolism, development, and neurobiology in Drosophila. However, specific LexA drivers for neuroendocrine cells and many other developmentally relevant systems remain limited. In a unique high school biology course, we generated a LexA-based enhancer trap collection by transposon mobilization. The initial collection provides a source of novel LexA-based elements that permit targeted gene expression in the corpora cardiaca, cells central for metabolic homeostasis, and other neuroendocrine cell types. The collection further contains specific LexA drivers for stem cells and other enteric cells in the gut, and other developmentally relevant tissue types. We provide detailed analysis of nearly 100 new LexA lines, including molecular mapping of insertions, description of enhancer-driven reporter expression in larval tissues, and adult neuroendocrine cells, comparison with established enhancer trap collections and tissue specific RNAseq. Generation of this open-resource LexA collection facilitates neuroendocrine and developmental biology investigations, and shows how empowering secondary school science can achieve research and educational goals.

The incidence of rectal cancer is increasing in patients younger than 50 years. Locally advanced rectal cancer is still treated with neoadjuvant radiation, chemotherapy and surgery, but recent evidence suggests that patients with a complete response can avoid surgery permanently. To define correlates of response to neoadjuvant therapy, we analyzed genomic and transcriptomic profiles of 738 untreated rectal cancers. APC mutations were less frequent in the lower than in the middle and upper rectum, which could explain the more aggressive behavior of distal tumors. No somatic alterations had significant associations with response to neoadjuvant therapy in a treatment-agnostic manner, but KRAS mutations were associated with faster relapse in patients treated with neoadjuvant chemoradiation followed by consolidative chemotherapy. Overexpression of IGF2 and L1CAM was associated with decreased response to neoadjuvant therapy. RNA-sequencing estimates of immune infiltration identified a subset of microsatellite-stable immune hot tumors with increased response and prolonged disease-free survival. DNA and RNA sequencing in large cohorts of patients with rectal cancer treated with neoadjuvant therapies identifies biomarkers of response that could inform patient selection for non-operative treatment strategies.

The faster a drug enters the brain, the greater its addictive potential, yet the brain circuits underlying the rate dependency to drug reward remain unresolved. With simultaneous PET-fMRI we linked dynamics of dopamine signaling, brain activity/connectivity, and self-reported ‘high’ in 20 adults receiving methylphenidate orally (results in slow delivery) and intravenously (results in fast delivery) (trial NCT03326245). We estimated speed of striatal dopamine increases to oral and IV methylphenidate and then tested where brain activity was associated with slow and fast dopamine dynamics (primary endpoint). We then tested whether these brain circuits were temporally associated with individual ‘high’ ratings to methylphenidate (secondary endpoint). A corticostriatal circuit comprising the dorsal anterior cingulate cortex and insula and their connections with dorsal caudate was activated by fast (but not slow) dopamine increases and paralleled ‘high’ ratings. These data provide evidence in humans for a link between dACC/insula activation and fast but not slow dopamine increases and document a critical role of the salience network in drug reward. The faster a drug enters the brain, the greater its addictive potential. Using simultaneous PET-fMRI in humans, here the authors report a neural circuit responding to fast but not slow dopamine increases from intravenous versus oral methylphenidate delivery.

Overexpressed EGFR and mutant K-Ras play vital roles in therapeutic resistance in colorectal cancer patients. To search for an effective therapeutic protocol is an urgent task. A secondary metabolite in the sponge Hippospongia sp., Heteronemin, has been shown to induce anti-proliferation in several types of cancers. A thyroxine-deaminated analogue, tetrac, binds to integrin αvβ3 to induce anti-proliferation in different cancers. Heteronemin- and in combination with tetrac-induced antiproliferative effects were evaluated. Tetrac enhanced heteronemin-induced anti-proliferation in HT-29 cells (KRAS WT CRC) and HCT-116 cells (KRAS MT CRC). Heteronemin and tetrac arrested cell cycle in different phases. Combined treatment increased the cell accumulation in sub-G1 and S phases. The combined treatment also induced the inactivation of EGFR signaling and downregulated the phosphorylated ERK1/2 protein in both cell lines. Heteronemin and the combination showed the downregulation of the phosphorylated and total PI3K protein in HT-29 cells (KRAS WT CRC). Results by NanoString technology and RT-qPCR revealed that heteronemin and combined treatment suppressed the expression of EGFR and downstream genes in HCT-116 cells (KRAS MT CRC). Heteronemin or combined treatment downregulated genes associated with cancer progression and decreased cell motility. Heteronemin or the combined treatment suppressed PD-L1 expression in both cancer cell lines. However, only tetrac and the combined treatment inhibited PD-L1 protein accumulation in HT-29 cells (KRAS WT CRC) and HCT-116 cells (KRAS MT CRC), respectively. In summary, heteronemin induced anti-proliferation in colorectal cancer cells by blocking the EGFR-dependent signal transduction pathway. The combined treatment further enhanced the anti-proliferative effect via PD-L1 suppression. It can be an alternative strategy to suppress mutant KRAS resistance for anti-EGFR therapy.

Background Hybrid zones play a central role in evolutionary biology because they serve as natural laboratories for studying how traits and taxa diverge. Changes in gene regulation make important contributions to this process. However, the degree to which admixture shapes gene regulatory variation in hybrid populations remains poorly understood. Here, we combine genome-wide resequencing and DNA methylation data from 295 hybrid baboons—members of a single, intensively studied natural population—to investigate how admixture affects the genetic architecture of this important epigenetic mark. Results We find that local genetic ancestry frequently predicts DNA methylation levels and recapitulates differences between the parent species. By performing methylation quantitative trait locus mapping, we show that these differences predominantly arise due to evolved differences in allele frequencies. Thus, admixture in the hybrid population increases variance in DNA methylation, including by introducing genetic variants affecting DNA methylation that would otherwise be invariant. Finally, we integrate massively parallel reporter assay data to show that admixture-derived variation in DNA methylation alters enhancer activity and gene expression. Conclusions Together, these results demonstrate how admixture can meaningfully alter the genetic architecture of gene regulatory traits in natural hybrid zones. They also suggest that the genetic architecture of DNA methylation is conserved across closely related primates, suggesting that genetic effects on gene regulation may remain stable over timescales that range into the millions of years.

Background Pancreatic adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by aggressive progression, pronounced stromal desmoplasia, and a limited response to targeted therapies. Although epidermal growth factor receptor (EGFR) inhibitors have shown promise in preclinical studies, their clinical efficacy has been modest, suggesting the existence of compensatory signaling networks. Methods An integrated analytical framework was employed, combining bulk transcriptomic analyses of TCGA-PDAC and GTEx datasets, DNA methylation profiling, protein–protein interaction (PPI) network analysis, immune infiltration estimation, and single-cell RNA sequencing. Expression patterns and clinical associations of integrin αvβ3 were evaluated using TCGA, GEPIA, UALCAN, and the Human Protein Atlas. Functional validation was performed using in vitro assays in pancreatic cancer cell lines to assess the effects of DL-N2, a tetrac-conjugated nanoparticle targeting integrin αvβ3, alone or in combination with gefitinib. Results Integrin αvβ3 (ITGAV/ITGB3) was upregulated in PDAC tissues compared with normal pancreatic tissue and was associated with poor prognosis. Single-cell transcriptomic profiling localized αvβ3 expression to malignant ductal cells and stromal fibroblasts. Computational analyses predicted strong associations of αvβ3 with EGFR, MMP2, and MMP9, implicating it in epithelial–mesenchymal transition (EMT), extracellular matrix (ECM) remodeling, and immune regulation. In vitro, experiments showed that DL-N2 suppressed basal and EGF-induced proliferation, decreased the expression of EGFR , PCNA , and CCND1 , and reduced angiogenic and invasive mediators, including VEGF-α , bFGF2 , and MMP9 . Notably, DL-N2 inhibited PD-L1 expression, linking αvβ3 signaling to immune evasion. In addition, both DL-N2 and gefitinib inhibited cell migration, and their combined treatment exerted an additive effect on the suppression of pancreatic cancer cell migration. Conclusion Our findings establish integrin αvβ3 as a multifunctional regulator of pancreatic cancer progression, integrating growth-associated signaling, extracellular matrix regulation, and immune-associated pathways. Targeting αvβ3 with DL-N2 remodels both tumor-intrinsic and microenvironmental pathways, potentially enhancing EGFR inhibition and restoring chemosensitivity. Dual blockade of αvβ3 and EGFR represents a rational therapeutic strategy to overcome drug resistance and improve outcomes in PDAC. Highlights Mechanistic Crosstalk Clarity : Ensure the introduction (which you've drafted well) leads directly to results that prove how integrin αvβ3 and EGFR interact. Mentioning FAK (Focal Adhesion Kinase) as the bridge is a common 2026 reviewer expectation for this pathway. Clinical Relevance : JTM editors look for \"human-centric\" data. If your paper relies on cell lines, ensure you have validated the expression of αvβ3 and EGFR in human PDAC tissue samples or publicly available databases (like TCGA or GTEx) to prove clinical significance. Address “Thyroid Hormone” Implications : Since you mentioned thyroid hormones (T3/T4) binding to αvβ3, reviewers may ask if patients on thyroid medication show different PDAC outcomes. Briefly addressing this \"translational\" clinical potential in your discussion can significantly strengthen your case

•Exit interviews complement clinical data and can validate patient reported outcomes.•In XTEND-1 exit interviews, the most common pre-study symptom was joint pain.•Improved physical functioning and pain was reported with efanesoctocog alfa.•All participants preferred efanesoctocog alfa over pre-study treatments. Hemophilia A is a rare bleeding disorder that leads to recurrent hemarthrosis, which can ultimately result in reduced mobility and poor quality of life. Qualitative exit interviews provide insights into patient perspectives and support the interpretation of quantitative trial data, such as patient-reported outcome measures. In the Phase 3 XTEND-1 study (NCT04161495) of efanesoctocog alfa in participants with severe hemophilia A, exit interviews were conducted to understand pre- and post-study experiences with pain and physical functioning and to evaluate participants’ treatment experiences. In XTEND-1, participants (≥12 years old) received once-weekly efanesoctocog alfa prophylaxis 50 IU/kg for 52 weeks (Arm A) or on-demand efanesoctocog alfa 50 IU/kg for 26 weeks followed by 26 weeks once-weekly prophylaxis (50 IU/kg; Arm B). Optional qualitative exit interviews were conducted using a semi-structured guide in a subset of participants following study completion. Interviews included open-ended questions about participants’ pre- and post-study experiences with hemophilia A and targeted questions relating to improvements in patient-reported outcomes assessed during XTEND-1, including the Haemophilia Quality of Life Questionnaire for Adults Physical Health subscale (Haem-A-QoL PH). Content validity of the Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Intensity 3a measure was also assessed, particularly the worst pain item. Exit interviews were conducted with 29 of 159 patients enrolled in XTEND-1 (mean [range] age 40 [16−73] years). Of 17 participants enrolled in Arm A, 13 (76.5%) reported a “wearing off” feeling with pre-study treatment, including more aches/pain, breakthrough bleeds, and limited physical activities. Joint pain was the most reported pre-study symptom (96.6%; n = 28/29), followed by a reduced ability to move without pain (89.7%, n = 26/29). Improvements following efanesoctocog alfa prophylaxis in ≥1 Haem-A-QoL PH domain were reported by 89.7% (n = 26/29) of participants, with improvements in joint pain, the ability to move without pain, and painful swellings reported by at least 21 (84%) participants. Participants reported that the PROMIS Pain Intensity 3a items were relevant, clear, and easy to answer. Most participants (96.6%) were “quite satisfied” or “very satisfied” with efanesoctocog alfa prophylaxis. All participants preferred efanesoctocog alfa over pre-study treatment. The exit interviews demonstrated that once-weekly efanesoctocog alfa prophylaxis resulted in patient-relevant and meaningful improvements in pain and physical functioning, consistent with the quantitative findings from XTEND-1. These results support the validity of the Haem-A-QoL PH and PROMIS Pain Intensity 3a assessed during XTEND-1, demonstrating the potential for change with efficacious treatment. ClinicalTrials.gov NCT04161495 https://clinicaltrials.gov/study/NCT04161495

Background Risk-reducing mastectomy (RRM) is offered to women with a BRCA1 or BRCA2 pathogenic variant, however, there are limited data on the impact on breast cancer mortality. Methods Participants were identified from a registry of women with BRCA1/2 pathogenic variants. We used a pseudo-randomised trial design and matched one woman with a RRM to one woman without a RRM on year of birth, gene, and country. We estimated the hazard ratio (HR) and 95% confidence intervals (CI) for dying of breast cancer in the follow-up period. Results There were 1654 women included; 827 assigned to the RRM arm and 827 assigned to the control arm. After a mean follow-up of 6.3 years, there were 20 incident breast cancers (including 15 occult cancers) and two breast cancer deaths in the RRM arm, and 100 incident breast cancers and 7 breast cancer deaths in the control arm (HR = 0.26; 95% CI 0.05–1.35; p  = 0.11). The probability of dying of breast cancer within 15 years after RRM was 0.95%. Conclusions In women with a BRCA1 or BRCA2 pathogenic variant, RRM reduces the risk of breast cancer, and the probability of dying of breast cancer is low.

Reduced fertility associated with normal aging may reflect the over-maturity of oocytes. It is increasingly important to reduce aging-induced infertility since recent trends show people marrying at later ages. 2,3,5,4′-Tetrahydroxystilbene-2- O -β-D-glucoside (THSG), a polyphenol extracted from Polygonum multiflorum , has been reported to have anti-inflammatory and anti-aging properties. To evaluate whether THSG can reduce aging-related ovarian damage in a female mouse model of aging, THSG was administered by gavage at a dose of 10 mg/kg twice weekly, starting at 4 weeks of age in a group of young mice. In addition, the effect of THSG in a group of aged mice was also studied in mice starting at 24 weeks of age. The number of oocytes in the THSG-fed group was higher than in the untreated control group. Although the percentage of secondary polar bodies (PB2) decreased during aging in the THSG-fed group, it decreased much more slowly than in the age-matched control group. THSG administration increased the quality of ovaries in young mice becoming aged. Western blotting analyses also indicated that CYP19, PR-B, and ER-β expressions were significantly increased in 36-week-old mice. THSG also increased oocyte numbers in aged mice compared to mice without THSG fed. Studies of qPCR and immunohistochemistry (IHC) analyses of ovaries in the aged mice groups were conducted. THSG increased gene expression of anti-Müllerian hormone (AMH), a biomarker of oocyte number, and protein accumulation in 40-week-old mice. THSG increased the expression of pgc1α and atp6, mitochondrial biogenesis-related genes, and their protein expression. THSG also attenuated the fading rate of CYP11a and CYP19 associated with sex hormone synthesis. And THSG maintains a high level of ER-β expression, thereby enhancing the sensitivity of estrogen. Our findings indicated that THSG increased or extended gene expression involved in ovarian maintenance and rejuvenation in young and aged mice. On the other hand, THSG treatments significantly maintained oocyte quantity and quality in both groups of young and aged mice compared to each age-matched control group. In conclusion, THSG can delay aging-related menopause, and the antioxidant properties of THSG may make it suitable for preventing aging-induced infertility.