Browse Articles
Discover research articles across all indexed journals
Anti-cancer compound screening identifies Aurora Kinase A inhibition as a means to favor CRISPR/Cas9 gene correction over knock-out
CRISPR gene therapy holds the potential to cure a variety of genetic diseases by causing a targeted DNA break, which is repaired by host DNA damage responses. One option to introduce precise gene corrections is via the homology-directed repair (HDR) pathway. The problem in utilizing this pathway is that CRISPR-induced double stranded DNA breaks are more likely to be erroneously repaired by the non-homologous end joining (NHEJ) pathway, which may introduce random insertions or deletions at the cut site. We screened a small library of oncological drug compounds to steer the DNA repair process towards preferential HDR activation. We included forty compounds in the screen based on their mechanism of action. After optimizing the toxicity and adding these compounds during gene editing, nine showed a potential benefit for HDR activation. Three were shown to be beneficial after validation: rucaparib, belinostat and alisertib. The Aurora Kinase A inhibitor alisertib in particular led to an over 4-fold increase in preferential gene correction over gene knock-out in two cell models (HEK293T and Hepa 1–6) at sub-micromolar dosages on the eGFP locus, prompting further validation. On the long term this pathway did show cytotoxicity especially in the HEK293T cells, indicating further mechanistic investigation is needed, but this toxicity was less pronounced in primary hepatocytes.
Reply to: Genomic insights into the 2020 mass die-off event among African elephants
Climate and human-modified landscapes influence spread of invasive agricultural pest Popillia japonica Newman in American Midwest and Great Plains
Abstract Japanese beetle (Popillia japonica) is an invasive agricultural pest throughout the eastern United States and its distribution is expanding westward. Understanding how climate and land use intensification interact to affect Japanese beetle population dynamics and spread is essential to predict which areas are vulnerable to increased pest pressure. In this study, we combine data from the Global Biodiversity Information Facility (GBIF) with data from local state agricultural agencies and University extension offices to model how land cover and climate affect Japanese beetle occurrences at the leading edge of an invasion front in the central United States over 5 years. We found that beetle occurrences were positively correlated with proportion of developed areas, proportion of corn and soybean, minimum temperature, and precipitation within counties, and negatively correlated with the proportion of grassland and pasture, and maximum temperature. We modeled Japanese beetle occurrences in the near future and for future climate scenarios and found high probability of occurrence for Japanese beetles across the entire region. Our study highlights the importance of supplementing community science data in rural areas and including a time variable when assessing habitat associations for invasive species in novel areas.
Clinical characteristics and short-term outcomes of pediatric lymphoma: a retrospective cohort study from a large tertiary hospital in a low- and middle-income country
Factors associated with wasting among pediatric cancer patients aged 2–17 years at Uganda cancer institute: A cross-sectional study
Introduction Wasting is a major concern among pediatric cancer patients and significantly affects treatment outcomes and quality of life. However, limited data exist on the prevalence of wasting and its associated factors in low-income contexts. This study determined the prevalence of wasting and its associated factors among pediatric cancer patients aged 2--17 years at the Uganda Cancer Institute. Methods An institutionally based, cross-sectional study was conducted among 270 systematically randomly selected caregiver‒child pairs. Univariate, bivariate, and multivariable analyses were conducted using STATA version 14. Variables with p-value < 0.05 were considered statistically significant. Results Among 270 pediatric cancer patients aged 2–17 years, 27.4% (n = 74) were wasted. Children aged 5 years and older had a 20% higher prevalence of wasting (aPR = 1.2; p = 0.002). Cancers near the gastrointestinal tract were associated with a 10% greater prevalence of wasting (aPR = 1.1; p = 0.028). Wasting was lower by 20% among children whose caregivers had tertiary education (aPR = 0.8; p = 0.002), whereas treatment effects increased wasting prevalence by 10% (aPR = 1.1; p = 0.013). Conclusion Wasting is a prevalent form of malnutrition among pediatric cancer patients requiring the integration of nutritional services to address the nutritional needs of children, especially those aged greater than 5 years, those with cancers along the gastro-intestinal tract and those experiencing treatment effects. Additionally, health and nutrition education programs tailored to the caregiver’s level of education are needed.
An injury-associated lobular microniche is associated with the classical tumor cell phenotype in pancreatic cancer
Abstract Pancreatic cancer is an aggressive disease with a dense fibrotic stroma and is often accompanied by chronic inflammation. Peritumoral inflammation is typically viewed as a reaction to nearby tumor growth. Here, we report that the inflamed pancreatic lobules are frequently invaded by tumor cells, forming a distinct, non-fibrotic tumor niche. Using a semi-supervised machine learning approach for annotations of clinical samples and multiplex protein profiling, we show that tumor cells at the invasion front are closely associated with acinar cells undergoing damage-induced changes, and with activated fibroblasts expressing markers of injury. The invaded lobules are linked to classical tumor phenotypes, in contrast to fibrotic areas where tumor cells display a more basal profile, highlighting microenvironment-dependent tumor subtype differences. In female mice, lobular invasion similarly aligns with the classical tumor phenotype. Together, our data reveal that pancreatic tumors colonize injured lobules, creating a unique niche that shapes tumor characteristics and contributes to disease biology.
Overexpression of alcohol dehydrogenase 1 A inhibits the progress of triple negative breast cancer via Wnt/β-catenin signaling
Abstract The identification of novel therapeutic targets in triple negative breast cancer (TNBC) continues to be of paramount importance. In this context, ADH1A (Alcohol Dehydrogenase 1 A), a protein involved in tyrosine metabolism, was comprehensively examined to assess its expression and functional roles in TNBC. A combination of bioinformatics approaches and local tissue analyses was utilized to determine the expression levels of ADH1A in TNBC samples. Genetic manipulation techniques were employed to alter ADH1A expression, and the subsequent effects on TNBC cell behavior were systematically analyzed. This study is the first to report on the alterations of 14 genes related to tyrosine metabolism within the TCGA-TNBC cohorts. Notably, reduced expression of these enzymes is associated with poorer survival outcomes in patients with TNBC. An analysis of the TCGA database revealed reduced levels of ADH1A in human TNBC tissues. Furthermore, ADH1A protein expression was diminished in TNBC tissues of patients who received local treatment, in contrast to the elevated expression observed in adjacent normal tissues. In the MDA-MB-231 and SUM159PT cell lines, ADH1A knockdown significantly promoted cell proliferation, migration, and invasion. On the contrary, ADH1A overexpression inhibited cell proliferation, migration, and invasion, while inducing cell apoptosis. Mechanistically, the overexpression of ADH1A may attenuate the malignant characteristics of TNBC cells by inhibiting the Wnt/β-catenin signaling pathway. In conclusion, ADH1A may be a useful biomarker for TNBC prognosis. This study is the first to reveal that ADH1A inhibits the malignant progression of TNBC via the Wnt/β-catenin signaling pathway.
Polish language questionnaires for monitoring athletes’ health and classifying reported symptoms
Perspectives of teachers of students with intellectual disabilities on the role of educational policies and systems in using Universal Design for Learning: A qualitative study
Universal Design for Learning is among the inclusive frameworks that has been incorporated in policies such as the “Every Student Succeeds Act of 2015” and the “Higher Education Opportunity Act of 2008”. However, little is known about the factors that influence its use with students with intellectual disabilities, while their teachers play a critical role in understanding those factors. Currently, there is a paucity of research that has examined their perspectives in Saudi Arabia. Thus, the objective of this qualitative study was to explore teachers’ perspectives on the role of educational policies and systems in using universal design for learning with their students. 14 teachers of students with intellectual disabilities were interviewed during the study. In the findings, the participants identified a number of factors that hinder its use, including: educational supervision; school management practices, and lack of access to the general curriculum, in addition to solutions to address them, such as providing legal/legislative support and funding for programs. The findings revealed unique experiences as well as commonalities among teachers, which are particularly important for policymakers, supervisors, principals, and teachers. Implications for future research, policy, and practice were presented.
Cortical evidence accumulation for visual perception occurs irrespective of reports
A privacy preserving and auditable blockchain framework for seccure securites trading
Fuzzy and fractional analysis of cancer tumor dynamics with depression effects on chemotherapy
Synthesis of novel phenoxyacetohydrazide compounds and evaluation therapeutic potential exhibit as anti-inflammatory and anti-angiogenic
This study aimed to design, synthesize, and evaluate novel morpholine-substituted phenoxyacetohydrazide derivatives as potential anti-inflammatory and anti-angiogenic agents. The compounds were synthesized and characterized by FTIR, NMR, mass spectrometry, and elemental analysis. In silico molecular docking revealed that compound 6e exhibited strong binding affinities toward vascular endothelial growth factor (VEGF), cyclooxygenase-1 (COX-1), and cyclooxygenase-2 (COX-2), with docking scores of –13.1622, –12.5301, and –12.6705 (kcal/mol) respectively. The in vitro anti-inflammatory activity, assessed via the human red blood cell (HRBC) membrane stabilization assay, showed that compound 6e achieved an IC₅₀ value of 155 μg/mL, indicating potent efficacy. Additionally, 6e demonstrated significant anti-angiogenic activity in both in vivo and ex vivo chick chorioallantoic membrane (CAM) models, inhibiting VEGF-induced angiogenesis in a dose-dependent manner and markedly reducing microvessel density and vessel length. In a rat model of alkali-induced corneal neovascularization, compound 6e substantially suppressed neovascular growth. Moreover, in the carrageenan-induced paw edema model, it effectively reduced edema, neutrophil infiltration, and myeloperoxidase activity. Collectively, these findings position compound 6e as a promising dual-action therapeutic candidate for treating chronic inflammation and pathological angiogenesis. This study underscores the potential of systematically designed phenoxyacetohydrazide scaffolds as multi-targeted therapeutic agents.
Experimental realization of a SU(3) color-orbit coupling in an ultracold gas
Experience-based integral reinforcement learning consensus for unknown multi-agent systems
Abstract This paper investigates an optimal consensus control problem and proposes a policy iteration algorithm based on online integral reinforcement learning for nonlinear multi-agent systems with unknown dynamics. Introducing a critic-actor neural network into the traditional policy iteration avoids the identification of unknown dynamics. To address the issue of local optima in online learning, an experience-based weight-tuning law is introduced to ensure the persistence of excitation conditions during the training phase. The theoretical results show that the system is asymptotically stable, and the network weights converge. Finally, the effectiveness and correctness are verified by several simulation studies.
A two-site collaborative study of electrical impedance myography for evaluation of disease progression in murine Duchenne muscular dystrophy models
Association between cardiometabolic risk factors and multidrug-resistant tuberculosis: A case-control study
Background Multidrug-resistant tuberculosis (MDR-TB) continues to be a major public health concern, especially in high-burden countries like Nepal. While individual risk factors are known, the cumulative impact of cardiometabolic factors on MDR-TB is not well understood. Methods A health-facility-based, age- and sex-matched 1:2 case-control study was conducted at MDR-TB treatment centers in Gandaki Province, Nepal. MDR-TB patients (cases) and drug-sensitive tuberculosis (DS-TB) patients (controls) were enrolled. Cases were defined as adults (≥18 years) with confirmed MDR-TB; controls were adults with sputum-positive DS-TB. Data on sociodemographics, cardiometabolic risk factors (alcohol, tobacco, abnormal body mass index, hypertension, diabetes), TB literacy, and treatment history were collected using a structured, pretested questionnaire by trained medical officers. Data were analyzed using Stata v13.0. Binary logistic regression was used to assess associations between risk factors and MDR-TB. Ethical approval was obtained from the Nepal Health Research Council and written informed consent was obtained from all participants. Results A total of 183 participants (61 cases, 122 controls) were included. Mean age of participants was 42.5 years (SD = 18.5); 73.8% were male. Most participants were from urban areas (74.9%), and 66.7% were unemployed. Cardiometabolic risk factors were present in 79.2% of participants. Alcohol and tobacco use were reported by 59.6% and 45.9%, respectively; 9.8% had diabetes and 7.1% had hypertension. Known TB contact and prior TB history were reported by 26.8% and 31.1% respectively. In multivariate analysis, unemployment (AOR: 5.24, 95% CI: 1.33–20.64), and known TB contact (AOR: 8.89, 95% CI: 2.46–32.15) were significantly associated with MDR-TB. Cardiometabolic risk factors were not significantly associated. Conclusion Known TB contact and unemployment were significantly associated with MDR-TB, while the cumulative effect of cardiometabolic risk factors showed no significant impact, indicating that interventions should prioritize established TB-related risk factors.