Growth Pathways Research Articles

Efficacy of Zenocutuzumab in NRG1 Fusion–Positive Cancer

BackgroundNeuregulin 1 (NRG1) fusions are recurrent oncogenic drivers found in multiple solid tumors. NRG1 binds to human epidermal growth factor receptor 3 (HER3), leading to heterodimerization with HER2 and activation of downstream growth and proliferation pathways. The efficacy and safety of zenocutuzumab, a bispecific antibody against HER2 and HER3, in patients with NRG1 fusion–positive solid tumors are unclear.MethodsIn this registrational, phase 2 clinical study, we assigned patients with advanced NRG1 fusion–positive cancer involving any tumor type to receive zenocutuzumab at a dose of 750 mg intravenously every 2 weeks. The primary end point was overall response (complete or partial response) according to investigator assessment. Secondary end points included duration of response, progression-free survival, and safety.ResultsA total of 204 patients with 12 tumor types were enrolled and treated. Among 158 patients who had measurable disease and were enrolled at least 24 weeks before the data-cutoff date, a response occurred in 30% (95% confidence interval [CI], 23 to 37). The median duration of response was 11.1 months (95% CI, 7.4 to 12.9); 19% of responses were ongoing at the data-cutoff date. Responses were observed in multiple tumor types — including in 27 of 93 patients (29%; 95% CI, 20 to 39) with non–small-cell lung cancer (NSCLC) and 15 of 36 patients (42%; 95% CI, 25 to 59) with pancreatic cancer — and across multiple NRG1 fusion partners. The median progression-free survival was 6.8 months (95% CI, 5.5 to 9.1). Adverse events were primarily grade 1 or 2. The most common adverse events that were considered by the investigator to be related to zenocutuzumab were diarrhea (in 18% of the patients), fatigue (in 12%), and nausea (in 11%). Infusion-related reactions (composite term) were observed in 14% of the patients. One patient discontinued zenocutuzumab owing to a treatment-related adverse event.ConclusionsZenocutuzumab showed efficacy in patients with advanced NRG1 fusion–positive cancer, notably NSCLC and pancreatic cancer, with mainly low-grade adverse events. (Funded by Merus; eNRGy ClinicalTrials.gov number, NCT02912949.)

The impact of genes and environment assessed longitudinally on psychological and somatic distress in twins from ages 15 to 35 years.

Genetically informative twin studies have consistently found that individual differences in anxiety and depression symptoms are stable and primarily attributable to time-invariant genetic influences, with non-shared environmental influences accounting for transient effects. We explored the etiology of psychological and somatic distress in 2279 Australian twins assessed up to six times between ages 12-35. We evaluated autoregressive, latent growth, dual-change, common, and independent pathway models to identify which, if any, best describes the observed longitudinal covariance and accounts for genetic and environmental influences over time. An autoregression model best explained both psychological and somatic distress. Familial aggregation was entirely explained by additive genetic influences, which were largely stable from ages 12 to 35. However, small but significant age-dependent genetic influences were observed at ages 20-27 and 32-35 for psychological distress and at ages 16-19 and 24-27 for somatic distress. In contrast, environmental influences were predominantly transient and age-specific. The longitudinal trajectory of psychological distress from ages 12 to 35 can thus be largely explained by forward transmission of a stable additive genetic influence, alongside smaller age-specific genetic innovations. This study addresses the limitation of previous research by exhaustively exploring alternative theoretical explanations for the observed patterns in distress symptoms over time, providing a more comprehensive understanding of the genetic and environmental factors influencing psychological and somatic distress across this age range.

Growth Pathway of CdS Nanoplatelets Investigated by In Situ X-ray Scattering and Optical Spectroscopy.

Two-dimensional (2D) CdS nanoplatelets (NPLs) have attracted much attention due to their sharp absorption peaks and unique optical properties, but their formation mechanism has not been clearly explained. In this study, the whole growth process of 2D CdS NPLs from the original precursor compounds to the final products was investigated by in situ small-angle X-ray scattering (SAXS), ultraviolet-visible (UV-vis), and transmission electron microscopy (TEM). It reveals that the growth of CdS NPLs can be divided into three stages, i.e. dissolution of the precursors Cd(OA)x(OAc)2-x and sulfur powder accompanied by the formation of CdS precursor compounds (PCs) from 30 to 120 °C (stage I), formation of the CdS magic-sized clusters (MSCs) and their growth into NPLs from 120 to 240 °C (stage II), and curling and uncurling growth of the NPLs at 240 °C (stage III). Dramatically, the shape of the NPLs changes from flat to curly when the temperature reaches 240 °C, but very interestingly, they become flat again after a prolonged stay at 240 °C. The curling and uncurling of NPLs is proposed to be driven by their surface stress imbalance induced by ligands.

Growth Pathway and Phase Transition From Quasi-layered Pt5Se4 to Layered PtSe2 Nanocrystals.

The discovery and control of phases is a significant endeavor for materials science. PtSe2, as a stable Pt─Se phase, is controllably synthesized for electronic, optoelectronic, and electrocatalytic applications, while research on another stable Pt─Se phase, Pt5Se4, is limited to calculations. Moreover, the growth mechanisms and phase transition of Pt─Se compounds remain unclear. Here, we report a two-step growth pathway of PtSe2 with a stable Pt5Se4 phase as intermediate and reveal the Pt-Pt5Se4-PtSe2 transition process. The synthesis of PtSe2 and Pt5Se4 nanocrystals is achieved by controlling the degree of selenization. Theoretical calculations prove that Pt5Se4 phase is thermodynamically favorable under Se-deficient conditions and PtSe2 nanocrystals are formed along with the diffusion of Pt and Se atoms. This work greatly enriches the knowledge on the growth mechanism and phase transition of Pt─Se compounds, and offers insights into the controlled synthesis of Pt5Se4 for future electrocatalysis and electronic devices.

Investigating how reproductive traits in rice respond to abiotic stress.

Oryza sativa is one of the most important crops and a food source for billions of people. Anthropic global warming, soil erosion, and unstable environmental conditions affect both its vegetative and reproductive growth, and consequently the final yield of its cultivation. The reproductive phase starts with the transition of apical meristem from vegetative to reproductive, which develops into a panicle, proceeds through the differentiation of the floret, and, after fertilization, the filling of the grain. The physiological events that occur during these stages influence the ability of new seeds to respond to stresses during the future seed germination phase, a key step for successful seedling growth and future plant establishment. This review explores the impacts of different abiotic stresses on the physiological and molecular pathways of the reproductive growth.

Competing pathways of intracranial aneurysm growth: linking regional growth distribution and hemodynamics.

The complex mix of factors, including hemodynamic forces and wall remodeling mechanisms, that drive intracranial aneurysm growth is unclear. This study focuses on the specific regions within aneurysm walls where growth occurs and their relationship to the prevalent hemodynamic conditions to reveal critical mechanisms leading to enlargement. The authors examined hemodynamic models of 67 longitudinally followed aneurysms, identifying 88 growth regions. These regions (of enlargement) were pinpointed through alignment and distance mapping between baseline and follow-up models. Aneurysm wall subdivisions were created based on saccular anatomy and flow-related characteristics, which were used to assess local hemodynamics. The distribution of growing regions across these subdivisions was then studied and stratified by aneurysm location and morphology to reveal distinct growth patterns. Statistical significance was evaluated using the Kruskal-Wallis and Mann-Whitney tests. Growth predominantly occurred in the body (p < 0.0001) of aneurysms, with anterior communicating artery (ACom) (p < 0.0001) and lateral (p = 0.002) aneurysms showing a significantly greater tendency for growth in this region. In comparison, middle cerebral artery (MCA) (p < 0.0001) and bifurcation (p = 0.0001) aneurysms demonstrated growth in both the dome and the body. Notable differences in growth distribution across saccular regions included ACom versus MCA (neck, p = 0.038), bifurcation versus lateral (neck, p = 0.008), and so forth. The central flow region saw the most growth (p < 0.0001); although not significant, ACom (p = 0.196) and lateral (p = 0.218) aneurysms showed a tendency for growth in inflow and central zones, while MCA (p = 0.001) and bifurcation (p < 0.0001) aneurysms were more likely to grow in the central flow region. Two primary mechanisms seem to influence aneurysm growth: high-flow impingement jets in the neck, body, and inflow zones leading to wall degeneration/thinning, mainly in ACom aneurysms; and slow, oscillatory flow conditions in the dome and central flow zones promoting wall remodeling/thickening, mainly in MCA aneurysms. This latter mechanism is also observed as secondary flows in ACom aneurysms. These findings emphasize the need to understand the distinct and sometimes concurrent mechanisms of aneurysm growth, advocating for targeted monitoring and interventions that mitigate rupture risks by considering the unique hemodynamic environments within different aneurysm regions and locations.

The Essential Role of Right Amount and Quality of Protein for Ensuring Child Growth and Maintenance of Bone and Muscle Mass

Protein is a vital macronutrient, essential for growth, tissue repair, and immune function. However, the impact of elevated protein intake during childhood and adolescence remains controversial. While high protein intake in older adults is often recommended for maintaining muscle mass and preventing frailty, excessive intake in younger populations has raised concerns about potential health risks, particularly related to obesity. This review aims to update current literature on the long-term effects of protein consumption in children and adolescents (ages 4-18) and to explore emerging methods for evaluating protein metabolism in this age group. The RDA for protein varies based on age, sex, and activity level. Generally, it is suggested that children consume about 0.95-1.3 grams of protein per kilogram of body weight per day, depending on age and specific requirements. In many developed countries, children and adolescents often consume protein at levels 2-3 times higher than the RDA, potentially leading to both positive and negative health outcomes. Protein is critical for normal growth and development during childhood and adolescence. Adequate intake supports muscle development, immune function, and the production of hormones. Studies suggest that elevated protein intake may be linked to increased Fat-Free Mass Index (FFMI), which is beneficial for muscle development and overall body composition. High protein diets have been associated with increased satiety, which can help in managing appetite and potentially reducing overall caloric intake, thus contributing to healthier weight maintenance. Some evidence suggests a correlation between high protein intake in infancy and childhood and increased risk of obesity later in life. This association may be due to the overactivation of growth pathways and increased insulin-like growth factor-1 (IGF-1) levels. Excessive protein intake has been hypothesized to strain kidney function, especially in individuals with pre-existing kidney conditions. However, current evidence in healthy children and adolescents is inconclusive. This narrative review emphasizes the need for a nuanced understanding of protein intake in children and adolescents, considering both the benefits and potential risks associated with high protein consumption. As research evolves, dietary guidelines may need to be adjusted to reflect the latest findings.

Exploring the Effects of Professional Learning Experiences on In-Service Teachers’ Growth: A Systematic Review of Literature

This systematic review examines the effects of professional learning (PL) experiences on in-service teachers’ self-perceived growth. The study compares formal and informal PL models, drawing on diverse approaches, such as coaching, mentorship, collaborative learning, and reflective practices, to understand how these frameworks impact teachers’ professional efficacy and instructional practices. Using databases like Scopus, Web of Science, and ERIC we analyzed 38 empirical studies, focusing on the teachers’ PL experiences and the resulting self-perceived professional growth across its various domains. The findings indicate that while formal PD sessions (e.g., structured workshops and seminars) support skill development, they often yield mixed results due to their limited adaptability to specific contextual needs. In contrast, informal PL approaches, like mentorship and peer collaboration, foster reflective and practical growth. Combining both PL methods provides the most comprehensive benefits, blending structured learning with the flexibility of informal settings. This review underscores the need for hybrid PL models that address collective and individualized growth pathways, recommending future research into context-sensitive, mixed PL designs to effectively support in-service teachers.

Transcriptome Analysis Reveals the Key Genes and Pathways for Growth, Ion Transport, and Oxidative Stress in Post-Larval Black Tiger Shrimp (Penaeus monodon) Under Acute Low Salt Stress.

As an abiotic stress factor, salinity significantly affects the physiological activities of crustaceans. In this study, transcriptome sequencing was used to evaluate the mechanism of ion transport and the physiological response of black tiger shrimp (Penaeus monodon) under low salt stress. Four hundred post larval (PL) stage P. monodon were distributed in eight experimental tanks and exposed to 3 or 5 ppt salt concentrations for 96h. Low salinity significantly reduced the survival rate of shrimp but simultaneously activated the activity of ion transporter enzymes Na+/K+-ATPase (NKA) and Ca2+/Mg2+-ATPase), the expression of NKA, galectin 10, and cytochrompe c peroxidase genes, and the activity and expression of antioxidant-related genes (superoxide dismutase, catalase, heat shock protein 60). Low salt stress activated the urea cycle but significantly inhibited glutathione metabolization-related indicators (glutamate dehydrogenase, glutaminase, glutamic acid). RNA-seq analysis identified 221 differentially expressed genes (78 up-regulated and 143 down-regulated). Quantitative real-time PCR and RNA-seq results of 11 of them were consistent, illustrating the validity of the transcriptomic predictions. Gene set enrichment analysis results showed that calcium ion transmembrane transport, calmodulin binding, the stress-activated protein kinase signaling cascade, and regulation of the cytosolic calcium ion concentration process were significantly enriched. These results showed that low salt stress activated the calcium-dominated ion transport pathway and promoted molting growth of P. monodon. They also indicate that there is potential for larval rearing shrimp under low salt conditions.

Understanding the Grain Production Growth Pathways Transition and Its Implications for Sustainable Grain Production in China

Understanding the Grain Production Growth Pathways Transition and Its Implications for Sustainable Grain Production in China

Ensuring Africa's Food Security by 2050: The Role of Population Growth, Climate-Resilient Strategies, and Putative Pathways to Resilience.

Africa is grappling with severe food security challenges driven by population growth, climate change, land degradation, water scarcity, and socio-economic factors such as poverty and inequality. Climate variability and extreme weather events, including droughts, floods, and heatwaves, are intensifying food insecurity by reducing agricultural productivity, water availability, and livelihoods. This study examines the projected threats to food security in Africa, focusing on changes in temperature, precipitation patterns, and the frequency of extreme weather events. Using an Exponential Growth Model, we estimated the population from 2020 to 2050 across Africa's five sub-regions. The analysis assumes a 5% reduction in crop yields for every degree of warming above historical levels, with a minimum requirement of 225 kg of cereals per person per year. Climate change is a critical factor in Africa's food systems, with an average temperature increase of approximately +0.3 °C per decade. By 2050, the total food required to meet the 2100-kilocalorie per adult equivalent per day will rise to 558.7 million tons annually, up from 438.3 million tons in 2020. We conclude that Africa's current food systems are unsustainable, lacking resilience to climate shocks and relying heavily on rain-fed agriculture with inadequate infrastructure and technology. We call for a transformation in food systems through policy reform, technological and structural changes, solutions to land degradation, and proven methods of increasing crop yields that take the needs of communities into account.

Developmentally cascading structures do not lose evolutionary potential, but compound developmental instability in rat molars.

Increasing variability down serially segmented structures, such as mammalian molar teeth and vertebrate limb segments, is a much-replicated pattern. The same phenotypic pattern has conflicting interpretations at different evolutionary scales. Macroevolutionary patterns are thought to reflect greater evolutionary potential in later-forming segments, but microevolutionary patterns are thought to reflect less evolutionary potential and greater phenotypic plasticity. We address this conflict by recalculating evolutionary potential (evolvability) from published mammalian molar data and directly measuring phenotypic plasticity from a controlled feeding experiment. Effects on lengths and widths are discordant in a way that suggests general growth pathways have a role in phenotypically plastic dental responses to nutrition. Effects on successive trait means do not necessarily increase downstream, contrary to long-standing hypotheses. We confirm prior findings of increasing non-inherited variance downstream, showing decoupling between effects on trait mean and variance. These patterns can be explained by a cascading model of tooth development compounding the effect of anatomically hyper-local developmental instability as an influence separate from general environmental effects on the developing embryo. When evaluated in terms of evolvability, not heritability, later-developing molars are equally or more evolvable than earlier-developing molars, aligning their microevolutionary potential with macroevolutionary patterns in other serially segmented structures.

Longitudinal DNA methylation profiles in saliva of offspring from mothers with gestational diabetes: associations with early childhood growth patterns

BackgroundThe prevalence of obesity and type 2 diabetes mellitus (T2DM) is rising globally, particularly among children exposed to adverse intrauterine environments, such as those associated with gestational diabetes mellitus (GDM). Epigenetic modifications, specifically DNA methylation, have emerged as mechanisms by which early environmental exposures can predispose offspring to metabolic diseases. This study aimed to investigate DNA methylation differences in children born to mothers with GDM compared to non-GDM mothers, using saliva samples, and to assess the association of these epigenetic patterns with early growth measurements.MethodsThis study analyzed saliva DNA methylation patterns in 30 children (15 born to GDM mothers and 15 to non-GDM mothers) from the EPIDG cohort. Samples were collected at two time points: 8–10 weeks postpartum and at one year of age. Epigenome-wide analysis of over 850,000 CpG sites was conducted using the Illumina Methylation EPIC Bead Chip. Differential methylation positions (DMPs) were identified with the limma package, using a significance threshold of p < 0.01 and delta β ≥ 5%. Correlation analysis examined associations between methylation and growth variables (weight, height, BMI and annual growth) using Spearman tests.ResultsWe identified 6,968 DMPs at the postpartum stage and 5,132 after one year, with 50 sites remaining differentially methylated over time, 16 of which maintained consistent methylation directionality. Functional analysis linked several of these DMPs to genes involved in inflammation and metabolic processes, including CYTH3 and FARP2, both implicated in growth and metabolic pathways. Significant correlations were found between specific CpG sites and growth-related variables such as weight, head circumference, height, and BMI.ConclusionsThis study’s longitudinal design reveals stable DNA methylation patterns in saliva samples that differentiate GDM-exposed children from controls across the first year of life, highlighting the feasibility of saliva as a minimally invasive biomarker source. The persistence of these epigenetic signatures underscores their potential as early indicators of metabolic risk, offering valuable insights into the long-term impact of maternal GDM on child health. Although the use of saliva offers a practical and non-invasive tool for pediatric epigenetic research, further studies are necessary to validate these findings in larger populations.

Investigating intrauterine exposure to methamphetamine on serine-threonine kinase pathway in male rat testis.

Today, methamphetamine (METH) is being used by adolescents and young adults. Our previous research demonstrated that intrauterine exposure to METH induces apoptosis in testicles and seminiferous tubes. However, based on available literature, the mechanism of this effect remains unidentified. This study aimed to investigate proteins involved in sperm growth and development pathways, such as testis-specific serine/threonine kinases (TSSK) and receptor-interacting protein kinases 2 (RIPK2), and to study the serine-threonine kinase pathway in the testes of rats whose mothers received intraperitoneal METH during pregnancy. In the present study, female rats during pregnancy received either 5 or 10 mg/kg of METH or normal saline for ten days. After reaching maturity, their testes were isolated and examined for histopathological and immunohistochemical mechanisms. Results were analyzed and reported using statistical software. Results revealed that following intrauterine exposure to METH, TSSK protein expression reduced from 52.68±2.4% in the control group to 48.04±2.29% in the 2 mg/kg/day group and 12.83±3.35% in the 5 mg/kg/day group with P=0.0029 and F=72.63. In addition, RIPK2 protein expression increased from 8.34±2.69% in the control group to 31.17±3.69% in the 2 mg/kg/day group and 98.49±4.66% in the 5 mg/kg/day group, with p=0.0037 and F=61.14. Histopathological findings indicated a reduction in the thickness of germ layers following intrauterine exposure to METH, with the seminiferous tubule's thickness decreasing. Inflammatory cell populations increased, and the number of vessels decreased due to intrauterine exposure to METH. Our study suggests intrauterine exposure to METH increases the prevalence of inflammatory cell populations, enhances RIPK2 protein expression, reduces the number of vessels, reduces the diameter of seminiferous tubes, decreases TSSK protein expression, and reduces the thickness of germ layers in testicular tissue. Apoptosis of spermatid cells observed in our previous study may be related to the signaling pathways of TSSK and RIPK2 proteins.

BRD4-targeted photodegradation nanoplatform for light activatable melanoma therapy.

The targeted protein degradation (TPD) strategy modulates tumor growth pathways by degrading proteins of interest (POIs) and has reshaped anti-tumor drug research and development. Recently, the emergence of photodegradation-targeting chimeras (PDTACs) and laser irradiation at specific sites enables precise spatiotemporal controllability of TPD. Capitalizing on the advances of PDTACs, herein, we report a nanoplatform for efficiently delivering PDTAC molecule for photodegradation of bromodomain-containing protein 4 (BRD4) proteins, the key activators of oncogenic transcription. The PDTAC molecule, named as PPa-JQ1, is synthesized through the covalent attachment of the BRD4-targeting ligand JQ1-acid, to the photosensitizer pyropheophorbide-a (PPa), utilizing a 1,6-hexanediamine linker. The PPa-JQ1 is further encapsulated by human serum albumin (HSA) to obtain the HSA@PPa-JQ1 nanoplatform, which facilitates targeted and efficacious delivery to melanoma lesions. Both in vitro and in vivo therapeutic outcomes demonstrate that HSA@PPa-JQ1 can efficiently generate reactive oxygen species (ROS) to degrade BRD4 upon light irradiation, which eventually induces tumor death. Our study represents the first case to validate the anti-tumor therapeutic efficacy of PDTACs by systemic administration, providing the foundation for further application of PDTACs.

An Examination of the Effects of Frugal (simple) Innovation Environmental and Economic Performance of SMEs

In this research, simple innovation and small and medium-sized enterprises (SME)s’ environmental and financial performance are under analysis. Simple innovation, characterized by resource-efficient and cost-effective approaches, is examined for its role in fostering sustainable solutions and enhancing business outcomes. The research highlights how SMEs adopting simple innovation minimize ecological footprints through optimized resource use and waste reduction while achieving cost savings and increased market competitiveness. The findings reveal a dual effect: simple innovation significantly benefits environmental performance but presents complexities in its financial outcomes, moderated by organizational proactivity. The results underline the strategic importance of simple innovation for addressing global challenges such as resource scarcity and economic inequality, offering a pathway for sustainable growth in both emerging and developed markets. This study provides actionable insights for SMEs and policymakers, emphasizing the need to integrate simple innovation into business strategies. Future research should explore sector-specific applications and long-term implications to maximize its potential.

Leveraging computational approaches in identifying novel HER-2 + breast cancer potential therapeutics: integrating virtual screening and molecular dynamics simulation

BackgroundBreast cancer, particularly the human epidermal growth factor receptor 2 positive subtype, presents a significant global health challenge due to its high prevalence and mortality rates. This study delves into the molecular intricacies of HER-2 positive breast cancer, with an emphasis on the role of the HER-2 oncoprotein and its associated signaling pathways in cell growth, differentiation, and survival. In our pursuit of overcoming the limitations of one of the leading therapeutic options, Lapatinib, such as its inhibition of hERG, we embarked on a comprehensive research journey.ResultThis study involved dual-stage molecular docking, initially with a library of PubChem-curated compounds, revealing Compound 90196902 as the best of the set. This was followed by the docking of DataWarrior-generated structural analogs of Compound 90196902, using various docking protocols such as standard precision, extra precision, and induced fit docking. Through this rigorous screening protocol, three promising drug candidates (Compound_56, Compound_81, and Compound_339) were identified, showing excellent interaction with the target. Additionally, binding free energy calculations, ADME and toxicity profiling, and molecular dynamics simulations presented these compounds as lead-like.ConclusionCompound_56 showed the most promising pharmacodynamic and pharmacokinetic properties, coupled with substantial structural stability. While immensely promising, further optimization and pre-clinical investigation are imperative to validate this compound as a viable alternative to existing therapies for HER-2 positive breast cancer.Graphical abstract

Updates on the Anticancer Profile of Lycopene and its Probable Mechanism Against Breast and Gynecological Cancer

Abstract: Natural substances are gaining interest as anticancer agents nowadays due to the adverse effects of synthetic drugs. Among various natural substances, lycopene has emerged as a strong antioxidant agent and has been found to be effective against prostate, breast, colon, ovarian, liver, endometrial cancers, etc. This article reviews the therapeutic potential and proposed mechanism of action of lycopene against breast and gynecological cancer from 2005 to now. Experimental studies suggest that lycopene can inhibit tumor growth by regulating various signaling pathways for cell growth, arresting the cell cycle, and inducing cell apoptosis. Lycopene is reported to combat breast cancer specifically via mechanisms, such as regulation of expression of p53 and Bax, suppression of cyclin D, inhibiting the activation of ERK and Akt signaling pathway, and gynecological cancer via various signaling pathways such as STAT3, Nrf2, and NF- κB, down-regulation of ITGB1, ITGA5, FAK, MMP9, and EMT markers, etc.

Genomic Selection and WssGWAS of Sheep Body Weight and Milk Yield: Imputing Low-Coverage Sequencing Data with Similar Genetic Background Panels.

Low-coverage whole-genome sequencing (LcWGS), a cost-effective genotyping method, offers greater flexibility in variant detection than does single-nucleotide polymorphism (SNP) chips. However, to our knowledge, no studies have explored the application of LcWGS in sheep. This study aimed to evaluate the feasibility of implementing LcWGS and genotype imputation and assess their applicability in genomic studies of body weight and milk yield in sheep. A total of 45,787 birth weight (BW), 31,135 weaning daily gain (WDG), 8,928 milk yield (MY), and 4,918 milk yield per unit of metabolic body weight (MWMY) data were analyzed. Among these, 2,366 sheep had imputed high-density genotypes. Simulated sequencing depths from 0.1 × to 3 × were imputed using the reference panels of 100-600 individuals. Genotype concordance with true data improved from 0.8875 to 0.9852 as the sequencing depth and panel size increased. The ssGBLUP method applied to the imputed data yielded higher accuracy for BW, WDG, MY, and MWMY than traditional ABLUP, notably increased MY accuracy from 0.61 to 0.66. Furthermore, a weighted single-step genome-wide association study identified key genes associated with BW (ANKS1B, OPRM1, CSMD1), WDG (TKDP5, GRP, RAX, IGFBP7), MY (CCSER1, FGGY, HOOK1), and MWMY (NDUFA10, ZNF385D, NWD1), revealing the importance of multiple pathways in sheep growth and milk production. This is the first study to assess the feasibility of combining LcWGS with genotype imputation for sheep genomic selection, balancing economic costs and imputation efficiency. Furthermore, we demonstrate an effective approach for identifying genetic variants linked to body weight and milk production, offering a cost-effective strategy for dairy sheep breeding.

Longikaurin A, a natural ent-kaurane, suppresses proliferation, invasion and tumorigenicity in oral squamous cell carcinoma cell by via inhibiting PI3K/Akt pathway in vitro and in vivo.

Background: Longikaurin A (LK-A), a naturally occurring ent-kaurane diterpenoid, has been identified as a promising anti-cancer agent. This study aims to elucidate the anti-tumorigenic effects of LK-A on oral squamous cell carcinoma (OSCC) cells and to unravel its underlying mechanisms. Methods: In vitro assays, including CCK-8 and EdU, were performed to assess cell viability and proliferation. Transwell migration and invasion assays evaluated cell mobility and invasive potential. Apoptotic effects were analyzed using Annexin V-FITC/PI staining and TUNEL assays. Western blot analysis was conducted to examine protein expression related to cell cycle, apoptosis, and the PI3K/Akt signaling pathway. In vivo experiments involved treating mouse xenograft models with LK-A and evaluating tumor growth and signaling pathway inhibition through immunohistochemistry and Western blot assays. Results: LK-A significantly suppressed cell viability and proliferation in a dose-dependent manner, with IC50 values of 4.36 μM and 4.93 μM at 24 h, and 1.98 μM and 2.89 μM at 48 h for CAL27 and TCA-8113 cells, respectively. EdU assays revealed a reduction in the EdU positive rate, and cell cycle analysis showed G2/M phase arrest. Western blot analysis confirmed decreased expression of CyclinB1 and Cdc2. LK-A significantly inhibited OSCC cell mobility and invasive potential, with downregulation of MMP-2 and MMP-9 expression. Apoptotic effects were confirmed by increased apoptosis, upregulation of Bax and cleaved caspase-3, and downregulation of Bcl-2. LK-A suppressed the PI3K/AKT signaling pathway, as evidenced by reduced phosphorylation of PI3K, AKT, and mTOR. The AKT activator SC79 reversed the antiproliferative and pro-apoptotic effects of LK-A. In vivo, LK-A significantly inhibited tumor growth in mouse xenograft models, with reduced tumor weights and volumes, and no significant loss in body weight. Immunohistochemistry and Western blot assays confirmed the inhibition of p-Akt and Ki-67 expression. Conclusion: These findings suggest that LK-A exerts potent antiproliferative, anti-migratory, and pro-apoptotic effects on OSCC cells through the suppression of the PI3K/AKT signaling pathway, demonstrating its potential as a therapeutic agent for OSCC.