Background : Bovine respiratory disease is the second most common cause of mortality in calves, resulting in significant reductions in growth rates as well as long‐term issues such as delays to age at first calving. It is also a leading cause of antimicrobial use in calves and a large time factor for farmers dealing with sick calves. Management of bovine respiratory disease is therefore an essential part of sustainable livestock farming. Aim of the article : This article discusses the use of thoracic ultrasound as a tool to support management of bovine respiratory disease, with examples of how it can be used on farm.

Abstract Background: The estrogen receptor (ER), cyclin-dependent kinase (CDK), and PI3K-AKT-mTOR (PAM) pathways are interconnected and drive hormone receptor (HR)+/HER2- advanced breast cancer (ABC). In the first line setting, endocrine therapy (ET) combined with a CDK4/6 inhibitor is the standard of care regimen for most patients with HR+/HER2- ABC. For patients in the second line setting, several inhibitors targeting components of the PAM pathway (e.g. PI3Kα, AKT, mTORC1) are approved in combination with ET. By only addressing a single target of the PAM pathway, the currently approved PI3Kα, AKT, mTORC1 inhibitors do not prevent adaptive resistance induced by the other uninhibited PAM targets. In a phase 1b clinical trial, gedatolisib, a multi-target PAM inhibitor, combined with ET and palbociclib showed promising efficacy and safety in patients with HR+/HER2- ABC, regardless of PIK3CA mutation status. Here we investigated the effects of gedatolisib and single-target PI3Kα and AKT inhibitors in combination with fulvestrant and/or palbociclib in breast cancer (BC) cell models with and without PAM pathway mutations and with varying levels of sensitivity to fulvestrant and palbociclib. Methods: Gedatolisib (pan-PI3K, mTORC1/2 inhibitor), inavolisib (PI3Kα inhibitor), capivasertib (AKT inhibitor) were tested as single agents or in combination with fulvestrant and/or palbociclib in treatment-naïve BC cell lines with or without PIK3CA mutations as well as in BC cell lines adapted to long-term treatment with fulvestrant and/or palbociclib. Cell viability, growth rate, cell cycle, DNA replication, apoptosis, and cell death were evaluated by luciferase-based and flow cytometry-based functional assays. Results: Gedatolisib reduced growth rates of treatment-naïve or fulvestrant/palbociclib-adapted BC cell lines, regardless of PIK3CA mutational status, and the addition of fulvestrant and/or palbociclib increased growth-inhibitory effects. From a functional standpoint, the gedatolisib/palbociclib/fulvestrant triplet inhibited DNA replication and/or induced apoptotic cell death more effectively than treatment with single drugs or drug doublets. The gedatolisib/palbociclib/fulvestrant triplet was more effective than PI3Kα and AKT inhibitors (inavolisib, capivasertib) combined with palbociclib and/or fulvestrant in the BC cell lines tested, regardless of PIK3CA mutational status or previous adaptation to palbociclib and/or fulvestrant. Conclusions: These results indicate that gedatolisib plus fulvestrant, with and without palbociclib, effectively controls the growth of treatment-naïve BC cells as well as BC cells adapted to palbociclib/fulvestrant treatment. Moreover, in contrast to the currently approved PI3Kα and AKT inhibitors, the gedatolisib/palbociclib/fulvestrant triplet is effective in BC cells with or without PIK3CA mutations. The combination of gedatolisib with ET and a CDK4/6 inhibitor is being evaluated in two ongoing Phase 3 clinical trials as first-line (VIKTORIA-2) or second-line (VIKTORIA-1) treatment of HR+/HER2- ABC with or without PIK3CA mutations. The non-clinical results presented here provide a strong mechanistic rationale for these clinical studies. Citation Format: S. Rossetti, A. Broege, L. Davis, M. Seibel, S. Stokke, J. Molden, I. Gorbatchevsky, B. Sullivan, L. Laing. Functional analysis of gedatolisib combined with fulvestrant and/or palbociclib in breast cancer cell models adapted to estrogen receptor and/or CDK4/6 inhibitors [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-11-30.

The use of synthetic herbicides is an effective way to control weeds, but their widespread use has negative environmental impacts. A bioherbicide made from purple nutsedge tubers can be an alternative for weed control. Purple nutsedge’s tuber contain allelopathy compounds that can inhibit the growth of other plants (weeds). This study aims to evaluate the response of various shapes and sizes of bioherbicide granules made from purple nutsedge’s tuber in suppressing the germination of weed seeds and crop seeds. The experiment used a completely randomized design one factor and eleven treatments: control without herbicide treatment, synthetic herbicide active ingredient oxyfluorfen 240 g/L, purple nutsedge’s tuber powder bioherbicide without carrier, very small round granule bioherbicide, small round granule, medium round granule, large round granule, very small cylindrical granule, small cylindrical granule, medium cylindrical granule, and large cylindrical granule. Each treatment was tested on four species: Bidens pilosa and Cynodon dactylon (weeds), cucumber, and rice (crops). The experimental results showed that the application of purple nutsedge’s tuber-based bioherbicides exerts a noticeable influence on several germination parameters. The smaller the bioherbicide granule, the higher the germination inhibition rate. Very small, round-shaped granule bioherbicides showed greater effectiveness in suppressing seed sprout percentage, reducing growth rate, increasing the percentage of abnormal sprouts, and inhibiting plumula and radicle growth.

Total kidney volume (TKV) is accepted by the Food and Drug Administration as a surrogate endpoint that is reasonably likely to predict clinical benefit in autosomal dominant polycystic kidney disease (ADPKD) and the most commonly used response biomarker for proof-of-concept intervention trials. However, the magnitude of treatment effect on TKV that would be predictive of a meaningful improvement in a clinical outcome, such as estimated glomerular filtration rate (eGFR), is unknown. Inference of this from observational studies has previously been approached by examining inter-individual variance in the relationship between TKV and GFR slopes over time. We developed a novel approach to modeling the intra-individual relationship between TKV and eGFR. Patients from the CRISP and HALT-A dataset were stratified by Mayo Imaging Class (MIC). Linear mixed models were fitted to eGFR with a fixed effect of log(TKV) and random intercepts, and the average slope within each MIC was estimated. We found that within each MIC there is a consistent, linear relationship between log(TKV) and eGFR. The model predicts that within classes 1C-1E, for each 1% point per year reduction in TKV growth rate, the rate of eGFR decline would be reduced by 0.40 to 0.52 mL/min/1.73 m2 per year. We have developed a new model that provides a framework for defining the magnitude of treatment effect on TKV that would support accelerated approval of a drug for ADPKD.

Soybean-derived trypsin inhibitor proteins (TIU) impair amino acid bioavailability and increase exogenous and endogenous nitrogen flow to the hindgut, thereby attenuating pig growth performance. High protein diets potentiate proteolytic fermentation induced alterations to the gut microbiome, which may increase opportunistic enterotoxigenic Escherichia coli (ETEC) proliferation and exacerbate disease. We hypothesized that feeding high TIU diets to nursery pigs would reduce growth rates and exacerbate F18 ETEC disease. Two hundred and eighty-eight (5.42 ± 0.93 kg BW; Camborough 1050 × 337, [PIC, Hendersonville, TN]) newly weaned pigs were evenly allotted across two control rooms (CON) and two challenge rooms (ETEC). Pigs were allotted based on sex and α-(1,2) fucosyltransferase (FUT1) genotype, with both factors evenly distributed across all pens. Pens were randomly assigned to corn-soy diets consisting of 1.1, 2.4, or 4.2 TIU/mg, creating six treatments: CON1.1, CON2.4, CON4.2, ETEC1.1, ETEC2.4, and ETEC4.2 (8 pens/treatment). On day 10 (day post-infection [dpi] 0), pigs in the ETEC rooms were orally inoculated with 5 ml of 3.8 × 109 cfu/ml of an F18 ETEC culture. Pooled pen feces were assessed for dry matter (DM) on dpi 0, 3, 5, 7, 9, 11, 14, and 21. Pen growth performance, medical treatments, and mortality were assessed prior to infection (dpi -10 to 0) and post infection (dpi 0 to 28). On dpi 5 and 12, one pig/pen was sacrificed to assess ileal mucosal attachment of F18 ETEC via in situ hybridization. Pen was the experimental unit and data were analyzed for the interactive and main effects of diet and challenge. Increasing dietary TIU to 4.2 TIU/mg led to a 13-16% decrease in ADG compared to the 1.1 TIU/mg diets, regardless of the challenge (P = 0.014). A diet × challenge interaction was observed regarding mortality, with ETEC2.4 showing a 20.8% mortality rate compared to 0% in CON2.4 (P = 0.001). Similarly, 22.9% of ETEC2.4 pigs required antibiotic treatment compared with 0% of CON2.4 pigs (P = 0.001). Fecal DM from dpi 0-21 showed no interaction, but ETEC pens had lower fecal DM compared to CON pens from dpi 3-11 (P < 0.0001). On dpi 5, ileal F18 attachment was increased in ETEC versus CON pigs (3.7 × 10-3 vs 0.1 × 10-3 F18 copies/μm2, P < 0.0001). By dpi 12, ileal F18 attachment did not differ between challenge groups (P > 0.05), suggesting disease resolution. In conclusion, diets at or greater than 2.4 TIU/mg decreased pig growth and reduced livability in ETEC-infected nursery pigs.

The combined use of phages and antibiotics offers an alternative avenue against multidrug-resistant bacteria. We have previously described the synergistic antibacterial effect of the phage pB23 and meropenem combination against carbapenem-resistant Acinetobacter baumannii (CRAB). The study uncovers the underlying molecular mechanism of phage resistance in CRAB mediated by a novel stop-gain mutation in the gene gtr9. Through phenotypic characterization of pleiotropy, including reduction of capsular polysaccharide production and biofilm formation caused by the mutation in gtr9, we revealed an evolutionary trade-off mechanism whereby phage-resistant CRAB exhibits reduced carbapenem resistance. The zebrafish infection model demonstrated that these phage-resistant mutants were attenuated in virulence in vivo. Throughout continuous passage experiments in vitro, gtr9 mutants displayed the stability of decreased growth rate, phage resistance, and virulence reduction. The combination therapy between phage pB23 and meropenem in different matrices exhibited consistent synergistic antibacterial activity in vitro, demonstrating its potential therapeutic in vivo. Collectively, our study reveals a trade-off mechanism underlying phage-antibiotic synergy, thereby providing a novel insight into bacterial resistance evolution and demonstrating the therapeutic potential of this approach against CRAB infections.

Early intervention in patients with Clonal Hematopoiesis (CH) is an area of intense investigation with no currently approved agents. With recent mechanistic data on metformin as a possible therapeutic agent in CH and its availability in clinical practice, we sought to investigate clonal dynamics of CH mutations in metformin users. We analyzed longitudinal targeted deep sequencing of 1,104 CH mutations in 863 metformin-treated type 2 diabetic participants in two longitudinal cohorts: WHI and BioVu with blood collected at a median of 15.8 and 6.1 years apart respectively. Metformin duration (per 6 months) was not significantly associated with overall CH growth rate in WHI (β = -0.05%/year; 95% confidence interval (CI): -0.11 to 0.01; P = 0.08; N = 543) and in BioVU (β = -0.09%/year; 95% CI: -0.22 to 0.05; P = 0.20; N = 561) . Inverse-variance weighted random-effect meta-analysis demonstrated a small, statistically significant association (β = -0.06%/year; 95% CI: -0.11 to -0.002; P = 0.04; N = 1,104) without significant heterogeneity (P = 0.60). These results were similar when only considering DNMT3A and DNMT3A R882 clones. In our cohorts, duration of metformin use among diabetic users was associated with a small reduction in CH growth rate (-0.06%/year), which is modest compared to typical DNMT3A clonal growth rates of 5-7% annually. Metformin's clinical utility for modulating clonal dynamics in real-world settings appear limited and its clinical use for this indication requires further investigation in prospective studies.

Plant-type ferredoxins (Fd) comprise small, soluble protein families that distribute electrons from photosystem I to various client proteins within the chloroplast stroma. In Chlamydomonas reinhardtii, the major, constitutively expressed FDX1/PetF supports Fd-NADP+ reductase (FNR) in NADPH production. The highly similar FDX2 is present only when its preferred nitrogen (N) source ammonium is absent, supplying Fd-dependent nitrite reductase (NiR) for nitrate/nitrite assimilation. Surprisingly, despite accumulating to ~10% of FDX1 abundance and preferential interaction with NiR, fdx2 mutants are asymptomatic when grown on nitrate, requiring to additionally deplete FDX1 for growth to be halted. A fdx1 knockout itself appears lethal, severe fdx1 knockdowns have reduced growth rates both in phototrophic and photoheterotrophic conditions, independent of the N source. Transcriptome analyses of fdx1 mutants revealed expression patterns similar to sulfur (S) deficient algae, and fdx1 strains have a reduced total cellular S content. S assimilation requires Fd-dependent sulfite reductase (SiR) activity, an enzyme distantly related to FDX2 client NiR. Expression defects are partially alleviated; growth and S content are less impacted with FDX2 expression. Our mutant analysis shows the two major Fds in Chlamydomonas focus on a specific subset of Fd-dependent metabolism, mostly supplying Fd-dependent enzymes involved in macronutrient assimilation (C/N/S).

Damage to ship structures leads to a reduction in strength, which increases the risk of structural failure. The vulnerability of damage in sandwich panel structures made of low-density steelpolyurethane elastomer needs to be evaluated and predictions made regarding failure modes, particularly crack propagation through the core thickness. Variations in structure thickness and the size of the initial crack are evaluated to determine the impact of structural design on damage under the ship’s operational loads. Finite element analysis, validated with experimental data, is used to simulate the dynamics of crack propagation. It was found that a thicker core and a smaller initial crack length result in slower crack propagation rates and shorter crack extensions. Increasing the core thickness from 15 mm to 24 mm reduced the crack propagation rate by up to 28% and improved crack extension resistance by as much as 54%. Thicker face and bottom plates further contributed an additional reduction in crack growth rate, providing an extra margin of structural toughness. Shorter initial cracks also proved significant, with propagation rates decreasing by about 73% when comparing a 25 mm crack to a 75 mm crack. These factors lowered the strength reduction factor (SRF ) and extended crack growth times, confirming that thicker cores and smaller initial cracks improve damage resistance in ship sandwich structures.

Background/objectives: Progression of pancreatic ductal adenocarcinoma (PDAC) and other carcinomas relies on cancer-associated fibroblasts (CAFs). A subset of CAFs is derived from adipose stromal cells (ASCs) recruited by tumors and the ASC-CAF conversion has been associated with invasiveness and poor prognosis. Methods: To explore the underlying molecular mechanisms, we used a model based on primary ASCs derived from human visceral adipose tissue co-cultured with human PDAC cell line Capan-1. To investigate cancer progression in vivo, we also used mice orthotopically grafted with mouse KPC cells. Results: Genomic analysis revealed that Capan-1 co-culture induces Wnt and TGFβ signaling and extracellular matrix (ECM) gene expression in ASC. We investigated the function of two markers of the fibroblastic transition highly induced by cancer cells: a long non-coding RNA LINC01614 and a Wnt signaling modulator SFRP4. By using ASCs with either SFRP4 or LINC01614 knocked out (ko), we showed that both genes are required for Wnt/TGFβ signaling and ECM induction in ASCs by Capan-1. Analysis of changes in Capan-1 genes that rely on LINC01614 and SFRP4 expression in ASCs also identified the Wnt and TGF pathways. SFRP4 ko in ASCs suppressed both migration and invasion of Capan-1 cells. We show that tumors in SFRP4 ko mice have less desmoplasia, less epithelial dedifferentiation, reduced growth rate, and reduced progression to metastasis. Conclusions: We conclude that SFRP4 promotes cancer progression in pancreatic cancer and is a promising therapeutic target.

Domoic acid production by a Pseudo-nitzschia australis strain under zinc and copper exposure.

Potential of tormentil rhizome ethanolic extract and its postbiotic metabolites for inhibiting enterotoxigenic E. coli growth: Implications for functional food applications.

Continuous antigen exposure initiates the developmental process of CD8+ T cell exhaustion, accompanied by a gradual increase in the expression of inhibitory receptors (IRs). Our previous study conceptualized T cell exhaustion as an over‐activation status induced by chronic antigen stimuli. To intervene in the developmental process of CD8+ T cell exhaustion, we adjusted the over‐activation status by intermittently blocking T cell activation signals with tacrolimus, a T cell activation inhibitor. Melanoma‐bearing mice received intermittent tacrolimus (IT) and/or programmed cell death 1 (PD1) blockade antibody. Exhaustion phenotype of CD8+ tumor‐infiltrating lymphocytes (CD8+TILs) was detected by flow cytometry. The expression levels of IRs (PD1 and CD223), as well as memory markers (Ly108 and CD127), were utilized to demarcate the extent of CD8+TILs exhaustion. Then, tyrosinase‐related protein 2 peptide (Trp2 180–188 ) was used to detect tumor‐specific CD8+ TILs. Furthermore, tumor growth rate and tumor weight were also evaluated. We found that IT and/or PD1 blockade enhanced the infiltration of functional CD8+TILs. The findings demonstrated that both IT therapy and PD1 blockade enhanced the antitumor immunity. Combining IT and PD1 blockade led to a greater reduction in tumor growth rate and tumor weight. IT therapy also improved the response of CD8+TILs to melanoma‐specific Trp2 180–188 peptide. A detailed analysis of the CD8+TILs showed that Ly108 and CD127 reduced dramatically as the expression of PD1 increased. In comparison to PD1 blockade, combined treatment (IT plus PD1 blockade) significantly increased the number of intermediate IRs‐expressing CD8+TILs, while reducing the number of high IRs‐expressing CD8+TILs. These results indicated that combined treatment enhanced the function and decelerated the increase in IRs expression of CD8+TILs, deferring the developmental process of CD8+TILs exhaustion.

Abstract The effects of impurities on avalanche generation of runaway electron (RE) are investigated using a relativistic bounce-averaged drift-kinetic equation that combines the effects of impurities, stochastic magnetic perturbations (SMFs), and synchrotron radiation (Hoppe et al 2021 Comput. Phys. Commun. 268 108098). The momentum range of RE is established through the balance between SMFs induced diffusion rate and acceleration rate (Li et al 2017 Plasma Phys. Control. Fusion 59 055003). Impurity injection affects momentum-space dynamics of RE by modifications to bremsstrahlung radiation and collision-induced pitch-angle scattering and slowing-down processes, which leads to enhancement of both the sustainment and avalanche threshold electric fields (E_s and E_av) as well as reduction of the avalanche growth rate. However, the inclusion of impurity contributions to the avalanche source term leads to a rapid increase in avalanche growth rate once the electric field exceeds E_av. Furthermore, parameter scans based on ITER and DIII-D demonstrate that higher post-TQ temperature and higher amount of injected high-Z impurities are beneficial for raising the avalanche threshold electric field. These results may provide some useful theoretical insights for strategies of suppressing RE.

Equine platelet lysate exhibits bacteriostatic effects against gram-negative clinical bacterial isolates.

Algal growth and photosynthetic responses of Dunaliella tertiolecta and Scenedesmus rubescens to methyl- and propylparaben mixtures.

Impact of DNA methyltransferases on bacterial fitness and genome stability in Escherichia coli.

The length of the spinal cord differs from that of the vertebral column in vertebrates, and their segmental positional relationship exhibits significant variability and complexity. However, research on the spinal cord structure of the Korean water deer and Siberian roe deer remains unexplored. This study aimed to investigate the anatomical structure of spinal cord segments and their association with vertebrae in these species, as well as to compare the findings with those from previously studied species. Morphometric analyses of the spinal cords and vertebrae were conducted using various measurement parameters. Notably, the cervical enlargement extended from C6 to T1, and the lumbar enlargement from L4 to S1, with significant decreases in spinal segment length observed in these regions. Transitions were noted around these enlargements, including shifts from caudal to cranial in spinal segments relative to vertebral segments and from acute to more obtuse trapezoidal shapes in dorsal rootlets. We propose that reduced growth rates at enlargements determine the positional relationship between the spinal cord and vertebrae. Since this study provides the first anatomical characterization of the spinal cord in these two deer species, our findings advance our understanding of spinal cord structure in Cervidae. Furthermore, through comparative analysis with previous studies, these findings elucidate the segmental positional relationship between the spinal cord and vertebral column, providing a foundation for further morphological and embryological studies across various species.

Objective: To explore the effects of pleiotropic regulator, catabolite control protein A (CcpA), on the biofilm formation of Streptococcus mutans (Sm). Methods: The CcpA knockout strain ΔccpA and complementation strain ΔccpA/pDL278-ccpA were constructed. The cell morphologies and growth curves of UA159 and ΔccpA cells were detected. The pH meter and acid tolerance assay were conducted to evaluate the effect of CcpA on the acid-producing and acid resistance capacity of Sm, respectively. Crystal violet assay (CVS), anthrone-sulfuric method, scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM) were conducted to evaluate the characteristics of Sm biofilms. Moreover, real-time fluorescence quantitative PCR (RT-qPCR) and electrophoretic mobility shift assay (EMSA) were employed to explore the molecular mechanism of CcpA in prompting the biofilm formation at transcriptional level. Results: Growth curve analysis indicated that ΔccpA demonstrated slightly reduced growth rate compared with UA159, while the final yield showed no significant difference. SEM observation showed ΔccpA bacteria formed loose biofilm architectures and exhibited a reduced capacity in synthesizing extracellular matrix, and these findings were further confirmed by CVS that ΔccpA (0.55±0.11) exhibited decreased biomass relative to UA159 (0.82±0.01) (P<0.01), while no significant difference between ΔccpA/pDL278-ccpA and UA159 (P>0.05). CLSM observation exhibited a reduced capacity to synthesize exopolysaccharides of ΔccpA strain, and these findings were further confirmed by data of anthrone-sulfuric method that ΔccpA exhibited decreased water-soluble glucans (0.10±0.01) and water-insoluble glucans (0.08±0.00) relative to UA159 (0.14±0.02, 0.20±0.03) (all P<0.01), while there was no significant difference between ΔccpA/pDL278-ccpA and UA159 (all P>0.05). RT-qPCR showed the expression levels of gtfB/C/D genes were markedly downregulated in ∆ccpA strain with different carbon resources (all P<0.05). Specifically, the promoter regions of gtfB and gtfC were directly regulated by CcpA. Conclusions: In summary, CcpA can trigger transcription of biofilm-formation genes via direct binding. Our study supports a role for CcpA as a crucial regulator that exploit the nuanced control of Sm biofilm formation.

Bacillus subtilis is a critical host for protein production, with many industrial strains relying on strong constitutive promoters. However, this kind of promoter typically imposes a heavy burden on the host from the early stage of fermentation, leading to reduced growth rate and biomass. To overcome the drawbacks of these promoters, we developed a xylose-inducible CRISPRi module to dynamically control the activity of these promoters. The strength of this module was finely tuned via promoter engineering and the xylose concentration. The addition of xylose inhibited the target promoter and favored cell growth at an early stage, while the consumption of xylose recovered the strength of the promoter and facilitated protein expression, resulting in better balance between cell growth and protein production. The yield of a target protein was increased by 38% using this module. Our work provides a simple and effective method to upgrade industrial strains driven by strong constitutive promoters.