Search Results (80)

Background: The New Zealand pine bark has been demonstrated in vitro to inhibit digestive enzymes involved in carbohydrate digestion (alpha-amylase, alpha-glucosidase, and dipeptidyl-peptidase 4 (DPP-4)). Objective: This study aims to investigate the inhibitory effects of the New Zealand pine bark on sucrose uptake and glycaemic responses in humans. Methods: A single-blind, randomised, placebo-controlled, crossover trial was carried out involving healthy adults (n = 40 (M: 12, F: 28), 30.1 ± 1.3 years, BMI 23.4 ± 0.5 kg/m², HbA1c 32.5 ± 0.6 mmol/mol, FBG 4.7 ± 0.1 mmol/L). A control (75 g of sucrose powder only), and two doses of the pine bark extract (50 and 400 mg) were provided on separate occasions, with 75 g of sucrose mixed in 250 mL of water. Blood samples were collected at −10, 0, 15, 30, 45, 60, 90, and 120 min via a finger prick test. A linear mixed model for repeated measures (SPSS v30, IBM) was applied, and data presented as model-adjusted mean ± SEM. Results: Compared to control (247.5 ± 14.0 mmol/L⋅min), the iAUCglucose was significantly reduced with the 400 mg dose (211.8 ± 13.9 mmol/L⋅min, 14.4% reduction, and p = 0.037), but not with 50 mg dose (220.8 ± 14.2 mmol/L⋅min, 10.8% reduction, and p = 0.184). Compared to control (9.1 ± 0.2 mmol/L), glucose peak value was significantly reduced with the 50 mg dose (8.6 ± 0.2 mmol/L, 5.5% reduction, and p = 0.016) but not with the 400 mg dose (8.7 ± 0.2 mmol/L, 4.4% reduction, and p = 0.093). There were no statistically significant changes in postprandial insulin levels with the pine bark extract compared to control. Conclusions: The New Zealand pine bark extract attenuated sucrose uptake with improved glycaemic responses, and may therefore be useful as a hypoglycaemic adjunct to the diet. Full article

Wheat (Triticum aestivum L.) omega-5 gliadin, a major allergen responsible for wheat-dependent exercise-induced anaphylaxis in humans, is encoded by genes located at the Gli-B1 locus on chromosome 1B, which exhibits genetic polymorphism. Gli-B1 alleles have generally been identified based on the electrophoretic mobilities of the encoded gamma-, omega-1,2, and omega-5 gliadins in acid polyacrylamide gel electrophoresis. However, the similar mobilities of omega-5 gliadin variants make it difficult to distinguish them among different wheat varieties. In this study, we optimized reverse-phase–ultra-performance liquid chromatography (RP-UPLC) conditions to separate omega-5 gliadins in the reference wheat cultivar Chinese Spring and its nullisomic–tetrasomic lines for chromosome 1B. Five chromatographic peaks corresponded to omega-5 gliadin, and the average relative standard deviation to each peak retention time ranged from 0.31% to 0.93%, indicating that the method is accurate and reproducible for fractionating omega-5 gliadins in gliadin extracts from wheat flour. Using the optimized RP-UPLC method, we analyzed omega-5 gliadins in 24 wheat varieties with the Gli-B1f allele. The result showed that the wheat varieties were sorted into eight groups according to the composition of omega-5 gliadin, indicating that the classification of Gli-B1 alleles based on A-PAGE could not explain the composition of omega-5 gliadin in wheat. We reclassified 73 wheat varieties containing 16 unique Gli-B1 alleles into 31 groups based on the chromatographic patterns of their omega-5 gliadins. Our results provide information on the specific Gli-B1 alleles of wheat varieties belonging to each group and demonstrate the potential for RP-UPLC to facilitate genetic studies of wheat varieties. Full article

Microbial adsorption is a cost-effective and environmentally friendly remediation method for heavy metal pollution. The adsorption mechanism of cadmium (Cd) by bacteria inhabiting extreme environments is largely unexplored. This study describes the biosorption of Cd²⁺ by Sphingomonas sp. M1-B02, which was isolated from the moraine on the north slope of Mount Everest and has a good potential for biosorption. The difference in Cd²⁺ adsorption of the strain after UV irradiation stimulation indicated that the adsorption reached 68.90% in 24 h, but the adsorption after UV irradiation increased to 80.56%. The genome of strain M1-B02 contained antioxidant genes such as mutL, recA, recO, and heavy metal repair genes such as RS14805, apaG, chrA. Hydroxyl, nitro, and etceteras bonds on the bacterial surface were involved in Cd²⁺ adsorption through complexation reactions. The metabolites of the strains were significantly different after 24 h of Cd²⁺ stress, with pyocyanin, L-proline, hypoxanthine, etc., being downregulated and presumably involved in Cd²⁺ biosorption and upregulated after UV-C irradiation, which may explain the increase in Cd²⁺ adsorption capacity of the strain after UV-C irradiation, while the strain improved the metabolism of the antioxidant metabolite carnosine, indirectly increasing the adsorption capacity of the strains for Cd²⁺. Full article

Intra-articular corticosteroids are a popular treatment choice for joint-associated pain and inflammation in horses despite recent work on the metabolic effects of these drugs. The goal of this project was to compare metabolic effects between intra-articular (IA) triamcinolone acetonide (TA) and an autologous protein solution (APS). Five mixed-breed geldings (4–9 years) were utilized for this project. Three identical and consecutive 28-day treatment blocks were used, with metacarpophalangeal IA treatments consisting of equal volumes of saline, a commercially available APS, or 9 mg of TA. Regular plasma and serum samples were collected for ACTH, cortisol, glucose, insulin, and thyroid hormone analysis, in addition to thyrotropin-releasing hormone (TRH) and oral sugar tests (OSTs). Significant treatment effects of IA TA were present at 48 h post-injection in both the TRH and the OST. There was also significant suppression by IA TA of baseline ACTH and cortisol between 2 h and 96 h post-treatment, hyperglycemia between 12 h and 48 h, and hyperinsulinemia at 32 h post-treatment. There were no treatment effects with respect to any measured thyroid hormones, nor were there any significant treatment effects of APS noted. Results suggest at least 2 days and up to 7 days should elapse between a single 9 mg IA TA treatment and OST and/or TRH testing. This study found that TA exhibits significant effects on ACTH, cortisol, glucose, and insulin, while the APS does not. Full article

Reducing high mechanical stress is imperative to heal diabetes-related foot ulcers. We explored the association of cumulative plantar tissue stress (CPTS) and plantar foot ulcer healing, and the feasibility of measuring CPTS, in two prospective cohort studies (Australia (AU) and The Netherlands (NL)). Both studies used multiple sensors to measure factors to determine CPTS: plantar pressures, weight-bearing activities, and adherence to offloading treatments, with thermal stress response also measured to estimate shear stress in the AU-study. The primary outcome was ulcer healing at 12 weeks. Twenty-five participants were recruited: 13 in the AU-study and 12 in the NL-study. CPTS data were complete for five participants (38%) at baseline and one (8%) during follow-up in the AU-study, and one (8%) at baseline and zero (0%) during follow-up in the NL-study. Reasons for low completion at baseline were technical issues (AU-study: 31%, NL-study: 50%), non-adherent participants (15% and 8%) or combinations (15% and 33%); and at follow-up refusal of participants (62% and 25%). These underpowered findings showed that CPTS was non-significantly lower in people who healed compared with non-healed people (457 [117; 727], 679 [312; 1327] MPa·s/day). Current feasibility of CPTS seems low, given technical challenges and non-adherence, which may reflect the burden of treating diabetes-related foot ulcers. Full article

Osimertinib is a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR) that is used for first-line therapy in EGFR mutated non-small cell lung cancer (NSCLC) based on the results of the randomized FLAURA trial (ClinicalTrials.gov number NCT02296125). We performed a retrospective analysis of baseline characteristics and clinical outcomes in 56 real-world patients treated with osimertinib. In total, 45% of patients were determined to be FLAURA-eligible and 55% were FLAURA-ineligible based on the published inclusion/exclusion criteria of the aforementioned trial. For clinical outcomes, the median osimertinib time to treatment discontinuation (TTD) for all patients was 16.9 months (95% CI: 12.6–35.1), whereas the median TTD was 31.1 months (95% CI: 14.9–not reached) in the FLAURA-eligible cohort and the median TTD was 12.2 months (95% CI: 8.1–34.6 months) in the FLAURA-ineligible cohort. Re-biopsy at acquired resistance disclosed both on- and off-target mechanisms. The most common therapies following osimertinib included local therapies followed by post-progression osimertinib, platinum-doublet chemotherapy with or without osimertinib, and osimertinib combinatory targeted therapies. The median overall survival for all patients was 32.0 months (95% CI: 15.7–not reached), the median survival was not reached for the FLAURA-eligible cohort, and it was 16.5 months for the FLAURA-ineligible cohort. Our data support the use of osimertinib in real-word settings and highlight the need for designing registration trials that are more inclusive of patient/disease characteristics seen in routine clinical practice. It is yet to be determined if the use of evolving first-line EGFR inhibitor combination strategies (either platinum-doublet chemotherapy plus osimertinib or amivantamab plus lazertinib) will similarly translate from clinical trials to real-word settings. Full article

Desmoplakin (DSP) is a large (~260 kDa) protein found in the desmosome, the subcellular structure that links the intermediate filament network of one cell to its neighbor. A mutation “hot-spot” within the NH₂-terminal of the DSP protein (residues 299–515) is associated with arrhythmogenic cardiomyopathy. In a subset of DSP variants, disease is linked to calpain hypersensitivity. Previous studies show that calpain hypersensitivity can be corrected in vitro through the addition of a bulky residue neighboring the cleavage site, suggesting that physically blocking calpain accessibility is a viable strategy to restore DSP levels. Here, we aim to find drug-like molecules that also block calpain-dependent degradation of DSP. To do this, we screened ~2500 small molecules to identify compounds that specifically rescue DSP protein levels in the presence of proteases. We find that several molecules, including sodium dodecyl sulfate, palmitoylethanolamide, GW0742, salirasib, eprosarten mesylate, and GSK1838705A prevent wildtype and disease-variant-carrying DSP protein degradation in the presence of both trypsin and calpain without altering protease function. Computational screenings did not predict which molecules would protect DSP, likely due to a lack of specific DSP–drug interactions. Molecular dynamic simulations of DSP–drug complexes suggest that some long hydrophobic molecules can bind in a shallow hydrophobic groove that runs alongside the protease cleavage site. Identification of these compounds lays the groundwork for pharmacological treatment for individuals harboring these hypersensitive DSP variants. Full article

Agricultural peatlands are the most productive soils in the UK for the cultivation of many food crops. Historical drainage of peat for agriculture (i.e., cropland and managed grassland), without consideration of other associated environmental and climatic impacts, has resulted in a significant emission of greenhouse gases (GHGs). There is a need to reduce GHG emissions without compromising the rural economy and jeopardizing food security in the UK to a greater extent than is currently being experienced. In March 2023, in a bid to identify alternative land management systems for agricultural peatlands to support the UK’s commitment to achieving net zero GHG emissions by 2050, a group of forty investigators met at a workshop convened by the AgriFood4NetZero Network+. The workshop reviewed the state of knowledge surrounding the Fens of Eastern England and their importance for food provision, the economy, cultural identity, and climate change mitigation. A broad consensus emerged for research into how GHG emissions from agricultural peatlands could be reduced, whether alternative farming methods, such as seasonal farming or paludiculture, would offer a solution, and how a localized approach for the Fens could be defined. The development of a holistic, inclusive, and plausible land use scenario that considers all aspects of ecosystem services provided by the Fens is urgently needed. Full article

Background: Immune-related adverse events (irAEs) challenge the use of immune checkpoint inhibitors (ICIs). We performed a retrospective study to evaluate response to infliximab for immune-related adverse event management, and infliximab’s effect on progression-free survival (PFS) and overall survival (OS) with a focus on melanoma and genitourinary cancers. Methods: We retrospectively reviewed records of all cancer patients exposed to infliximab after immune checkpoint inhibitor (ICI) treatment from 2004 to 2021 at the MD Anderson Cancer Center. Survival was assessed utilizing the Kaplan–Meier method. Univariate and multivariate logistic regression was utilized to evaluate predictors of infliximab response, OS, and PFS. Results: We identified 185 cancer patients (93 melanoma and 37 genitourinary cancers) treated with ICI and who received infliximab to treat irAEs. Within 3 months of treatment initiation, 71% of the patients responded to infliximab, 27% had no response, and 2% had unknown response. Among different irAEs, colitis was associated with increased response to infliximab at 3 months, irrespective of the type of malignancy. We evaluated best tumor response before and after infliximab in the entire cohort and again in the melanoma and genitourinary (GU); the findings were similar in the melanoma cohort and the entire cohort, where best tumor response before and after infliximab was not significantly different. In the melanoma cohort, acute kidney injury (AKI) was associated with increased risk of death, p = 0.0109, and having response to infliximab was associated with decreased risk of death, p = 0.0383. Interestingly in GU cancer patients, myositis was associated with increased risk of death, p = 0.0041, and having a response to infliximab was marginally associated with decreased risk of death, p = 0.0992. As regards PFS, in a multivariate Cox regression model, having a history of cardiovascular disease remained significantly associated with shorter PFS in the melanoma cohort. For patients with GU cancers, response to infliximab was associated with longer PFS. Conclusions: Our study is among the largest retrospective analyses of infliximab use for irAE management. Patients with colitis were the best responders to infliximab. AKI before initiation of infliximab in the melanoma subcohort and myositis in GU subcohort are associated with higher risk of death. Our results indicate no association between infliximab and cancer progression with the exception of genitourinary cancers. Full article

B-cell acute lymphoblastic leukaemia (B-ALL) is characterised by diverse genomic alterations, the most frequent being gene fusions detected via transcriptomic analysis (mRNA-seq). Due to its hypervariable nature, gene fusions involving the Immunoglobulin Heavy Chain (IGH) locus can be difficult to detect with standard gene fusion calling algorithms and significant computational resources and analysis times are required. We aimed to optimize a gene fusion calling workflow to achieve best-case sensitivity for IGH gene fusion detection. Using Nextflow, we developed a simplified workflow containing the algorithms FusionCatcher, Arriba, and STAR-Fusion. We analysed samples from 35 patients harbouring IGH fusions (IGH::CRLF2 n = 17, IGH::DUX4 n = 15, IGH::EPOR n = 3) and assessed the detection rates for each caller, before optimizing the parameters to enhance sensitivity for IGH fusions. Initial results showed that FusionCatcher and Arriba outperformed STAR-Fusion (85–89% vs. 29% of IGH fusions reported). We found that extensive filtering in STAR-Fusion hindered IGH reporting. By adjusting specific filtering steps (e.g., read support, fusion fragments per million total reads), we achieved a 94% reporting rate for IGH fusions with STAR-Fusion. This analysis highlights the importance of filtering optimization for IGH gene fusion events, offering alternative workflows for difficult-to-detect high-risk B-ALL subtypes. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in humans in late 2019 and spread rapidly, becoming a global pandemic. A zoonotic spillover event from animal to human was identified as the presumed origin. Subsequently, reports began emerging regarding spillback events resulting in SARS-CoV-2 infections in multiple animal species. These events highlighted critical links between animal and human health while also raising concerns about the development of new reservoir hosts and potential viral mutations that could alter the virulence and transmission or evade immune responses. Characterizing susceptibility, prevalence, and transmission between animal species became a priority to help protect animal and human health. In this study, we coalesced a large team of investigators and community partners to surveil for SARS-CoV-2 in domestic and free-ranging animals around Ohio between May 2020 and August 2021. We focused on species with known or predicted susceptibility to SARS-CoV-2 infection, highly congregated or medically compromised animals (e.g., shelters, barns, veterinary hospitals), and animals that had frequent contact with humans (e.g., pets, agricultural animals, zoo animals, or animals in wildlife hospitals). This included free-ranging deer (n = 76 individuals), free-ranging mink (n = 57), multiple species of bats (n = 59), and other wildlife in addition to domestic cats (n = 275) and pigs (n = 184). In total, we tested 792 individual animals (34 species) via rRT-PCR for SARS-CoV-2 RNA. SARS-CoV-2 viral RNA was not detected in any of the tested animals despite a major peak in human SARS-CoV-2 cases that occurred in Ohio subsequent to the peak of animal samplings. Importantly, we did not test for SARS-CoV-2 antibodies in this study, which limited our ability to assess exposure. While the results of this study were negative, the surveillance effort was critical and remains key to understanding, predicting, and preventing the re-emergence of SARS-CoV-2 in humans or animals. Full article

Subunit or inactivated vaccines comprise the majority of vaccines used against viral and bacterial pathogens. However, compared to their live/attenuated counterparts, these vaccines often demonstrate reduced immunogenicity, requiring multiple boosters and or adjuvants to elicit protective immune responses. For this reason, studies of adjuvants and the mechanism through which they can improve inactivated vaccine responses are critical for the development of vaccines with increased efficacy. Studies have shown that the direct conjugation of adjuvant to antigen promotes vaccine immunogenicity, with the advantage of both the adjuvant and antigen targeting the same cell. Using this strategy of direct linkage, we developed an inactivated influenza A (IAV) vaccine that is directly conjugated with the Toll-like receptor 7/8 agonist resiquimod (R848) through a heterobifunctional crosslinker. Previously, we showed that this vaccine resulted in improved protection and viral clearance in newborn nonhuman primates compared to a non-adjuvanted vaccine. We subsequently discovered that the choice of linker used to conjugate R848 to the virus alters the stimulatory activity of the vaccine, promoting increased maturation and proinflammatory cytokine production from DC differentiated in vitro. With this knowledge, we explored how the choice of crosslinker impacts the stimulatory activity of these vaccines. We found that the linker choice alters signaling through the NF-κB pathway in human monocyte-derived dendritic cells (moDCs). Further, we extended our analyses to in vivo differentiated APC present in human peripheral blood, replicating the linker-dependent differences found in in vitro differentiated cells. Finally, we demonstrated in a mouse model that the choice of linker impacts the amount of IAV-specific IgG antibody produced in response to vaccination. These data enhance our understanding of conjugation approaches for improving vaccine immunogenicity. Full article

Fibropapillomatosis (FP) is a neoplastic disease most often found in green turtles (Chelonia mydas). Afflicted turtles are burdened with potentially debilitating tumors concentrated externally on the soft tissues, plastron, and eyes and internally on the lungs, kidneys, and the heart. Clinical signs occur at various levels, ranging from mild disease to severe debilitation. Tumors can both progress and regress in affected turtles, with outcomes ranging from death due to the disease to complete regression. Since its official description in the scientific literature in 1938, tumor growth rates have been rarely documented. In addition, FP tumors come in two very different morphologies; yet, to our knowledge, there have been no quantified differences in growth rates between tumor types. FP tumors are often rugose in texture, with a polypoid to papillomatous morphology, and may or may not be pedunculated. In other cases, tumors are smooth, with a skin-like surface texture and little to no papillose structures. In our study, we assessed growth-rate differences between rugose and smooth tumor morphologies in a rehabilitation setting. We measured average biweekly tumor growth over time in green turtles undergoing rehabilitation at the University of Florida Whitney Laboratory Sea Turtle Hospital in St. Augustine, Florida, and compared growth between rugose and smooth tumors. Our results demonstrate that both rugose and smooth tumors follow a similar active growth progression pattern, but rugose tumors grew at significantly faster rates (p = 0.013) than smooth ones. We also documented regression across several examined tumors, ranging from −0.19% up to −10.8% average biweekly negative growth. Our study offers a first-ever assessment of differential growth between tumor morphologies and an additional diagnostic feature that may lead to a more comprehensive understanding and treatment of the disease. We support the importance of tumor morphological categorization (rugose versus smooth) being documented in future FP hospital- and field-based health assessments. Full article

Lactiplantibacillus pentosus, commonly isolated from commercial cucumber fermentation, is a promising candidate for starter culture formulation due to its ability to achieve complete sugar utilization to an end pH of 3.3. In this study, we conducted a comparative genomic analysis encompassing 24 L. pentosus and 3 Lactiplantibacillus plantarum isolates autochthonous to commercial cucumber fermentation and 47 lactobacillales reference genomes to determine species specificity and provide insights into niche adaptation. Results showed that metrics such as average nucleotide identity score, emulated Rep-PCR-(GTG)₅, computed multi-locus sequence typing (MLST), and multiple open reading frame (ORF)-based phylogenetic trees can robustly and consistently distinguish the two closely related species. Phylogenetic trees based on the alignment of 587 common ORFs separated the L. pentosus autochthonous cucumber isolates from olive fermentation isolates into clade A and B, respectively. The L. pentosus autochthonous clade partitions into subclades A.I, A.II, and A.III, suggesting substantial intraspecies diversity in the cucumber fermentation habitat. The hypervariable sequences within CRISPR arrays revealed recent evolutionary history, which aligns with the L. pentosus subclades identified in the phylogenetic trees constructed. While L. plantarum autochthonous to cucumber fermentation only encode for Type II-A CRISPR arrays, autochthonous L. pentosus clade B codes for Type I-E and L. pentosus clade A hosts both types of arrays. L. pentosus 7.8.2, for which phylogeny could not be defined using the varied methods employed, was found to uniquely encode for four distinct Type I-E CRISPR arrays and a Type II-A array. Prophage sequences in varied isolates evidence the presence of adaptive immunity in the candidate starter cultures isolated from vegetable fermentation as observed in dairy counterparts. This study provides insight into the genomic features of industrial Lactiplantibacillus species, the level of species differentiation in a vegetable fermentation habitat, and diversity profile of relevance in the selection of functional starter cultures. Full article

Nausea and vomiting are common gastrointestinal side effects of oxaliplatin chemotherapy used for the treatment of colorectal cancer. However, the mechanism underlying oxaliplatin-induced nausea and vomiting is unknown. The stomach is involved in the emetic reflex but no study investigated the effects of oxaliplatin treatment on the stomach. In this study, the in vivo effects of oxaliplatin treatment on eating behaviour, stomach content, intrinsic gastric neuronal population, extrinsic innervation to the stomach, levels of mucosal serotonin (5-hydroxytryptamine, 5-HT), and parasympathetic vagal efferent nerve activity were analysed. Chronic systemic oxaliplatin treatment in mice resulted in pica, indicated by increased kaolin consumption and a reduction in body weight. Oxaliplatin treatment significantly increased the stomach weight and content. The total number of myenteric and nitric oxide synthase-immunoreactive neurons as well as the density of sympathetic, parasympathetic, and sensory fibres in the stomach were decreased significantly with oxaliplatin treatment. Oxaliplatin treatment significantly increased the levels in mucosal 5-HT and the number of enterochromaffin-like cells. Chronic oxaliplatin treatment also caused a significant increase in the vagal efferent nerve activity. The findings of this study indicate that oxaliplatin exposure has adverse effects on multiple components of gastric innervation, which could be responsible for pica and gastric dysmotility. Full article