Flavonoids are not only widely applied in the food, pharmaceutical and cosmetic industries, but also possess diverse biological functions that play crucial roles in plant physiology, growth and development, and ecology. The camphor tree (Cinnamomum camphora (L.)) holds significant economic and ecological value; however, its flavonoid composition and the underlying biosynthetic mechanisms remain largely unexplored. In this study, widely targeted metabolomics and transcriptomics were integrated to comprehensively analyze the leaves of C. camphora. The results revealed significant metabolic differences among fresh leaves of different C. camphora chemotypes. with both DAMs and DEGs being significantly enriched in the flavonoid biosynthesis pathway. Quercetin-5-O-glucuronide, rhamnetin-3-O-glucoside, juglanin, catechin and (-)-epicatechin were identified as the major DAMs. Furthermore, the key enzymes involved in the flavonoid biosynthetic pathway, such as PAL, C4H, and 4CL, CHS, CHI, F3H, FLS, DFR, ANS, LAR, C3H, and HCT were identified. Among these, CcC4H1 was identified as a hub gene in co-expression network. Compared with the control, transient overexpression of CcC4H1 significantly increased the total flavonoid content in C. camphora leaves by 1.45-fold (reaching 2.42 mg/g), while significantly elevating the flavonoids compounds such as 8-C-methylquercetin 3-xyloside, 2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3-[(2S,3S,4 R,5S,6 R)-2,3,5-trihydroxy-6-methyloxan-4-yl]oxychromen-4-one, and rhamnetin-3-O-glucoside, with increases ranging from 1.88- to 22.79-fold. These findings provide important insights into the molecular regulation mechanisms of flavonoid biosynthesis in camphor trees and provide important information for the selection of varieties rich in flavonoids.
Carlos Antón-Plágaro, Kai-en Chen, Qian Guo
et al.
Abstract Endosomal retrieval and recycling of integral cargo proteins is essential for cell and organism development and homeostasis and is orchestrated through a specialised endosomal nanodomain, the retrieval sub-domain. Sub-domain dysfunction is associated with human disease, but our mechanistic understanding of its function remains poorly described. Here, using proximity proteomics of retrieval sub-domain components Retromer and Retriever we identify mechanistic details of retrieval sub-domain composition and organization, including an unrecognised complexity in the interface with RAB GTPase switching. Combining X-ray crystallography and in silico predictions with biochemical and cellular analysis, we reveal that Retromer directly associates and recruits the RAB10 regulators DENND4A, DENND4C, TBC1D1, and TBC1D4, and the RAB35 regulator TBC1D13 to regulate retrieval sub-domain function. The retrieval sub-domain therefore constitutes a hub for integrating cargo recycling with the regulated switching of selected RAB GTPases. We propose this constitutes a major component of the neuroprotective role of the retrieval sub-domain.
Manuel Fuertes-Recuero, José L. López-Hernández, Alejandra Ramírez-Lago
et al.
Chimpanzees (<i>Pan troglodytes</i>) rescued from the illegal wildlife trade often suffer from chronic, traumatic injuries that require specialized and prolonged medical treatment in wildlife rehabilitation centers. We present the case report of a two-year-old male chimpanzee admitted at the Tchimpounga Chimpanzee Rehabilitation Center in the Republic of Congo with a chronic periorbital abscess, likely caused by a machete wound sustained during the poaching of his mother. Despite receiving extended antimicrobial therapy, his condition was never fully controlled and progressed to a chronic orbital infection, causing him discomfort and producing chronic purulent discharge. Enucleation was performed under general anesthesia using ketamine and medetomidine, with surgical approach adapted to the distinctive orbital anatomy of chimpanzees. During the procedure, ligation of the optic nerve and ophthalmic vessels was required due to the confined orbital apex and extensive vascularization, ensuring adequate haemostasias and procedural safety. The chimpanzee made an uneventful postoperative recovery, resuming normal feeding and social behavior within 48 h, with complete wound healing occurring within two weeks. This case report highlights the importance of prompt surgical intervention when conservative medical management fails to resolve refractory ocular infections in chimpanzees. It also emphasizes the importance of specific anesthetic protocols, refined surgical techniques and tailored postoperative care in wildlife rehabilitation centers. Documenting and sharing detailed case reports such as this contributes to the limited veterinary literature on great ape surgery and supports evidence-based clinical decision-making to improve the welfare and treatment outcomes of rescued chimpanzees.
Abstract Stem cell differentiation must be regulated by intricate and complex interactions between cells and their surrounding environment, ensuring normal organ and tissue morphology such as the liver1. Though it is well acknowledged that microgravity provides necessary mechanical force signals for cell fate2, how microgravity affects growth, differentiation, and communication is still largely unknown due to the lack of real experimental scenarios and reproducibility tools. Here, Rotating Flat Chamber (RFC) was used to simulate ground-based microgravity effects to study how microgravity effects affect the differentiation of HepaRG (hepatic progenitor cells) cells. Unexpectedly, the results show that RFC conditions could promote HepaRG cell differentiation which exhibited increased expression of Alpha-fetoprotein (AFP), albumin (ALB), and Recombinant Cytokeratin 18 (CK18). Through screening a series of mechanical receptors, the ion channel TRPML1 was critical for promoting the differentiation effect under RFC conditions. Once TRPML1 was activated by stimulated microgravity effects, the concentration of lysosomal calcium ions was increased to activate the Wnt/β-catenin signaling pathway, which finally led to enhanced cell differentiation of HepaRG cells. In addition, the cytoskeleton was remodeled under RFC conditions to influence the expression of PI (3,5) P2, which is the best-known activator of TRPML1. In summary, our findings have established a mechanism by which simulated microgravity promotes the differentiation of HepaRG cells through the TRPML1 signaling pathway, which provides a potential target for the regulation of hepatic stem/progenitor cell differentiation and embryonic liver development under real microgravity conditions.
Abstract Introduction The intraventricular pressure gradient (IVPG) measured by color M-mode echocardiography (CMME) and two-dimensional speckle tracking echocardiography (2D-STE) have emerged as novel imaging techniques for heart function evaluation. Various experimental and clinical studies have been conducted on animals, but reports on ruminant species are limited. Objectives This study aimed to determine the concomitant changes in IVPG and 2D-STE in goats before and after sedation and highlight the relationship between the parameters obtained from the two imaging techniques. Methods Ten male goats were included and the full conventional echocardiographic protocol, including 2D, M-mode, spectral Doppler, tissue Doppler imaging (TDI), 2D-STE, and CMME were performed before and after sedation with xylazine (50 ug /kg BW/IM). The analysis of 2D-STE at the apical and mid-levels of the left ventricle and the IVPG were assessed using special software. Results The results showed good quality data obtained for the evaluation of heart functions through conventional echocardiography, CMME, and 2D-STE. Xylazine administration significantly reduces mitral inflow and TDI velocities as well as the total IVPG and basal IVPG. (P < 0.05). Sedation also significantly disturbed the contractility of the segmental myocardium at the mid and apical levels. The radial and circumferential strains and strain rates, in addition to the synchrony time index, were reduced accordingly (p < 0.05). Conclusion This study utilizes two novel imaging techniques to assess changes observed in cardiac function in goats after sedation. Xylazine, an α2-agonist, induces loading alterations that disproportionately affect wall mechanics, reducing circumferential and radial shortening as well as IVPG parameters. Our findings confirm that CMME and 2D-STE are sensitive tools to detect subtle, region-specific alterations in the IVPG and myocardial function, respectively, in ruminants, complementing conventional echocardiographic indices. This may have important implications for both clinical monitoring and experimental designs where α₂-adrenergic agonists are employed.
Virginia Byers Kraus, Alexander Reed, Erik J. Soderblom
et al.
Objective: To further validate a serum proteomics panel for predicting radiographic (structural) knee OA progression. Design: Serum peptides were targeted by multiple-reaction-monitoring mass spectrometry in the New York University cohort (n = 104). Knee OA progression was defined as joint space narrowing ≥1 in the tibiofemoral compartment of one knee per study participant over a 24-month follow-up. The discriminative ability of an 11-peptide panel was evaluated by multivariable logistic regression and area under the receiver operating characteristic curve (AUC), without and with demographic characteristics of age, sex, and body mass index. The association of each peptide with OA progression was assessed by odds ratios (OR) in multivariable logistic regression models adjusted for demographics. Results: The cohort included 46 (44%) knee OA progressors. The panel of 11 peptides alone yielded AUC = 0.66 (95% CI [0.55, 0.77]) for discriminating progressors from non-progressors; demographic traits alone yielded AUC = 0.66 (95% CI [0.55, 0.77]). Together the 11 peptides and demographics yielded AUC = 0.72 (95% CI [0.62, 0.83]). CRAC1 had the highest odds for predicting OA progression (OR 2.014, 95% CI [0.996, 4.296], p = 0.058). Conclusions: We evaluated a parsimonious serum proteomic panel and found it to be a good discriminator of knee radiographic OA progression from non-progression. Since these biomarkers are quantifiable in serum, they could be deployed relatively easily to provide a simple, cost-effective strategy for identifying and monitoring individuals at high risk of knee OA progression.
Introduction: Fibrotic scar in the heart is known to act as a substrate for arrhythmias. Regions of fibrotic scar are associated with slowed or blocked conduction of the action potential, but the detailed mechanisms of arrhythmia formation are not well characterised and this can limit the effective diagnosis and treatment of scar in patients. The aim of this computational study was to evaluate different representations of fibrotic scar in models of 2D 10 × 10 cm ventricular tissue, where the region of scar was defined by sampling a Gaussian random field with an adjustable length scale of between 1.25 and 10.0 mm.Methods: Cellular electrophysiology was represented by the Ten Tusscher 2006 model for human ventricular cells. Fibrotic scar was represented as a spatially varying diffusion, with different models of the boundary between normal and fibrotic tissue. Dispersion of activation time and action potential duration (APD) dispersion was assessed in each sample by pacing at an S1 cycle length of 400 ms followed by a premature S2 beat with a coupling interval of 323 ms. Vulnerability to reentry was assessed with an aggressive pacing protocol. In all models, simulated fibrosis acted to delay activation, to increase the dispersion of APD, and to generate re-entry.Results: A higher incidence of re-entry was observed in models with simulated fibrotic scar at shorter length scale, but the type of model used to represent fibrotic scar had a much bigger influence on the incidence of reentry.Discussion: This study shows that in computational models of fibrotic scar the effects that lead to either block or propagation of the action potential are strongly influenced by the way that fibrotic scar is represented in the model, and so the results of computational studies involving fibrotic scar should be interpreted carefully.
Andrea Paterno, Giovanni Polsinelli, Bruno Federico
Background: Brain-Derived Neurotrophic Factor (BDNF) serum levels are reduced in patients with Parkinson’s Disease (PD).Objectives: This study aimed to assess the effect of exercise intensity, volume and type on BDNF levels in patients with PD.Methods: We searched clinicaltrials.gov, CINAHL, Embase, PubMed, Scopus, Web of Science for both controlled and non-controlled studies in patients with PD, published between 2003 and 2022, which assessed Brain-Derived Neurotrophic Factor before and after different exercise protocols. Exercise intensity was estimated using a time-weighted average of Metabolic Equivalent of Task (MET), while exercise volume was estimated by multiplying MET for the duration of exercise. Exercise types were classified as aerobic, resistance, balance and others. We computed two distinct standardized measures of effects: Hedges’ g to estimate differences between experimental and control group in pre-post intervention BDNF changes, and Cohen’s d to measure pre-post intervention changes in BDNF values for each study arm. Meta-regression and linear regression were used to assess whether these effect measures were associated with intensity, volume and type. PROSPERO registration number: CRD42023418629.Results: Sixteen studies (8 two-arm trials and 8 single-arm trials) including 370 patients with PD were eligible for the systematic review. Selected studies had a large variability in terms of population and intervention characteristics. The meta-analysis showed a significant improvement in BDNF levels in the exercise group compared to the control group, Hedges’ g = 0.70 (95% CI: 0.03, 1.38), with substantial heterogeneity (I2 = 76.0%). Between-group differences in intensity were positively associated with change in BDNF in a subset of 5 controlled studies. In the analysis which included non-controlled studies, intensity and total exercise volume were both positively associated with BDNF change. No difference was found according to exercise type.Conclusion: Exercises of greater intensity may increase BDNF levels in patients with PD, while the role of volume of exercise needs to be further explored.
Zeynab Arbabi, Abdolali Banaiefar, Sajjad Arshadi
et al.
Background and Aim: Metabolic syndrome refers to a set of metabolic disorders related to obesity, such as abdominal obesity, increased body fat mass, lipid disorders, hypertension, increased blood glucose, and insulin resistance. The present study was conducted with the aim of determining the effect of 8 weeks of CXWORX exercises combined with inulin consumption on some indicators of oxidative stress in obese women with metabolic syndrome.
Materials and Methods: Forty eight obese women with metabolic syndrome in the age range of 30 to 40 years were randomly divided into Control, inulin, CX exercise and combined groups were included. Subjects were present in the laboratory environment and 5 cc of blood was taken from their brachial vein. Blood sample was taken to measure malondialdehyde and xanthine oxidase (pre-test). Then the aforementioned interventions were performed on the studied groups for a period of 8 weeks. Finally, blood sampling was done again to measure the variables (post-test).
Results: The results of the correlated t-test revealed that in all three groups, the intervention led to a significant decrease in malondialdehyde compared to the pre-test; However, xanthine oxidase variable did not change significantly in the exercise group and significantly decreased in the inulin and combined groups compared to the pre-test. ANOVA results revealed that compared to the control group, the amount of malondialdehyde is significant only in the combined group (P≤0.05). The amount of this variable in the combined group decreased significantly compared to the exercise and inulin group (P≤0.05). No significant difference was observed between the exercise and inulin groups (P>0.05). Amount of xanthine oxidase, a significant difference had between the inulin and combination groups with the control group (P≤0.05). No significant difference was observed between the exercise and inulin groups (P>0.05). Despite this, a significant difference in xanthine oxidase levels was observed between the combined group with the exercise and inulin groups (P≤0.05).
Conclusion: Based on the available findings, it is concluded that the implementation of CX exercises combined with the use of inulin reduces the oxidative stress function more than the application of each of them alone in women with metabolic syndrome.
Kimberly J Morgan, Karen Doggett, Fansuo Geng
et al.
The nucleoporin (NUP) ELYS, encoded by AHCTF1, is a large multifunctional protein with essential roles in nuclear pore assembly and mitosis. Using both larval and adult zebrafish models of hepatocellular carcinoma (HCC), in which the expression of an inducible mutant kras transgene (krasG12V) drives hepatocyte-specific hyperplasia and liver enlargement, we show that reducing ahctf1 gene dosage by 50% markedly decreases liver volume, while non-hyperplastic tissues are unaffected. We demonstrate that in the context of cancer, ahctf1 heterozygosity impairs nuclear pore formation, mitotic spindle assembly, and chromosome segregation, leading to DNA damage and activation of a Tp53-dependent transcriptional programme that induces cell death and cell cycle arrest. Heterozygous expression of both ahctf1 and ranbp2 (encoding a second nucleoporin), or treatment of heterozygous ahctf1 larvae with the nucleocytoplasmic transport inhibitor, Selinexor, completely blocks krasG12V-driven hepatocyte hyperplasia. Gene expression analysis of patient samples in the liver hepatocellular carcinoma (LIHC) dataset in The Cancer Genome Atlas shows that high expression of one or more of the transcripts encoding the 10 components of the NUP107–160 subcomplex, which includes AHCTF1, is positively correlated with worse overall survival. These results provide a strong and feasible rationale for the development of novel cancer therapeutics that target ELYS function and suggest potential avenues for effective combinatorial treatments.
Roman Gabor, Ladislav Cvrček, Martina Doubková
et al.
This study is focused on the preparation of new hybrid layers intended for surface modification of Ti-6Al-4V alloys for potential orthopaedic and dental applications. Combination of the technology of physical vapour deposition (PVD) and subsequent micro-arc oxidation (MAO) was utilized for the deposition of Ti and ZrTi to form hybrid oxide layers. The oxide layers were prepared using an alkaline electrolyte with glycerol as an additive under micro-arc discharge conditions with different Si content on their surfaces. The hybrid ZrTi coatings with a Zr/Si structure achieved the best tribological properties described by a low friction coefficient of 0.3 and high abrasion resistance. There was also an increase in corrosion potential and polarization resistance of hybrid ZrTi coatings. Although the proliferation of human bone marrow mesenchymal stem cells was slower on these hydrophilic Ti and ZrTi coatings than both on uncoated Ti-6Al-4V and the reference tissue culture polystyrene dishes, both types of hybrid coating promoted greater osteogenic differentiation of these cells, indicated by approx. twice as high activity of alkaline phosphatase. The hybrid oxide layers newly developed in this study – especially the layers with Zr – are therefore promising for coating metallic bone implants.
Materials of engineering and construction. Mechanics of materials
Francisco H. F. Pereira, Gisele L. dos Santos, Francisco H. D. de Lacerda
et al.
ABSTRACT In the semi-arid region of northeastern Brazil, soil and climate conditions can increase the risk of soil salinization, particularly when poor-quality water is used for irrigation. Therefore, techniques that improve the yields of melon culture under adverse conditions, such as salinity, are of great relevance to the production sector. The objective of this study was to evaluate the effectiveness of hydrogen peroxide (H2O2) in acclimatizing melon trees subjected to irrigation water with different salinity levels. The treatments consisted of irrigation water with two electrical conductivities (0.3 and 5.0 dS m-1) and four concentrations of H2O2 (0, 5, 10, and 15 µmol L-1). The experimental design used was randomized blocks, arranged in a 2 × 4 factorial scheme, with four replicates and four plants per plot. Increase in salinity of irrigation water reduced the growth, gas exchange, and production of melon plants. However, H2O2, at a concentration of 6.35 µmol L-1, yielded improvements in physiology, growth, and production, in addition to reducing the deleterious effects of saline stress on melon production.
Proposed mechanism. A Doxorubicin (DOX) targets the BCAA catabolic pathway in TNBCs, by downregulating BCKDK and augmenting clearance of intracellular BCKAs. B Genetic or pharmacological (high BT2 concentration) inhibition of BCKDK results in increased cell death, decreased intracellular BCKAs, dysregulated mitochondrial function, ATP insufficiency, SESN2 activation, and inhibition of mTORC1 signaling and protein synthesis. C BCKDK inhibition (siRNA mediated or low-BT2 concentration) exacerbates DOX-induced cytotoxicity and caspase activity.
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cytology
The NR5A-family nuclear receptors are highly conserved and function within the somatic follicle cells of the ovary to regulate folliculogenesis and ovulation in mammals; however, their roles in Drosophila ovaries are largely unknown. Here, we discover that Ftz-f1, one of the NR5A nuclear receptors in Drosophila, is transiently induced in follicle cells in late stages of oogenesis via ecdysteroid signaling. Genetic disruption of Ftz-f1 expression prevents follicle cell differentiation into the final maturation stage, which leads to anovulation. In addition, we demonstrate that the bHLH/PAS transcription factor Single-minded (Sim) acts as a direct target of Ftz-f1 to promote follicle cell differentiation/maturation and that Ftz-f1’s role in regulating Sim expression and follicle cell differentiation can be replaced by its mouse homolog steroidogenic factor 1 (mSF-1). Our work provides new insight into the regulation of follicle maturation in Drosophila and the conserved role of NR5A nuclear receptors in regulating folliculogenesis and ovulation.
R. P. Vynogradova, V. M. Danilova, S. V. Komisarenko
Although the protein nature of enzymes was identified in the 40s of the 20th century, (we wrote about this in our previous article), their molecular structure and the specific mechanism of action remained unknown. Researchers of the next generations faced the challenges and a major breakthrough was achieved. In 1960, American biochemists S. Moore and W. Stein determined the complete amino acid sequence of enzyme ribonuclease. It was one of the first proteins and the first enzyme whose primary structure was established. In 1972, for this discovery, they received the Nobel Prize in Chemistry jointly to Christian Anfinsen who worked on the same problem. Works of Nobel Laureates in Chemistry in 1997 – Jens Christian Skou (for the discovery of the Na+,K+-activated ATPase), Paul Boyer and John Walker (for the discovery of the mechanism of action of H+-ATP synthase – the most important enzyme for bioenergy) were a huge step forward in the deciphering the mechanisms of enzyme action. The second half of the 20th century was marked by another outstanding discovery in the field of biology and medicine – the identification and characterization of prions – the proteins that cause neurodegenerative spongiform encephalopathies in humans and animals. For this work, American biochemist Stanley B. Prusiner received the Nobel Prize in Physiology or Medicine in 1997. This discovery is of great theoretical significance for biochemical science. The development of new research methods and technological advances formed the basis for significant scientific achievements in this field of biochemistry and molecular biology. This was the golden era of protein chemistry.
Background and Aims: Single nucleotide polymorphisms in miRNA binding sites, which are located in mRNA 3' untranslated regions (3'-UTRs), were recently found to influence microRNA-target interactions. Specifically, such polymorphisms can modulatebinding affinity or create or destroy miRNA-binding sites; such variants have also been found to be associated with cancer risk. In this study, we explored the effect of a functional variant at the miR-214 binding site in the methylenetetrahydrofolate reductase gene (rs114673809) on gastric cancer (GC) risk in a hospital-based case-control study in a Chinese Han population. Methods and Results: We genotyped the rs114673809 polymorphism in 345 gastric cancer patients and 376 cancer-free controls using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technique. The functions of rs114673809 were investigated using a luciferase activity assay and validated by immunoblotting. We found that participants carrying the rs114673809 AA genotype or A allele had a significantly increased risk of gastric cancer (OR = 1.667, 95% CI = 1.044-2.660, P = 0.034; OR = 1.261, 95% CI = 1.017-1.563, P = 0.037, respectively) compared to those carrying the GG genotype and G allele. In addition, rs114673809 modified the binding of hsa-miR-214 to MTHFR as well as MTHFR protein levels in gastric cancer patients. Conclusion: Our data suggested that rs114673809, which is located at the miR-214 binding site in the 3'-UTR of MTHFR, may play an important role in the development of gastric cancer in a Chinese Han population.
This review is on ultrastructure and subcellular physiology at normal and abnormal neuromuscular junctions. The clinical and electrophysiological findings in myasthenia gravis, Lambert-Eaton myasthenic syndrome (LEMS), congenital myasthenic syndromes, and botulinum intoxication are discussed. Single fiber electromyography (SFEMG) helps to explain the basis of testing neuromuscular junction function by repetitive nerve stimulation (RNS). SFEMG requires skill and patience and its availability is limited to a few centers. For RNS supramaximal stimulation is essential and so is display of the whole waveform of each muscle response at maximum amplitude. The amplitudes of the negative phase of the first and fourth responses are measured from baseline to negative peak, and the percent change of the fourth response compared with the first represents the decrement or increment. A decrement greater than 10% is accepted as abnormal and smooth progression of response amplitude train and reproducibility form the crux. In suspected LEMS the effect of fast rates of stimulation should be determined after RNS response to slow rates of stimulation. Caution is required to avoid misinterpretation of potentiation and pseudofacilitation.
D. Stoyanova-Koleva, M. Stefanova, M. Zhiponova
et al.
The leaf structure and chloroplast ultrastructure of kidney tea (Orthosiphon stamineus Benth.) was studied in in vitro culture on standard MS medium supplemented with or without plant growth regulators (PGRs). The cytokinin N6-benzyladenine (BA) negatively affected the structure of the palisade parenchyma and chloroplast ultrastructure and increased the stomatal frequency of the adaxial epidermis. The auxin indole-3-butyric acid (IBA) did not modify the morphology of regenerated leaf tissues as well as the chloroplast ultrastructure. The effect of both PGRs applied in combination was manifested in well-differentiated mesophyll parenchyma, typical chloroplast ultrastructure and increased stomatal frequency on both leaf surfaces. This protocol can be suggested for further ex vitro propagation.