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Frontiers in Nutrition 2024Phospholipids (PLs) and long-chain polyunsaturated fatty acids (LCPUFAs) are naturally present in breast milk and play important roles in promoting the growth of the...
A combination of phospholipids and long chain polyunsaturated fatty acids supports neurodevelopmental outcomes in infants: a randomized, double-blind, controlled clinical trial.
Phospholipids (PLs) and long-chain polyunsaturated fatty acids (LCPUFAs) are naturally present in breast milk and play important roles in promoting the growth of the infant. Several studies have investigated the effects of the combination of PLs and LCPUFAs on neurodevelopment. However, data on the effectiveness of infant formula containing both PLs and LCPUFAs on the neurodevelopment of infants is still scarce. This randomized, double-blind, controlled clinical study was designed to evaluate the effect of an infant formula enriched with PLs and LCPUFAs on growth parameters and neurodevelopmental outcomes in term infants up to 365 days of age. Infants were enrolled within 30 days of birth who were then randomly assigned to either a control group ( = 150) or an investigational group ( = 150). Both groups consist of cow's milk-based formula which were generally identical in terms of composition, except that the investigational formula was additionally supplemented with PLs and LCPUFAs. The infants were followed for the first year of life. Breastfed infants were the reference ( = 150). Bayley Scales of Infant Development [3rd edition (Bayley-III)], Carey Toddler Temperament Scales (TTS), MacArthur-Bates Communicative Development Inventories (CDI), Single Object Attention and Free Play Tasks were used to evaluate neurodevelopmental outcomes of infant at 365 days of age. In addition, Ages and Stages Questionnaires (ASQ) were also conducted at 120, 180, and 275 days of age. Compared to breastfeeding, both infant formulas were well-tolerated and provided adequate growth, with no adverse events being reported throughout the study. Infants of the investigational group showed higher mean scores in Bayley-III cognitive performance (104.3 vs. 99.0, < 0.05), language (106.9 vs. 104.5, < 0.05), and motor skills (109.2 vs. 103.9, < 0.05) compared the control group. Similar results were being reported for other developmental scales including TTS and ASQ. Notably, the test scores of infants fed the investigational formula were similar to those who were breastfed. Our results indicate that PL and LCPUFA supplementation may be beneficial for neurodevelopment of infants throughout the first year of life. Further studies are needed to investigation long-term effects PL and LCPUFA on neurodevelopment in early life.
PubMed: 38938667
DOI: 10.3389/fnut.2024.1358651 -
BMC Plant Biology Jun 2024Salt is an important factor that affects crop productivity. Plant hexokinases (HXKs) are key enzymes in the glycolytic pathway and sugar signaling transduction pathways...
BACKGROUND
Salt is an important factor that affects crop productivity. Plant hexokinases (HXKs) are key enzymes in the glycolytic pathway and sugar signaling transduction pathways of plants. In previous studies, we identified and confirmed the roles of GmHXK2 in salt tolerance.
RESULTS
In this study, we analyzed the tissue-specific expression of GmHXK2 at different growth stages throughout the plant's life cycle. The results showed that GmHXK2 was expressed significantly in all tissues at vegetative stages, including germination and seedling. However, no expression was detected in the pods, and there was little expression in flowers during the later mature period. Arabidopsis plants overexpressing the GmHXK2 (OE) had more lateral roots. The OE seedlings also produced higher levels of auxin and ascorbic acid (AsA). Additionally, the expression levels of genes PMM, YUC4/YUC6/YUC8, and PIN/LAX1,LAX3, which are involved respectively in the synthesis of AsA and auxin, as well as polar auxin transport, were upregulated in OE plants. This upregulation occurred specifically under exogenous glucose treatment. AtHKT1, AtSOS1, and AtNHX1 were up-regulated in OE plants under salt stress, suggesting that GmHXK2 may modulate salt tolerance by maintaining ion balance within the cells and alleviating damage caused by salt stress. Additionally, we further confirmed the interaction between GmHXK2 and the protein GmPMM through yeast two-hybridization and bimolecular fluorescence complementation assays, respectively.
CONCLUSION
The expression of GmHXK2 gene in plants is organ-specific and developmental stage specific. GmHXK2 not only regulates the synthesis of AsA and the synthesis and distribution of auxin, but also promotes root elongation and induces lateral root formation, potentially enhancing soil water absorption. This study reveals the crosstalk between sugar signaling and hormone signaling in plants, where GmHXK2 acts as a glucose sensor through its interaction with GmPMM, and sheds light on the molecular mechanism by which GmHXK2 gene is involved in salt tolerance in plants.
Topics: Seedlings; Indoleacetic Acids; Salt Tolerance; Glycine max; Ascorbic Acid; Gene Expression Regulation, Plant; Plant Proteins; Arabidopsis; Plants, Genetically Modified
PubMed: 38937682
DOI: 10.1186/s12870-024-05301-3 -
Scientific Reports Jun 2024Milk is a good source of nutrition but is also a source of allergenic proteins such as α-lactalbumin, β-lactoglobulin (BLG), casein, and immunoglobulins. The Clustered...
Milk is a good source of nutrition but is also a source of allergenic proteins such as α-lactalbumin, β-lactoglobulin (BLG), casein, and immunoglobulins. The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas technology has the potential to edit any gene, including milk allergens. Previously, CRISPR/Cas has been successfully employed in dairy cows and goats, but buffaloes remain unexplored for any milk trait. In this study, we utilized the CRISPR/Cas9 system to edit the major milk allergen BLG gene in buffaloes. First, the editing efficiency of designed sgRNAs was tested in fibroblast cells using the T7E assay and Sanger sequencing. The most effective sgRNA was selected to generate clonal lines of BLG-edited cells. Analysis of 15 single-cell clones, through TA cloning and Sanger sequencing, revealed that 7 clones exhibited bi-allelic (-/-) heterozygous, bi-allelic (-/-) homozygous, and mono-allelic (-/+) disruptions in BLG. Bioinformatics prediction analysis confirmed that non-multiple-of-3 edited nucleotide cell clones have frame shifts and early truncation of BLG protein, while multiple-of-3 edited nucleotides resulted in slightly disoriented protein structures. Somatic cell nuclear transfer (SCNT) method was used to produce blastocyst-stage embryos that have similar developmental rates and quality with wild-type embryos. This study demonstrated the successful bi-allelic editing (-/-) of BLG in buffalo cells through CRISPR/Cas, followed by the production of BLG-edited blastocyst stage embryos using SCNT. With CRISPR and SCNT methods described herein, our long-term goal is to generate gene-edited buffaloes with BLG-free milk.
Topics: Animals; Lactoglobulins; Buffaloes; Gene Editing; CRISPR-Cas Systems; RNA, Guide, CRISPR-Cas Systems; Milk; Fibroblasts
PubMed: 38937564
DOI: 10.1038/s41598-024-65359-9 -
Neuroscience and Biobehavioral Reviews Jun 2024The prenatal and neonatal periods are two of the most important developmental stages of the human brain. It is therefore crucial to understand normal brain development... (Review)
Review
The prenatal and neonatal periods are two of the most important developmental stages of the human brain. It is therefore crucial to understand normal brain development and how early connections are established during these periods, in order to advance the state of knowledge on altered brain development and eventually identify early brain markers of neurodevelopmental disorders and diseases. In this systematic review (Prospero ID: CRD42024511365), we compiled resting state functional magnetic resonance imaging (fMRI) studies in healthy fetuses and neonates, in order to outline the main characteristics of typical development of the functional brain connectivity during the prenatal and neonatal periods. A systematic search of five databases identified a total of 12 573 articles. Of those, 28 articles met pre-established selection criteria based determined by the authors after surveying and compiling the major limitations reported within the literature. Inclusion criteria were: (1) resting state studies; (2) presentation of original results; (3) use of fMRI with minimum one Tesla; (4) a population ranging from 20 weeks of GA to term birth (around 37-42 weeks of PMA); (5) singleton pregnancy with normal development (absence of any complications known to alter brain development). Exclusion criteria were: (1) preterm studies; (2) post-mortem studies; (3) clinical or pathological studies; (4) twin studies; (5) papers with a sole focus on methodology (i.e. focused on tool and analysis development); (6) volumetric studies; (7) activation map studies; (8) cortical analysis studies; (9) conference papers. A risk of bias assessment was also done to evaluate each article's methodological rigor. 1877 participants were included across all the reviewed articles. Results consistently revealed a developmental gradient of increasing functional brain connectivity from posterior to anterior regions and from proximal-to-distal regions. A decrease in local small-world organization shortly after birth was also observed; small-world characteristics were present in fetuses and newborns, but appeared weaker in the latter group. Also, the posterior-to-anterior gradient could be associated with earlier development of the sensorimotor networks in the posterior regions while more complex higher-order networks (e.g. attention-related) mature later in the anterior regions. The main limitations of this systematic review stem from the inherent limitations of functional imaging in fetuses, mainly: unevenly distributed populations and limited sample sizes; fetal movements in the womb and other imaging obstacles; and a large voxel resolution when imaging a small brain. Another limitation specific to this review is the relatively small number of included articles compared to very a large search result, which may have led to relevant articles having been overlooked.
PubMed: 38936564
DOI: 10.1016/j.neubiorev.2024.105778 -
Molecular Immunology Jun 2024Immune cells in the human lung are associated with idiopathic pulmonary fibrosis. However, the contribution of different immune cell subpopulations to the pathogenesis...
Immune cells in the human lung are associated with idiopathic pulmonary fibrosis. However, the contribution of different immune cell subpopulations to the pathogenesis of pulmonary fibrosis remains unclear. We used single-cell RNA sequencing data to investigate the transcriptional profiles of immune cells in the lungs of 5 IPF patients and 3 subjects with non-fibrotic lungs. In an identifiable population of immune cells, we found increased percentage of CD8 T cells in the T cell subpopulation in IPF. Monocle analyzed the dynamic immune status and cell transformation of CD8 T cells, as well as the cytotoxicity and exhausted status of CD8 T cell subpopulations at different stages. Among CD8 T cells, we found differences in metabolic pathways in IPF and Ctrl, including lipid, amino acid and carbohydrate metabolic. By analyzing the metabolites of CD8 T cells, we found that different populations of CD8 T cells in IPF have unique metabolic characteristics, but they also have multiple identical up-regulated or down-regulated metabolites. In IPF, signaling pathways associated with fibrosis were enriched in CD8 T cells, suggesting that CD8 T cells may have an important contribution to fibrosis. Finally, we analyzed the interactions between CD8 T cells and other cells. Together, these studies highlight key features of CD8 T cells in the pathogenesis of IPF and help to develop effective therapeutic targets.
PubMed: 38936318
DOI: 10.1016/j.molimm.2024.06.008 -
Ecotoxicology and Environmental Safety Jun 2024Our environment is increasingly polluted with various molecules, some of which are considered endocrine disruptors. Metals and phthalates, originating from industrial...
Our environment is increasingly polluted with various molecules, some of which are considered endocrine disruptors. Metals and phthalates, originating from industrial activities, agricultural practices, or consumer products, are prominent examples of such pollutants. We experimentally investigated the impacts of the heavy metal cadmium and the phthalate DEHP on the moth Spodoptera littoralis. More specifically, larvae were reared in laboratory conditions, where they were exposed to diets contaminated with either two doses of cadmium at concentrations of 62.5 µg/g or 125 µg/g, two doses of DEHP at 100 ng/g and 10 µg/g, or a combination of both low and high doses of the two compounds, with a control group for comparison. Our findings indicate that cadmium delays the developmental transition from larva to adult. Notably, the combination of cadmium and DEHP exacerbated this delay, highlighting a synergistic effect. In contrast, DEHP alone did not affect larval development. Additionally, we observed that cadmium exposure, both alone and in combination with DEHP, led to a lower mass at all larval stages. However, cadmium-exposed individuals that reached adulthood eventually reached a similar mass to those in other groups. Interestingly, while our results did not show any effect of the treatments on hatching success, there was a higher adult mortality rate in the cadmium-treated groups. This suggests that while moths may prioritize reproductive success, their survival at the adult stage is compromised by cadmium exposure. In conclusion, our study demonstrates the impact of cadmium on the development, mass, and adult survival of moths, and reveals synergistic effects when combined with DEHP. These results confirm cadmium as an endocrine disruptor, even at low doses. These insights underscore the importance of understanding the toxicological effects of low doses of pollutants like cadmium and DEHP, both individually and in combination.
PubMed: 38936052
DOI: 10.1016/j.ecoenv.2024.116605 -
PLoS Pathogens Jun 2024The cGMP-dependent protein kinase (PKG) is the sole cGMP sensor in malaria parasites, acting as an essential signalling hub to govern key developmental processes...
The cGMP-dependent protein kinase (PKG) is the sole cGMP sensor in malaria parasites, acting as an essential signalling hub to govern key developmental processes throughout the parasite life cycle. Despite the importance of PKG in the clinically relevant asexual blood stages, many aspects of malarial PKG regulation, including the importance of phosphorylation, remain poorly understood. Here we use genetic and biochemical approaches to show that reduced cGMP binding to cyclic nucleotide binding domain B does not affect in vitro kinase activity but prevents parasite egress. Similarly, we show that phosphorylation of a key threonine residue (T695) in the activation loop is dispensable for kinase activity in vitro but is essential for in vivo PKG function, with loss of T695 phosphorylation leading to aberrant phosphorylation events across the parasite proteome and changes to the substrate specificity of PKG. Our findings indicate that Plasmodium PKG is uniquely regulated to transduce signals crucial for malaria parasite development.
PubMed: 38935780
DOI: 10.1371/journal.ppat.1012360 -
Frontiers in Genetics 2024In recent years, burgeoning research has underscored the pivotal role of non-coding RNA in orchestrating the growth, development, and pathogenesis of various diseases...
In recent years, burgeoning research has underscored the pivotal role of non-coding RNA in orchestrating the growth, development, and pathogenesis of various diseases across organisms. However, despite these advances, our understanding of the specific contributions of long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) to lens development remains notably limited. Clarifying the intricate gene regulatory networks is imperative for unraveling the molecular underpinnings of lens-related disorders. In this study, we aimed to address this gap by conducting a comprehensive analysis of the expression profiles of messenger RNAs (mRNAs), lncRNAs, and circRNAs at critical developmental time points of the mouse lens, encompassing both embryonic (E10.5, E12.5, and E16.5) and postnatal stages (P0.5, P10.5, and P60). Leveraging RNA-sequencing technology, we identified key transcripts pivotal to lens development. Our analysis revealed differentially expressed (DE) mRNAs, lncRNAs, and circRNAs across various developmental stages. Particularly noteworthy, there were 1831 co-differentially expressed (CO-DE) mRNAs, 150 CO-DE lncRNAs, and 13 CO-DE circRNAs identified during embryonic stages. Gene Ontology (GO) enrichment analysis unveiled associations primarily related to lens development, DNA conformational changes, and angiogenesis among DE mRNAs and lncRNAs. Furthermore, employing protein-protein interaction networks, mRNA-lncRNA co-expression networks, and circRNA-microRNA-mRNA networks, we predicted candidate key molecules implicated in lens development. Our findings underscore the pivotal roles of lncRNAs and circRNAs in this process, offering fresh insights into the pathogenesis of lens-related disorders and paving the way for future exploration in this field.
PubMed: 38933921
DOI: 10.3389/fgene.2024.1405715 -
Frontiers in Pharmacology 2024Mefunidone is a novel synthetic compound and is better when compared to pirfenidone for the anti-fibrotic treatment of renal fibrosis in end-stage renal disease. We...
BACKGROUND
Mefunidone is a novel synthetic compound and is better when compared to pirfenidone for the anti-fibrotic treatment of renal fibrosis in end-stage renal disease. We conducted this first-in-human, phase I clinical trial to determine the safety, tolerability, and pharmacokinetic (PK) (including food effect) profiles of mefunidone administered orally as single and multiple ascending doses in healthy subjects.
METHODS
Part A assessed single ascending doses of mefunidone from 25 mg to 800 mg or placebo once daily in the fasting state. Part A also assessed the effect of food on tolerability and PK in the 100 mg cohort. Part B consisted of three treatment groups who received 100 mg, 200 mg, or 400 mg of mefunidone or placebo twice daily (BID, ) on days 1-6 and once in the morning on day 7.
RESULTS
Single oral doses of mefunidone up to 800 mg and multiple doses of mefunidone up to 400 mg BID were all well-tolerated. Mefunidone behaved with ideal dose proportionality within the single-dose range of 50 mg-600 mg and the multiple-dose range of 100 mg BID to 400 mg BID by day 7. High-fat fed conditions led to a delay in T by approximately 1 h and a slight reduction of approximately 20% in C compared to that in fasting conditions, but it did not significantly affect systemic exposure.
CONCLUSION
Mefunidone exhibited favorable pharmacokinetics and safety profiles. The present study informed and supported further developmental clinical studies of mefunidone.
CLINICAL TRIAL REGISTRATION
clinicaltrials.gov, identifier CXHL1900206.
PubMed: 38933669
DOI: 10.3389/fphar.2024.1414066 -
Frontiers in Plant Science 2024leaves are highly valued in traditional Chinese medicine for their substantial concentration of flavonoids, which play a crucial role in manifesting the plant's...
leaves are highly valued in traditional Chinese medicine for their substantial concentration of flavonoids, which play a crucial role in manifesting the plant's therapeutic properties. This study investigated the metabolomic, transcriptomic and proteomic profiles of leaves from two cultivars, (J) and (R), at three different developmental stages. Metabolite identification and analysis revealed a total of 1,412 and 1,421 metabolites with known structures were found. Flavonoids made up of 33%, including 10 significant accumulated icariin analogues. Transcriptomic analysis unveiled totally 41,644 differentially expressed genes (DEGs) containing five encoded genes participated in icariin biosynthesis pathways. Totally, 9,745 differentially expressed proteins (DEPs) were found, including Cluster-47248.2.p1 (UDP-glucuronosy/UDP-glucosyltransferase), Cluster-30441.2.p1 (O-glucosyltransferase), and Cluster-28344.9.p1 (anthocyanidin 3-O-glucoside 2 "-O-glucosyltransferase-like) through proteomics analysis which are involved to icariin biosynthesis. Protein-protein interaction (PPI) assay exhibited, totally 12 proteins showing a strong relationship of false discovery rate (FDR) <0.05 with these three proteins containing 2 leucine-rich repeat receptor kinase-like protein SRF7, and 5 methyl jasmonate esterase 1. Multi-omics connection networks uncovered 237 DEGs and 72 DEPs exhibited significant associations with the 10 icariin analogues. Overall, our integrated omics approach provides comprehensive insights into the regulatory network underlying icariin synthesis in , offering valuable resources for further research and development in medicinal plant cultivation and pharmaceutical applications.
PubMed: 38933461
DOI: 10.3389/fpls.2024.1409601