BackgroundIron (Fe) and zinc (Zn) deficiencies affect more than two billion people globally. Moreover, phytic acid (PA), an essential phosphorus storage molecule, acts at the same time as an inhibitor of Fe and Zn, forming insoluble complexes; thus, there is a need for balanced compositions of these three substances. Biofortification breeding in staple food crops to combat malnutrition is a straightforward approach. However, evaluating the genetic diversity of the gene pool and the trade-offs between grain nutrients and morphophysiological and yield traits is important. Grain colour is influenced by nutrient composition, including that of minerals such as iron. Therefore, diverse germplasms of 813 genotypes, including Triticum aestivum, Triticum durum, and Triticosecale, were screened for grain colour. A core collection of 26 genotypes was evaluated for the micronutrient concentration over two growing seasons. Further, five contrasting genotypes were chosen to estimate the bioavailability of Fe and Zn.ResultsHigh diversity of grain Fe (31–54 mg kg−1) and Zn (15–38 mg kg−1) was found among the genotypes. High heritability estimates (> 80%) and genetic advance as a percentage of the mean (GAM; > 20) for quality traits indicated strong genetic control supported by a strong positive correlation between grain colour and micronutrients. For morphophysiological and yield traits, moderate heritability and GAM indicated that genotypic and environmental factors contributed to the inheritance of these traits. Overall, the Fe and Zn concentrations and their bio-availabilities were highest for bread wheat (34–52 mg kg−1 Fe, 25–37 mg kg−1 Zn, 5 PA:Fe and 7 PA:Zn molar ratios), followed by Triticosecale (44–46 mg kg−1, 27–30 mg kg−1 Zn, 6 PA:Fe and 9 PA:Zn molar ratios) and durum wheat (36–48 mg kg−1 Fe, 24–31 mg kg−1 Zn, 8 PA:Fe and 13 PA:Zn molar ratios).ConclusionsThe desirable genotypes (E-1 coded as TA87, for example) with characteristics of amber/yellow grain colour, high grain yield (5020 kg ha−1), Fe (51 mg kg−1), Zn (37 mg kg−1) and low PA:Fe and Zn ratios (5.3 and 7.4, respectively) should be selected for future breeding programs. The study paves the way to simplify the biofortification breeding efforts by identifying (i) grain colour as a potential morphological marker for Fe, (ii) enhanced bioavailability in bread wheat compared to durum and triticale, (iii) mineral concentration and yield can be improved simultaneously to combat malnutrition without yield penalty. However, the association of grain nutrients and colour should be evaluated in diverse environments to assess stability and heritability of the marker trait as well as nutrients. This information will aid in the selection of suitable breeding approaches for biofortification and yield enhancement for improved food security.

BackgroundAging affects the reparative potency of mesenchymal stem/stromal cells (MSCs) by diminishing their proliferation and differentiation capability; making them unsuitable for regenerative purposes. Earlier we showed that MSCs acquire the expression of CD45 as a consequence of aging, and this increased expression is associated with downregulated expression of osteogenic markers and upregulated expression of adipogenic and osteoclastogenic markers. However, whether CD45 is actively involved in the aging-mediated deregulated differentiation in the MSCs was not elucidated.ResultsIn the present study, we showed that pharmacological inhibition of CD45-specific phosphatase activity in the aged MSCs restores their differentiation potential to young-like. Investigation of the molecular mechanism involved in the process showed that several regulatory kinases like p38, p44/42, Src, and GSK3β are in their dephosphorylated form in the aged MSCs, and importantly, this status gets reversed by the application of a CD45-specific PTP inhibitor. Conversely, pharmacological inhibition of these kinases in young MSCs imposes an aged-like gene expression profile on them. Additionally, we also showed that the secretome of aged MSCs affects the viability and differentiation of primary chondrocytes, and this detrimental effect is reversed by treating aged MSCs with the PTP inhibitor. Our data demonstrate that the aging-mediated expression of CD45 in MSCs alters their differentiation profile by dephosphorylating several kinases and treating the aged MSCs with a CD45 PTP activity inhibitor rejuvenates them.ConclusionsCD45 can be used as an aging marker for mesenchymal stem cells. Alteration of CD45 phosphatase activity could have significant implications for the use of MSCs in regenerative medicine.Graphical abstractThe rejuvenating effect of CD45-specific PTP inhibitor on aged MSCs: Aging diminishes the reparative potency of mesenchymal stem/stromal cells (MSCs) by increasing CD45 expression in them. This increased expression of CD45 leads to the downregulation of osteogenic and chondrogenic markers and upregulation of adipogenic and osteoclastogenic markers. Inhibition of CD45-specific phosphatase activity in aged MSCs restores their differentiation potential to young-like by restoring the phosphorylation status of various regulatory kinases (p38, p44/42, Src, and GSK3β). Elevated expression of osteoclastic markers in aged MSCs, also reversed after CD45-specific PTP inhibitor treatment. These findings suggest that targeting CD45 phosphatase activity could enhance the regenerative capabilities of aged MSCs, making them more suitable for therapeutic applications

BackgroundVaricose veins (VV) are spectrum of common vascular diseases having complex genetic etiology. The Castor Zinc Finger 1 (CASZ1) gene has been involved in vascular development and its variant has shown association with VV in various ethnicities, but CASZ1 susceptibility to VV risk is unexplored in the South Asian Indian population. The objective of this study was to estimate the association of the CASZ1 gene variations and VV susceptibility in the South Asian Indians, and to examine the evolutionary patterns of these variants compared to other populations.MethodologyPopulation based case control analysis was conducted on all CASZ1 variants present in the Global Screening Array, including the established VV variant rs11121615 with a focus on validating and identification of both novel and established genetic markers to capture a full spectrum of population-specific genetic markers unique to studied population group. Linkage disequilibrium patterns and cumulative variant effects were also analyzed, followed by selection pressure assessment using neutrality tests.ResultsThree CASZ1 variants rs72860191 (OR 1.58, 95% CI 1.07–2.32, p = 0.01), rs7519604 (OR 1.43, 95% CI 1.05–1.94, p = 0.01), and rs11121615 (OR 0.69, 95% CI 0.50–0.95, p = 0.02) were observed to be significantly associated with VV. Haplotype analysis identified unique haplotype structure of South Asian Indians compared to other global populations. Moreover, the cumulative OR was observed to be higher than the independently estimated values (OR = 2.41, 95% CI 1.48–3.94), indicating genotypic epistasis of VV associated variants. The neutrality tests revealed balancing selection within CASZ1 in the studied population compared to other populations,ConclusionThe present study identified CASZ1 variants and their epistatic interactions is associated with VV susceptibility supported with evidence of balancing selection, provides crucial insights into the genetic architecture of VV in studied group, highlighting the impact of evolutionary forces on disease susceptibility.

In the progression of gastric cancer (GC), various cell types in the tumor microenvironment (TME) exhibit upregulated expression of programmed death ligand 1 (PD-L1), leading to impaired T-cell function and evasion of immune surveillance. Infection with H. pylori and EBV leads to increased PD-L1 expression in various cell types within TME, resulting in immune suppression and facilitating immune escape of GC cells. In the TME, mesenchymal stem cells (MSCs), M1-like tumor-associated macrophages (MI-like TAM), and myeloid-derived suppressor cells (MDSCs) contribute to the upregulation of PD-L1 expression in GC cells. Conversely, mast cells, M2-like tumor-associated macrophages (M2-like TAM), and tumor-associated neutrophils (TANs) exhibit elevated levels of PD-L1 expression in response to the influence of GC cells. Together, these factors collectively contribute to the upregulation of PD-L1 expression in GC. This review aims to provide a comprehensive summary of the cellular expression patterns of PD-L1 in GC and the underlying molecular mechanisms. Understanding the complex regulatory pathways governing PD-L1 expression may offer novel insights for the development of effective immunotherapeutic interventions.

Fluoride (F), as a natural element found in a wide range of sources such as water and certain foods, has been proven to be beneficial in preventing dental caries, but concerns have been raised regarding its potential deleterious effects on overall health. Sodium fluoride (NaF), another form of F, has the ability to accumulate in reproductive organs and interfere with hormonal regulation and oxidative stress pathways, contributing to reproductive toxicity. While the exact mechanisms of F-induced reproductive toxicity are not fully understood, this review aims to elucidate the mechanisms involved in testicular and ovarian injury. In males, F exposure at different doses has been associated with reduced testis weight, reduced sperm quality in terms of count, motility, and viability, as well as abnormal sperm morphology and disruption of seminiferous tubules by altering hormone levels (especially testosterone), impairing spermatogenesis, and inducing oxidative stress and zinc deficiency. Similarly, administration of F can impact female reproductive health by affecting ovarian function, hormone levels, oocyte quality, and the regularity of the estrous cycle. However, the impact of F exposure on LH, FSH, and GnRH levels is controversial between males and females. In both males and females, F exerts its adverse effects by triggering apoptosis, autophagy, inflammation, mitochondrial dysfunction, reduction in ATP synthesis, and modulation of important genes involved in steroidogenesis. Furthermore, genetic susceptibility and individual variations in F metabolism may contribute to different responses to fluoride exposure.

BackgroundAssam's aromatic Joha rice is a unique rice class famous for its aroma, taste, and nutritional benefits, which fetch high market prices in domestic and international markets. Joha landraces are inherently poor yielders due to their strong aroma and predominantly photoperiod sensitivity. Hybridization involving non-aromatic HYVs improves yield with concomitant loss of quality. In this context, mutation breeding, a sustainable approach where genetic mutations are induced to create desirable traits, often provides useful allelic variation in specific morpho-agronomic traits. The present study delves into the genetic characterization of a photoperiod-insensitive mutant. As part of our mutation breeding programme, this mutant was isolated from a gamma ray-induced M2 population of a Joha rice landrace, Kon Joha.ResultsThe mutant was unique, and a single recessive gene conditions the induced photoperiod insensitivity. Mutant gene tagging involved 402 SSR and InDel markers, and later polymorphic markers were used for bulk segregant analysis (BSA) in the F2 population of ‘mutant × Kalijeera (distant parent)’. BSA revealed an association between the SSR marker RM527 and this mutant trait. This marker is present on chromosome 6 of the rice genome. Using chromosome 6-specific SSR markers in polymorphic screening and BSA revealed another associated marker, RM19725, for the mutant trait. The genomic interval between RM527 and RM19725 harbors a photoperiod-insensitive gene, Hd1, on chromosome 6. Cloning and sequencing of Hd1 genomic fragments from the parents and mutants revealed a single-base deletion in exon 2, leading to a frameshift mutation in the Hd1 protein. This mutation in exon 2 leads to severe structural abnormalities in the CCT domain of the Hd1 protein that is critical for the interaction of the repressing complex with conserved response elements in the florigen gene under long-day conditions, thereby causing photoperiod insensitivity.ConclusionsThe mutant's pleasant aroma and other quality characteristics, comparable to those of the parent cultivar, hold significant promise. They expand its potential use in a structured breeding programme aimed at developing high-value aromatic Joha rice. This rice, resilient to winter- and summer-growing environments and with broad seasonal adaptability, could revolutionize the rice market. The practical value of our research is underscored by this exciting possibility.

BackgroundOutstanding exercise performance has been associated with an exacerbated vagal outflow. Nevertheless, during high-altitude hypobaric-hypoxia (HH), there is a baroreflex-dependent parasympathetic withdrawal and exercise performance deterioration. Notably, vagal control is pivotal in exercise performance, and exogenous oxytocin (OXY) administration has been shown to enhance parasympathetic drive; however, no evidence shows their role in exercise performance during HH. Then, this study aimed to examine the effect of prolonged exogenous oxytocin (OXY) administration on exercise performance during hypobaric hypoxia (HH) in rats.ResultsA vehicle group (n = 6) and an OXY group (n = 6) performed incremental exercise and baroreflex tests during both normobaric normoxia (NN) and HH (PO2: 100 mmHg, simulated 3,500 m) prior (pre-) and after (post-) 14 days of administration. The results showed that at pre-, there were no significant differences in exercise performance between the two groups, while at post-, the OXY group exhibited similar performance between NN and HH, while the Vehicle group maintained a significant decline in performance at HH compared to NN. At post-, the Vehicle group also demonstrated a reset in the baroreflex and a worse bradycardic response in HH, which was reversed in the OXY group, while the hypoxic ventilatory response was similar in both groups.ConclusionThe findings suggest prolonged OXY administration prevents impaired exercise performance and vagal control during short-term HH.

The aberrant expression of placental imprinted genes due to epigenetic alterations during pregnancy can impact fetal development. We investigated the impact of dietary modification of low vitamin B12 with varying doses of folic acid on the epigenetic control of imprinted genes and fetal development using a transgenerational model of C57BL/6J mice. The animals were kept on four distinct dietary combinations based on low vitamin B12 levels and modulated folic acid, mated in the F0 generation within each group. In the F1 generation, each group of mice is split into two subgroups; the sustained group was kept on the same diet, while the transient group was fed a regular control diet. After mating, maternal placenta (F1) and fetal tissues (F2) were isolated on day 20 of gestation. We observed a generation-wise opposite promoter CpG methylation and gene expression trend of the two developmental genes Dlk1 and Grb10, with enhanced gene expression in both the sustained and transient experimental groups in F1 placentae. When fetal development characteristics and gene expression were correlated, there was a substantial negative association between placental weight and Dlk1 expression (r = − 0.49, p < 0.05) and between crown-rump length and Grb10 expression (r = − 0.501, p < 0.05) in fetuses of the F2 generation. Consistent with these results, we also found that H3K4me3 at the promoter level of these genes is negatively associated with all fetal growth parameters. Overall, our findings suggest that balancing vitamin B12 and folic acid levels is important for maintaining the transcriptional status of imprinted genes and fetal development.

BackgroundAquaculture and salmon farming can cause environmental problems due to the pollution of the surrounding waters with nutrients, solid wastes and chemicals, such as antibiotics, which are used for disease control in the aquaculture facilities. Increasing antibiotic resistance in human-impacted environments, such as coastal waters with aquaculture activity, is linked to the widespread use of antibiotics, even at sub-lethal concentrations. In Chile, the world's second largest producer of salmon, aquaculture is considered the primary source of antibiotics residues in the coastal waters of northern Patagonia. Here, we evaluated whether the structure and diversity of marine bacterial community, the richness of antibiotic resistance bacteria and the frequency of antibiotic resistance genes increase in communities from the surface seawater of an area with salmon farming activities, in comparison with communities from an area without major anthropogenic disturbance.ResultsThe taxonomic structure of bacterial community was significantly different between areas with and without aquaculture production. Growth of the culturable fraction under controlled laboratory conditions showed that, in comparison with the undisturbed area, the bacterial community from salmon farms displayed a higher frequency of colonies resistant to the antibiotics used by the salmon industry. A higher adaptation to antibiotics was revealed by a greater proportion of multi-resistant bacteria isolated from the surface seawater of the salmon farming area. Furthermore, metagenomics data revealed a significant higher abundance of antibiotic resistant genes conferring resistance to 11 antibiotic families in the community from salmon farms, indicating that the proportion of bacteria carrying the resistance determinants was overall higher in salmon farms than in the undisturbed site.ConclusionsOur results revealed an association between bacterial communities and antibiotic resistance from surface seawater of a coastal area of Chile. Although the total bacterial community may appear comparable between sites, the cultivation technique allowed to expose a higher prevalence of antibiotic resistant bacteria in the salmon farming area. Moreover, we demonstrated that metagenomics (culture-independent) and phenotypic (culture-dependent) methods are complementary to evaluate the bacterial communities’ risk for antibiotic resistance, and that a human—influenced environment (such as salmon farms) can potentiate bacteria to adapt to environmental stresses, such as antibiotics.