Jiedu Xiaozheng Yin Inhibits the Progression of Colitis Associated Colorectal Cancer by Stimulating Macrophage Polarization Towards an M1 Phenotype via the TLR4 Pathway.

To investigate the effect of Jiedu Xiaozheng Yin (JXY) on the polarization of macrophages in colitis-associated colon cancer (CAC). An orthotopic model of CAC was established to monitor changes in the pathological state of mice. Colon length, number of colon tumors were recorded, and indices for liver, spleen, and thymus were calculated. Hematoxylin and eosin (H&E) staining was employed to observe intestinal mucosal injury and tumor formation. Immunohistochemistry (IHC) staining was utilized to investigate the effect of JXY on M1 and M2 polarization of macrophages in the colonic mucosa of CAC mice. For in vitro experiments, RT-qPCR (Reverse Transcription-quantitative PCR) and flow cytometry were used to observe the effect of JXY on various M1-related molecules such as IL-1ß, TNF-α, iNOS, CD80, CD86, and its phagocytic function as well as M2-related molecules including Arg-1, CD206, and IL-10. Subsequently, after antagonizing the TLR4 pathway with antagonists (TAK242, PDTC, KG501, SR11302, LY294002), the expression of IL-6, TNF-α, iNOS, and IL-1ß mRNA were detected by RT-qPCR. In vivo experiments, the results showed that JXY improved the pathological condition of mice in general. And JXY treatment decreased the shortening of colon length and number of tumors as compared to non-treated CAC mice. Additionally, JXY treatment improved the lesions in the colonic tissue and induced a polarization of intestinal mucosal macrophages towards the M1 phenotype, while inhibiting polarization towards the M2 phenotype. In vitro experiments further confirmed that JXY treatment promoted the activation of macrophages towards the M1 phenotype, leading to increased expression of IL-1ß, TNF-α, iNOS, CD80, CD86, as well as enhanced phagocytic function. JXY treatment concomitantly inhibited the expression of M2-phenotype related molecules Arginase-1 (Arg-1), CD206, and IL-10. Furthermore, JXY inhibited M1-related molecules such as IL-6, TNF-α, iNOS, and IL-1ß after antagonizing the TLR4 pathway. Obviously, JXY could exhibit inhibitory effects on the development of colon tumors in mice with CAC by promoting M1 polarization through TLR4-mediated signaling and impeding M2 polarization of macrophages.

StCoExpNet: a global co-expression network analysis facilitates identifying genes underlying agronomic traits in potatoes.

KEY MESSAGE: We constructed a gene expression atlas and co-expression network for potatoes and identified several novel genes associated with various agronomic traits. This resource will accelerate potato genetics and genomics research. Potato (Solanum tuberosum L.) is the world's most crucial non-cereal food crop and ranks third in food production after wheat and rice. Despite the availability of several potato transcriptome datasets at public databases like NCBI SRA, an effort has yet to be put into developing a global transcriptome atlas and a co-expression network for potatoes. The objectives of our study were to construct a global expression atlas for potatoes using publicly available transcriptome datasets, identify housekeeping and tissue-specific genes, construct a global co-expression network and identify co-expression clusters, investigate the transcriptional complexity of genes involved in various essential biological processes related to agronomic traits, and provide a web server (StCoExpNet) to easily access the newly constructed expression atlas and co-expression network to investigate the expression and co-expression of genes of interest. In this study, we used data from 2299 publicly available potato transcriptome samples obtained from 15 different tissues to construct a global transcriptome atlas. We found that roughly 87% of the annotated genes exhibited detectable expression in at least one sample. Among these, we identified 281 genes with consistent and stable expression levels, indicating their role as housekeeping genes. Conversely, 308 genes exhibited marked tissue-specific expression patterns. We exemplarily linked some co-expression clusters to important agronomic traits of potatoes, such as self-incompatibility, anthocyanin biosynthesis, tuberization, and defense responses against multiple pathogens. The dataset compiled here constitutes a new resource (StCoExpNet), which can be accessed at https://stcoexpnet.julius-kuehn.de . This transcriptome atlas and the co-expression network will accelerate potato genetics and genomics research.

Filaggrin Mutation Status and Prevention of Atopic Dermatitis with Maternal Probiotic Supplementation.

The World Allergy Organization recommends probiotics in the prevention of atopic dermatitis in high-risk populations. Mutations in the filaggrin gene (FLG) result in an increased risk of atopic dermatitis through disruption of the skin keratin layer. This exploratory study investigated whether the preventive effect of maternal probiotics was evident in children with and without FLG mutations. DNA was collected from children (n = 228) from the Probiotic in the Prevention of Allergy among Children in Trondheim (ProPACT) study. Samples were analysed for 3 common FLG mutations (R501X, R2447X, and 2282del4). Overall, 7% of children had heterozygous FLG mutations; each child had only one of the 3 mutations. Mutation status had no association with atopic dermatitis (RR = 1.1; 95% CI 0.5 to 2.3). The risk ratio (RR) for having atopic dermatitis following maternal probiotics was 0.6 (95% CI 0.4 to 0.9) and RR was similar if the child expressed an FLG mutation (RR = 0.6; 95% CI 0.1 to 4.1) or wildtype FLG (RR = 0.6; 95% CI 0.4 to 0.9). The preventive  effect of probiotics for atopic dermatitis was also evident in children without FLG mutation. Larger confirmatory studies are needed.

Using drone-retrieved multispectral data for phenomic selection in potato breeding.

Predictive breeding approaches, like phenomic or genomic selection, have the potential to increase the selection gain for potato breeding programs which are characterized by very large numbers of entries in early stages and the availability of very few tubers per entry in these stages. The objectives of this study were to (i) explore the capabilities of phenomic prediction based on drone-derived multispectral reflectance data in potato breeding by testing different prediction scenarios on a diverse panel of tetraploid potato material from all market segments and considering a broad range of traits, (ii) compare the performance of phenomic and genomic predictions, and (iii) assess the predictive power of mixed relationship matrices utilizing weighted SNP array and multispectral reflectance data. Predictive abilities of phenomic prediction scenarios varied greatly within a range of - 0.15 and 0.88 and were strongly dependent on the environment, predicted trait, and considered prediction scenario. We observed high predictive abilities with phenomic prediction for yield (0.45), maturity (0.88), foliage development (0.73), and emergence (0.73), while all other traits achieved higher predictive ability with genomic compared to phenomic prediction. When a mixed relationship matrix was used for prediction, higher predictive abilities were observed for 20 out of 22 traits, showcasing that phenomic and genomic data contained complementary information. We see the main application of phenomic selection in potato breeding programs to allow for the use of the principle of predictive breeding in the pot seedling or single hill stage where genotyping is not recommended due to high costs.

Trade-offs between root-secreted acid phosphatase and root morphology traits, and their contribution to phosphorus acquisition in Brassica napus.

Oilseed rape (Brassica napus) is one of the most important oil crops in the world and shows sensitivity to low phosphorus (P) availability. In many soils, organic P (Po) is the main component of the soil P pool. Po must be mineralised to Pi through phosphatases, and then taken up by plants. However, the relationship between root-secreted acid phosphatases (APase) and root morphology traits, two important P-acquisition strategies in response to P deficiency, is unclear among B. napus genotypes. This study aimed to understand their relationship and how they affect P acquisition, which is crucial for the sustainable utilisation of agricultural P resources. This study showed significant genotypic variations in root-secreted APase activity per unit root fresh weight (SAP) and total root-secreted APase activity per plant (total SAP) among 350 B. napus genotypes. Seed yield was positively correlated with total SAP but not significantly correlated with SAP. Six root traits of 18 B. napus genotypes with contrasting root biomass were compared under normal Pi, low Pi and Po. Genotypes with longer total root length (TRL) reduced SAP, but those with shorter TRL increased SAP under P deficiency. Additionally, TRL was important in P-acquisition under three P treatments, and total SAP was also important in P-acquisition under Po treatment. In conclusion, trade-offs existed between the two P-acquisition strategies among B. napus genotypes under P-deficient conditions. Total SAP was an important root trait under Po conditions. These results might help to breed B. napus with greater P-acquisition ability under low P availability conditions.

Pollen diet diversity across bee lineages varies with lifestyle rather than colony size.

The shift to a pollen diet and the evolution of more highly organized societies, i.e., eusocial, were key milestones in bee diversification over their evolutionary history, culminating in a high dependence on feeding broods with a large variety of floral resources. Here, we hypothesized that obligatory eusocial bees have a wider diet diversity than their relatives with solitary lifestyles, and this would be related to colony size. To test both hypotheses, we surveyed diet breadth data (palynological analysis) based on the Shannon-Wiener index (H') for 85 bee taxa. We also obtained colony size for 47 eusocial bee species. These data were examined using phylogenetic comparative methods. The results support the generalist strategy as a derived trait for the bee taxa evaluated here. The dietary diversity of eusocial bees (H': 2.1, on average) was 67.5% higher than that of noneusocial bees (H': 1.21, on average). There was, however, no relationship between diet breadth and colony size, indicating that smaller colonies can harvest a pollen variety as diverse as larger colonies. Taken together, these results provide new insights into the impact of lifestyle on the diversity of collected pollen. Furthermore, this work sheds light on an advantage of living in more highly structured societies irrespective of the size of the colony.

The Effect of Micronutrients on Obese Phenotype of Adult Mice Is Dependent on the Experimental Environment.

The environment of the test laboratory affects the reproducibility of treatment effects on physiological phenotypes of rodents and may be attributed to the plasticity of the epigenome due to nutrient-gene-environment interactions. Here, we explored the reproducibility of adding a multi-vitamin-mineral (MVM) mix to a nutrient-balanced high-fat (HF) diet on obesity, insulin resistance (IR), and gene expression in the tissues of adult male mice. Experiments of the same design were conducted in three independent animal facilities. Adult C57BL/6J male mice were fed an HF diet for 6 weeks (diet induced-obesity model) and then continued for 9-12 weeks on the HF diet with or without 5-fold additions of vitamins A, B1, B6, B12, Zn, and 2-fold Se. The addition of the MVM affected body weight, fat mass, gene expression, and markers of IR in all three locations (p < 0.05). However, the direction of the main effects was influenced by the interaction with the experimental location and its associated environmental conditions known to affect the epigenome. In conclusion, MVM supplementation influenced phenotypes and expression of genes related to adipose function in obese adult male mice, but the experimental location and its associated conditions were significant interacting factors. Preclinical studies investigating the relationship between diet and metabolic outcomes should acknowledge the plasticity of the epigenome and implement measures to reproduce studies in different locations.

Allelic variation in the autotetraploid potato: genes involved in starch and steroidal glycoalkaloid metabolism as a case study.

BACKGROUND: Tuber starch and steroidal glycoalkaloid (SGA)-related traits have been consistently prioritized in potato breeding, while allelic variation pattern of genes that underlie these traits is less explored. RESULTS: Here, we focused on the genes involved in two important metabolic pathways in the potato: starch metabolism and SGA biosynthesis. We identified 119 genes consisting of 81 involved in starch metabolism and 38 in the biosynthesis of steroidal glycoalkaloids, and discovered 96,166 allelic variants among 2,169 gene haplotypes in six autotetraploid potato genomes. Comparative analyses revealed an uneven distribution of allelic variants among gene haplotypes and that the vast majority of deleterious mutations in these genes are retained in heterozygous state in the autotetraploid potato genomes. Leveraging full-length cDNA sequencing data, we find that approximately 70% of haplotypes of the 119 genes are transcribable. Population genetic analyses identify starch and SGA biosynthetic genes that are potentially conserved or diverged between potato varieties with varying starch or SGA content. CONCLUSIONS: These results deepen the understanding of haplotypic diversity within functionally important genes in autotetraploid genomes and may facilitate functional characterization of genes or haplotypes contributing to traits related to starch and SGA in potato.

PGAP2-Related Hyperphosphatasia-Mental Retardation Syndrome: Report of a Novel Patient, Toward a Broadening of Phenotypic Spectrum and Therapeutic Perspectives.

PGAP2 gene has been known to be the cause of "hyperphosphatasia, mental retardation syndrome-3" (HPMRS3). To date, 14 pathogenic variants in PGAP2 have been identified as the cause of this syndrome in 24 patients described in single-case reports or small clinical series with pan-ethnic distribution. We aim to present a pediatric PGAP2-mutated case, intending to further expand the clinical phenotype of the syndrome and to report our experience on a therapeutic approach to drug-resistant epilepsy.We present the clinical, neuroradiological, and genetic characterization of a Caucasian pediatric subject with biallelic pathogenic variants in the PGAP2 gene revealed by next generation sequencing analysis.We identified a subject who presented with global developmental delay and visual impairment. Brain magnetic resonance imaging showed mild hypoplasia of the inferior cerebellar vermis and corpus callosum and mild white matter reduction. Laboratory investigations detected an increase in alkaline phosphatase. At the age of 13 months, he began to present epileptic focal seizures with impaired awareness, which did not respond to various antiseizure medications. Electroencephalogram (EEG) showed progressive background activity disorganization and multifocal epileptic abnormalities. Treatment with high-dose pyridoxine showed partial benefit, but the persistence of seizures and the lack of EEG amelioration prompted us to introduce ketogenic diet treatment.Our case provides a further phenotypical expansion of HPMRS3 to include developmental and epileptic encephalopathy. Due to the limited number of patients reported so far, the full delineation of the clinical spectrum of HPMRS3 and indications for precision medicine would benefit from the description of new cases and their follow-up evaluations.

Veterinary systems biology for bridging the phenotype-genotype gap via computational modeling for disease epidemiology and animal welfare.

Veterinary systems biology is an innovative approach that integrates biological data at the molecular and cellular levels, allowing for a more extensive understanding of the interactions and functions of complex biological systems in livestock and veterinary science. It has tremendous potential to integrate multi-omics data with the support of vetinformatics resources for bridging the phenotype-genotype gap via computational modeling. To understand the dynamic behaviors of complex systems, computational models are frequently used. It facilitates a comprehensive understanding of how a host system defends itself against a pathogen attack or operates when the pathogen compromises the host's immune system. In this context, various approaches, such as systems immunology, network pharmacology, vaccinology and immunoinformatics, can be employed to effectively investigate vaccines and drugs. By utilizing this approach, we can ensure the health of livestock. This is beneficial not only for animal welfare but also for human health and environmental well-being. Therefore, the current review offers a detailed summary of systems biology advancements utilized in veterinary sciences, demonstrating the potential of the holistic approach in disease epidemiology, animal welfare and productivity.

Heterogeneity of sensitization profiles and clinical phenotypes among patients with seasonal allergic rhinitis in Southern European countries-The @IT.2020 multicenter study.

BACKGROUND: Pollen allergy poses a significant health and economic burden in Europe. Disease patterns are relatively homogeneous within Central and Northern European countries. However, no study broadly assessed the features of seasonal allergic rhinitis (SAR) across different Southern European countries with a standardized approach. OBJECTIVE: To describe sensitization profiles and clinical phenotypes of pollen allergic patients in nine Southern European cities with a uniform methodological approach. METHODS: Within the @IT.2020 multicenter observational study, pediatric and adult patients suffering from SAR were recruited in nine urban study centers located in seven countries. Clinical questionnaires, skin prick tests (SPT) and specific IgE (sIgE) tests with a customized multiplex assay (Euroimmun Labordiagnostika, Lübeck, Germany) were performed. RESULTS: Three hundred forty-eight children (mean age 13.1 years, SD: 2.4 years) and 467 adults (mean age 35.7 years SD: 10.0 years) with a predominantly moderate to severe, persistent phenotype of SAR were recruited. Grass pollen major allergenic molecules (Phl p 1 and/or Phl p 5) ranged among the top three sensitizers in all study centers. Sensitization profiles were very heterogeneous, considering that patients in Rome were highly poly-sensitized (sIgE to 3.8 major allergenic molecules per patient), while mono-sensitization was prominent and heterogeneous in other cities, such as Marseille (sIgE to Cup a 1: n = 55/80, 68.8%) and Messina (sIgE to Par j 2: n = 47/82, 57.3%). Co-sensitization to perennial allergens, as well as allergic comorbidities also broadly varied between study centers. CONCLUSIONS: In Southern European countries, pollen allergy is heterogeneous in terms of sensitization profiles and clinical manifestations. Despite the complexity, a unique molecular, multiplex, and customized in-vitro IgE test detected relevant sensitization in all study centers. Nevertheless, this geographical diversity in pollen allergic patients imposes localized clinical guidelines and study protocols for clinical trials of SAR in this climatically complex region.

SCFAs Supplementation Rescues Anxiety- and Depression-like Phenotypes Generated by Fecal Engraftment of Treatment-Resistant Depression Rats.

Alteration of gut microbiota and microbial metabolites such as short-chain fatty acids (SCFAs) coexisted with stress-generated brain disorders, including depression. Herein, we investigated the effect of SCFAs in a treatment-resistant depression (TRD) model of rat. Rats were exposed to chronic-unpredictable mild stress (CUMS) and repeated adrenocorticotropic hormone (ACTH) injections to generate a TRD-like phenotype. The cecal contents of these animals were engrafted into healthy-recipient rats and allowed to colonize for 4 weeks (TRD-FMT group). Blood, brain, colon, fecal, and cecal samples were collected for molecular studies. Rats exposed to CUMS + ACTH showed TRD-like phenotypes in sucrose-preference (SPT), forced swim (FST), and elevated plus maze (EPM) tests. The TRD-FMT group also exhibited anxiety- and depression-like behaviors. Administration of SCFAs (acetate, propionate, and butyrate at 67.5, 25, and 40 mM, respectively) for 7 days exerted robust antidepressant and antianxiety effects by restoring the levels of SCFAs in plasma and fecal samples, and proinflammatory cytokines (TNF-α and IL-6), serotonin, GABA, norepinephrine, and dopamine in the hippocampus and/or frontal cortex of TRD and TRD-FMT animals. SCFAs treatment elevated the expression of free-fatty acid receptors 2/3, BDNF, doublecortin, and zonula-occludens, and reduced the elevated plasma levels of kynurenine and quinolinic acid and increased mucus-producing goblet cells in TRD and TRD-FMT animals. In 16S sequencing results, decreased microbial diversity in TRD rats corresponds with differences in the genus of Faecalibacterium, Anaerostipes, Allobaculum, Blautia, Peptococcus, Rombustia, Ruminococcaceae_UCG-014, Ruminococcaceae_UCG-002, Solobacterium, Subdolibacterium, and Eubacterium ventriosum. SCFAs may impart beneficial effects via modulation of tryptophan metabolism, inflammation, neurotransmitters, and microbiota-gut-brain axis in TRD rats.

Bartter syndrome-like phenotype in a patient with type 2 diabetes mellitus.

Bartter syndrome (BS) is a rare genetic tubulopathy affecting the loop of Henle leading to salt wasting. It is commonly seen in utero or in the early neonatal period. Rare cases of acquired BS are reported in association with infections like tuberculosis, granulomatous conditions like sarcoidosis, autoimmune diseases and drugs. The mainstay of management includes potassium, calcium and magnesium supplementation. We report the case of a woman in her 50s with a history of type 2 diabetes mellitus for the last 10 years, who presented with diabetic foot ulcers and generalised weakness with ECG changes suggestive of hypokalaemia. She had severe hypokalaemia with high urine potassium excretion and hypochloraemic metabolic alkalosis. She poorly responded to intravenously administered potassium supplements and had persistent hypokalaemia. On further evaluation of the persistent hypokalaemia, a diagnosis of idiopathic Bartter-like phenotype was made. She responded well to tablet indomethacin and is presently asymptomatic and is being maintained on tablet indomethacin after 6 months of follow-up.

[Zhuyu Pills promote polarization of macrophages toward M2 phenotype to prevent atherosclerosis via PPARγ/NF-κB signaling pathway].

This article aims to investigate the effect of Zhuyu Pills on atherosclerosis and decipher the underlying mechanism. The mouse model of atherosclerosis was induced by a high-fat diet, and the total modeling period was 12 weeks. A total of 47 ApoE~(-/-) mice successfully modeled were randomized into 5 groups, including 10 in the model group, 9 in each of low-, medium-, and high-dose(130.54, 261.08 and 522.16 mg·kg~(-1)·d~(-1), respectively) Zhuyu Pills groups, and 10 in the atorvastatin calcium(10.40 mg·kg~(-1)·d~(-1)) group. In addition, 10 C57BL/6J mice were included as the normal group. The mice in the normal group and model group were administrated with an equal volume of sterile distilled water, and those in other groups with corresponding agents by gavage once a day for 12 weeks. At the end of drug intervention, the levels of total cholesterol(TC), triglyceride(TG), high-density lipoprotein cholesterol(HDL-C), and low-density lipoprotein cholesterol(LDL-C) were measured by the biochemical method. Hematoxylin-eosin(HE) staining was employed to observe the plaque distribution in the aortic region. The serum levels of pro-inflammatory cytokines tumor necrosis factor-α(TNF-α) and interleukin(IL)-6 in M1 macrophages and anti-inflammatory cytokines IL-13 and IL-4 in M2 macrophages were determined by enzyme-linked immunosorbent assay(ELISA). The expression levels of inducible nitric oxide synthase(iNOS) and arginase-1(Arg-1) were examined by immunofluorescence. Real-time fluorescence quantitative polymerase chain reaction(real-time PCR) was employed to measure the mRNA levels of peroxisome proliferator-activated receptor γ(PPARγ), nuclear factor-κB(NF-κB), Arg-1, and iNOS in the aorta. Western blot was employed to determine the protein levels of PPARγ and NF-κB in the aorta. The results showed that compared with the normal group, the modeling elevated the TC, TG, and LDL-C levels, lowered the HDL-C level, caused large area thickening of the aortic intima, elevated the TNF-α and IL-6 levels, lowered the IL-4 and IL-13 levels, down-regulated the mRNA and protein levels of PPARγ and Arg-1, and up-regulated the mRNA and protein levels of iNOS and NF-κB in the aorta(P<0.01). Compared with the model group, low-, medium-, and high-dose Zhuyu Pills and atorvastatin calcium lowered the TC, TG, and LDL-C levels, elevated the HDL-C level, reduced the plaque area in a concentration-dependent manner, lowered the TNF-α and IL-6 levels, elevated the IL-4 and IL-13 levels, up-regulated the mRNA and protein levels of PPARγ and Arg-1, and down-regulated the mRNA and protein levels of NF-κB and iNOS in the aorta(P<0.05 or P<0.01). In conclusion, Zhuyu Pills may play an anti-atherosclerosis role by regulating PPARγ/NF-κB signaling pathway, inhibiting the polarization of macrophages toward the M1 phenotype, promoting the polarization of macrophages toward the M2 phenotype, and improving the inflammatory microenvironment of macrophages.

A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder.

Nicotinamide adenine dinucleotide (NAD) is essential for embryonic development. To date, biallelic loss-of-function variants in 3 genes encoding nonredundant enzymes of the NAD de novo synthesis pathway - KYNU, HAAO, and NADSYN1 - have been identified in humans with congenital malformations defined as congenital NAD deficiency disorder (CNDD). Here, we identified 13 further individuals with biallelic NADSYN1 variants predicted to be damaging, and phenotypes ranging from multiple severe malformations to the complete absence of malformation. Enzymatic assessment of variant deleteriousness in vitro revealed protein domain-specific perturbation, complemented by protein structure modeling in silico. We reproduced NADSYN1-dependent CNDD in mice and assessed various maternal NAD precursor supplementation strategies to prevent adverse pregnancy outcomes. While for Nadsyn1+/- mothers, any B3 vitamer was suitable to raise NAD, preventing embryo loss and malformation, Nadsyn1-/- mothers required supplementation with amidated NAD precursors (nicotinamide or nicotinamide mononucleotide) bypassing their metabolic block. The circulatory NAD metabolome in mice and humans before and after NAD precursor supplementation revealed a consistent metabolic signature with utility for patient identification. Our data collectively improve clinical diagnostics of NADSYN1-dependent CNDD, provide guidance for the therapeutic prevention of CNDD, and suggest an ongoing need to maintain NAD levels via amidated NAD precursor supplementation after birth.

Repeated immunization with ATRA-containing liposomal adjuvant transdifferentiates Th17 cells to a Tr1-like phenotype.

In many autoimmune diseases, autoantigen-specific Th17 cells play a pivotal role in disease pathogenesis. Th17 cells can transdifferentiate into other T cell subsets in inflammatory conditions, however, there have been no attempts to target Th17 cell plasticity using vaccines. We investigated if autoantigen-specific Th17 cells could be specifically targeted using a therapeutic vaccine approach, where antigen was formulated in all-trans retinoic acid (ATRA)-containing liposomes, permitting co-delivery of antigen and ATRA to the same target cell. Whilst ATRA was previously found to broadly reduce Th17 responses, we found that antigen formulated in ATRA-containing cationic liposomes only inhibited Th17 cells in an antigen-specific manner and not when combined with an irrelevant antigen. Furthermore, this approach shifted existing Th17 cells away from IL-17A expression and transcriptomic analysis of sorted Th17 lineage cells from IL-17 fate reporter mice revealed a shift of antigen-specific Th17 cells to exTh17 cells, expressing functional markers associated with T cell regulation and tolerance. In the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, vaccination with myelin-specific (MOG) antigen in ATRA-containing liposomes reduced Th17 responses and alleviated disease. This highlights the potential of therapeutic vaccination for changing the phenotype of existing Th17 cells in the context of immune mediated diseases.

Pharmacological management of fragile X syndrome: a systematic review and narrative summary of the current evidence.

INTRODUCTION: Fragile X syndrome (FXS) is the most common inherited cause of Intellectual Disability. There is a broad phenotype that includes deficits in cognition and behavioral changes, alongside physical characteristics. Phenotype depends upon the level of mutation in the FMR1 (fragile X messenger ribonucleoprotein 1) gene. The molecular understanding of the impact of the FMR1 gene mutation provides an opportunity to target treatment not only at symptoms but also on a molecular level. METHODS: We conducted a systematic review to provide an up-to-date narrative summary of the current evidence for pharmacological treatment in FXS. The review was restricted to randomized, blinded, placebo-controlled trials. RESULTS: The outcomes from these studies are discussed and the level of evidence assessed against validated criteria. The initial search identified 2377 articles, of which 16 were included in the final analysis. CONCLUSION: Based on this review to date there is limited data to support any specific pharmacological treatments, although the data for cannabinoids are encouraging in those with FXS and in future developments in gene therapy may provide the answer to the search for precision medicine. Treatment must be person-centered and consider the combination of medical, genetic, cognitive, and emotional challenges.

Understanding the Molecular Regulatory Networks of Seed Size in Soybean.

Soybean being a major cash crop provides half of the vegetable oil and a quarter of the plant proteins to the global population. Seed size traits are the most important agronomic traits determining the soybean yield. These are complex traits governed by polygenes with low heritability as well as are highly influenced by the environment as well as by genotype x environment interactions. Although, extensive efforts have been made to unravel the genetic basis and molecular mechanism of seed size in soybean. But most of these efforts were majorly limited to QTL identification, and only a few genes for seed size were isolated and their molecular mechanism was elucidated. Hence, elucidating the detailed molecular regulatory networks controlling seed size in soybeans has been an important area of research in soybeans from the past decades. This paper describes the current progress of genetic architecture, molecular mechanisms, and regulatory networks for seed sizes of soybeans. Additionally, the main problems and bottlenecks/challenges soybean researchers currently face in seed size research are also discussed. This review summarizes the comprehensive and systematic information to the soybean researchers regarding the molecular understanding of seed size in soybeans and will help future research work on seed size in soybeans.

Unlocking dynamic root phenotypes for simultaneous enhancement of water and phosphorus uptake.

Phosphorus (P) and water are crucial for plant growth, but their availability is challenged by climate change, leading to reduced crop production and global food security. In many agricultural soils, crop productivity is confronted by both water and P limitations. The diminished soil moisture decreases available P due to reduced P diffusion, and inadequate P availability diminishes tissue water status through modifications in stomatal conductance and a decrease in root hydraulic conductance. P and water display contrasting distributions in the soil, with P being concentrated in the topsoil and water in the subsoil. Plants adapt to water- and P-limited environments by efficiently exploring localized resource hotspots of P and water through the adaptation of their root system. Thus, developing cultivars with improved root architecture is crucial for accessing and utilizing P and water from arid and P-deficient soils. To meet this goal, breeding towards multiple advantageous root traits can lead to better cultivars for water- and P-limited environments. This review discusses the interplay of P and water availability and highlights specific root traits that enhance the exploration and exploitation of optimal resource-rich soil strata while reducing metabolic costs. We propose root ideotype models, including 'topsoil foraging', 'subsoil foraging', and 'topsoil/subsoil foraging' for maize (monocot) and common bean (dicot). These models integrate beneficial root traits and guide the development of water- and P-efficient cultivars for challenging environments.

OsbZIP1 regulates phosphorus uptake and nitrogen utilization, contributing to improved yield.

Increasing nutrient uptake and use efficiency in plants can contribute to improved crop yields and reduce the demand for fertilizers in crop production. In this study, we characterized a rice mutant, 88n which showed long roots under low nitrogen (N) or phosphorus (P) conditions. Low expression levels of N transporter genes were observed in 88n root, and total N concentration in 88n shoots were decreased, however, C concentrations and shoot dry weight in 88n were comparable to that in WT. Therefore, 88n showed high nitrogen utilization efficiency (NUtE). mRNA accumulation of Pi transporter genes was higher in 88n roots, and Pi concentration and uptake activity were higher in 88n than in WT. Therefore, 88n also showed high phosphorus uptake efficiency (PUpE). Molecular genetic analysis revealed that the causal gene of 88n phenotypes was OsbZIP1, a monocot-specific ortholog of the A. thaliana bZIP transcription factor HY5. Similar to the hy5 mutant, chlorophyll content in roots was decreased and root angle was shallower in 88n than in WT. Finally, we tested the yield of 88n in paddy fields over 3 years because 88n mutant plants showed higher PUpE and NUtE activity and different root architecture at the seedling stage. 88n showed large panicles and increased panicle weight/plant. Taken together, a mutation in OsbZIP1 could contribute to improved crop yields.