The choroid plexus (CP) compartment in the ventricles of the brain comprises fenestrated vasculature and, therefore, it is permeable to blood-borne mediators of inflammation. Here, we explored whether T-cell activation in the CP plays a role in regulating central nervous system (CNS) inflammation. We show that CD4 T cells injected into the lateral ventricles adhere to the CP, transmigrate across its epithelium, and undergo antigen-specific activation and proliferation. This process is enhanced following peripheral immune stimulation and significantly impacts the immune signaling induced by the CP. Ex vivo studies demonstrate that T-cell harboring the CP through its apical surface is a chemokine- and adhesion molecule-dependent process. We suggest that, within the CNS, the CP serves an immunological niche, which rapidly responds to peripheral inflammation and, thereby, promotes two-way T-cell trafficking that impact adaptive immunity in the CNS.

End-stage renal disease (ESRD) is associated with an increased susceptibility to infectious diseases, including infection with Mycobacterium tuberculosis (Mtb). Mucosal-associated invariant T (MAIT) cells recognize vitamin B metabolites produced by many bacterial species, including Mtb, and may play an important role in providing protective immunity against tuberculosis infection in the lung. To date, little is known about MAIT cell frequency, phenotype, or function in ESRD patients.

Cyclic dinucleotides are bacterial signal transducers that bind to host intracellular protein, stimulator of interferon genes (STING) encoded by Tmem173. In this study, we demonstrate that STING triggers adaptive immune responses that control Th17 differentiation. Cyclic dinucleotides recognition enables classical dendritic cells (cDCs) that predominantly express CD103 to induce Th17 lymphocytes in an IL-6/IL-1β-dependent manner in gut. STING expression in human lamina propria is associated with the severity of mucosal inflammation and clinical disease activity in patients with Crohn's disease. Mice deficient in Tmem173 fail to mount Th17 responses to cyclic dinucleotides or prevent immune evasion of enteroinvasive pathogens. In summary, STING in mucosal cDCs controls Th17 subspecification that is essential for host defenses against microbial infection in gut-associated immune system.

The role of tyrosyl-DNA phosphodiesterase 2 (Tdp2) involved in the repair of 5'-end-blocking DNA lesions is still poorly explored in plants. To gain novel insights, Medicago truncatula suspension cultures overexpressing the MtTdp2α gene (Tdp2α-13C and Tdp2α-28 lines, respectively) and a control (CTRL) line carrying the empty vector were investigated. Transmission electron microscopy (TEM) revealed enlarged nucleoli (up to 44% expansion of the area, compared to CTRL), the presence of nucleolar vacuoles, increased frequency of multinucleolate cells (up to 4.3-fold compared to CTRL) and reduced number of ring-shaped nucleoli in Tdp2α-13C and Tdp2α-28 lines. Ultrastructural data suggesting for enhanced nucleolar activity in MtTdp2α-overexpressing lines were integrated with results from bromouridine incorporation. The latter revealed an increase of labeled transcripts in both Tdp2α-13C and Tdp2α-28 cells, within the nucleolus and in the extra-nucleolar region. MtTdp2α-overexpressing cells showed tolerance to etoposide, a selective inhibitor of DNA topoisomerase II, as evidenced by DNA diffusion assay. TEM analysis revealed etoposide-induced rearrangements within the nucleolus, resembling the nucleolar caps observed in animal cells under transcription impairment. Based on these findings it is evident that MtTdp2α-overexpression enhances nucleolar activity in plant cells.

Elemental selenium is one of the dominant selenium species in soil, but the mechanism of its uptake by plants is still unclear. In this study, nanoparticles of elemental selenium (SeNPs) with different sizes were prepared, and their uptake and transformation in wheat (Triticum aestivum L.) were analyzed in hydroponic experiments by HPLC-ICP-MS. We found that the SeNPs can be absorbed by wheat seedlings, and the process is energy independent. The addition of aquaporins inhibitor caused 92.5 and 93.4% inhibition of chemosynthesized SeNPs (CheSeNPs) and biosynthesized SeNPs (BioSeNPs) absorption by wheat roots, respectively. The 40 nm SeNPs uptake by wheat roots was 1.8-fold and 2.2-fold higher than that of 140 and 240 nm, respectively. The rate of SeNPs uptake in wheat was much slower than that of selenite [Se (IV)], and CheSeNPs were more efficiently absorbed than BioSeNPs. The SeNPs were rapidly oxidized to Se (IV) and converted to organic forms [selenocystine (SeCys2), se-methyl-selenocysteine (MeSeCys), and selenomethionine (SeMet)] after they were absorbed by wheat roots. Additionally, we demonstrated that the aquaporin function in some way is related to the absorption of SeNPs. The particle size and synthesis method of the SeNPs affected their uptake rates by plants. Taken together, our results provide a deep understanding of the SeNPs uptake mechanism in plants.

Nrat1 is a member of the natural resistance-associated macrophage protein (Nramp) family of metal ion transporters in all organisms. Different from other Nramp members capable of transporting divalent metals, Nrat1 specifically transports trivalent aluminum (Al) ion. However, molecular mechanism underlying the Al transport selectivity of Nrat1 remains unknown. Here, we performed structure-function analyses of Nrat1 and other Nramp members to gain insights into the determinants of ion selectivity. A phylogenetic analysis showed that plant Nramp transporters could be divided into five groups. OsNrat1 was found in one of the individual clades and clustered with SbNrat1 and ZmNrat1 on the evolutionary tree. Structural modeling revealed that Nrat1 transporters adopted a common LeuT fold shared by many Nramp-family transporters that likely employed an identical transport mechanism. Sequence alignment and evolutionary conservation analysis of amino acids identified a metal-permeation pathway of Nrat1 centered at the metal binding site. The metal binding site of Nrat1 was characterized by two conserved sequence motifs, i.e., the Asp-Pro-Ser-Asn motif (motif A) and the Ala-Ile-Ile-Thr motif (motif B). Replacement of the Ala-Met-Val-Met motif B of the OsNramp3 manganese (Mn) transporter to that of Nrat1 resulted in a partial gain of Al transport activity and a total loss of Mn in yeast. Conversely, substitution of the motif B of OsNrat1 with that of OsNramp3 altered the Al transport activity. These observations indicated the metal binding site, particularly the motif B, as a key determinant of Al selectivity of Nrat1.

Reference genome sequences have become key platforms for genetics and breeding of the major crop species. Sugarcane is probably the largest crop produced in the world (in weight of crop harvested) but lacks a reference genome sequence. Sugarcane has one of the most complex genomes in crop plants due to the extreme level of polyploidy. The genome of modern sugarcane hybrids includes sub-genomes from two progenitors Saccharum officinarum and S. spontaneum with some chromosomes resulting from recombination between these sub-genomes. Advancing DNA sequencing technologies and strategies for genome assembly are making the sugarcane genome more tractable. Advances in long read sequencing have allowed the generation of a more complete set of sugarcane gene transcripts. This is supporting transcript profiling in genetic research. The progenitor genomes are being sequenced. A monoploid coverage of the hybrid genome has been obtained by sequencing BAC clones that cover the gene space of the closely related sorghum genome. The complete polyploid genome is now being sequenced and assembled. The emerging genome will allow comparison of related genomes and increase understanding of the functioning of this polyploidy system. Sugarcane breeding for traditional sugar and new energy and biomaterial uses will be enhanced by the availability of these genomic resources.

Chemical derivatives of artemisinin, a sesquiterpene lactone produced by Artemisia annua, are the active ingredient in the most effective treatment for malaria. Comprehensive phytochemical analysis of two contrasting chemotypes of A. annua resulted in the characterization of over 80 natural products by NMR, more than 20 of which are novel and described here for the first time. Analysis of high- and low-artemisinin producing (HAP and LAP) chemotypes of A. annua confirmed the latter to have a low level of DBR2 (artemisinic aldehyde Δ11(13) reductase) gene expression. Here we show that the LAP chemotype accumulates high levels of artemisinic acid, arteannuin B, epi-deoxyarteannuin B and other amorpha-4,11-diene derived sesquiterpenes which are unsaturated at the 11,13-position. By contrast, the HAP chemotype is rich in sesquiterpenes saturated at the 11,13-position (dihydroartemisinic acid, artemisinin and dihydro-epi-deoxyarteannunin B), which is consistent with higher expression levels of DBR2, and also with the presence of a HAP-chemotype version of CYP71AV1 (amorpha-4,11-diene C-12 oxidase). Our results indicate that the conversion steps from artemisinic acid to arteannuin B, epi-deoxyarteannuin B and artemisitene in the LAP chemotype are non-enzymatic and parallel the non-enzymatic conversion of DHAA to artemisinin and dihyro-epi-deoxyarteannuin B in the HAP chemotype. Interestingly, artemisinic acid in the LAP chemotype preferentially converts to arteannuin B rather than the endoperoxide bridge containing artemisitene. In contrast, in the HAP chemotype, DHAA preferentially converts to artemisinin. Broader metabolomic and transcriptomic profiling revealed significantly different terpenoid profiles and related terpenoid gene expression in these two morphologically distinct chemotypes.

PIGT encodes a subunit of the glycosylphosphatidylinositol transamidase complex, which catalyzes the attachment of proteins to GPI-anchors. A homozygous PIGT variant c.550G>A (p. E184K) in a Chinese boy with multiple malformations, hypotonia, seizure and profound development delay was identified by panel sequencing. Pathogenicity of the variant was confirmed by flow cytometry. The expression of CD16 and CD24 of this proband reduced to 16.92 and 22.16% compare with normal control respectively while which of his parents and sister were normal. This mutation raised the mRNA level on the peripheral blood mono nuclear cells of this patient. This study expanded the variant spectrum of MCAHS3, and CD16 could be an effective marker to evaluate the pathogenicity of PIGT mutation.

Heterosis, the superiority of hybrids over their parents for quantitative traits, represents a crucial issue in plant and animal breeding as well as evolutionary biology. Heterosis has given rise to countless genetic, genomic and molecular studies, but has rarely been investigated from the point of view of systems biology. We hypothesized that heterosis is an emergent property of living systems resulting from frequent concave relationships between genotypic variables and phenotypes, or between different phenotypic levels. We chose the enzyme-flux relationship as a model of the concave genotype-phenotype (GP) relationship, and showed that heterosis can be easily created in the laboratory. First, we reconstituted in vitro the upper part of glycolysis. We simulated genetic variability of enzyme activity by varying enzyme concentrations in test tubes. Mixing the content of "parental" tubes resulted in "hybrids," whose fluxes were compared to the parental fluxes. Frequent heterotic fluxes were observed, under conditions that were determined analytically and confirmed by computer simulation. Second, to test this model in a more realistic situation, we modeled the glycolysis/fermentation network in yeast by considering one input flux, glucose, and two output fluxes, glycerol and acetaldehyde. We simulated genetic variability by randomly drawing parental enzyme concentrations under various conditions, and computed the parental and hybrid fluxes using a system of differential equations. Again we found that a majority of hybrids exhibited positive heterosis for metabolic fluxes. Cases of negative heterosis were due to local convexity between certain enzyme concentrations and fluxes. In both approaches, heterosis was maximized when the parents were phenotypically close and when the distributions of parental enzyme concentrations were contrasted and constrained. These conclusions are not restricted to metabolic systems: they only depend on the concavity of the GP relationship, which is commonly observed at various levels of the phenotypic hierarchy, and could account for the pervasiveness of heterosis.

Circular RNAs (circRNAs), expressed abundantly and universally in various eukaryotes, are involved in growth and development of animals. Our previous study on circRNA sequencing revealed that circSVIL, an exonic circular, expressed differentially among skeletal muscle at 11 embryo age (E11), 16 embryo age (E16), and 1 day post-hatch (P1). In this study, we aim to investigate the effect of circSVIL on the development of skeletal muscle. We detected the expression level of circSVIL in embryonic leg muscle during E10 to P1. As a result, we found that circSVIL had a high expression level during late embryonic development of skeletal muscle. Through dual-luciferase assay, RNA immunoprecipitation and biotin-coupled miRNA pull down, we found chicken circSVIL could functions as miR-203 sponges and upregulated the mRNA level of c-JUN and MEF2C. In chicken, circSVIL could promote the proliferation and differentiation of myoblast, and antagonize the functions of miR-203. Altogether our data suggest that circSVIL promotes the embryonic skeletal muscle development by sequestering miR-203 in chicken.

To life scientists, one important feature offered by RNAseq, a next-generation sequencing tool used to estimate changes in gene expression levels, lies in its unprecedented resolution. It can score countable differences in transcript numbers among thousands of genes and between experimental groups, all at once. However, its high cost limits experimental designs to very small sample sizes, usually N = 3, which often results in statistically underpowered analysis and poor reproducibility. All these issues are compounded by the presence of experimental noise, which is harder to distinguish from instrumental error when sample sizes are limiting (e.g., small-budget pilot tests), experimental populations exhibit biologically heterogeneous or diffuse expression phenotypes (e.g., patient samples), or when discriminating among transcriptional signatures of closely related experimental conditions (e.g., toxicological modes of action, or MOAs). Here, we present a leveraged signal-to-noise ratio (LSTNR) thresholding method, founded on generalized linear modeling (GLM) of aligned read detection limits to extract differentially expressed genes (DEGs) from noisy low-replication RNAseq data. The LSTNR method uses an agnostic independent filtering strategy to define the dynamic range of detected aggregate read counts per gene, and assigns statistical weights that prioritize genes with better sequencing resolution in differential expression analyses. To assess its performance, we implemented the LSTNR method to analyze three separate datasets: first, using a systematically noisy in silico dataset, we demonstrated that LSTNR can extract pre-designed patterns of expression and discriminate between "noise" and "true" differentially expressed pseudogenes at a 100% success rate; then, we illustrated how the LSTNR method can assign patient-derived breast cancer specimens correctly to one out of their four reported molecular subtypes (luminal A, luminal B, Her2-enriched and basal-like); and last, we showed the ability to retrieve five different modes of action (MOA) elicited in livers of rats exposed to three toxicants under three nutritional routes by using the LSTNR method. By combining differential measurements with resolving power to detect DEGs, the LSTNR method offers an alternative approach to interrogate noisy and low-replication RNAseq datasets, which handles multiple biological conditions at once, and defines benchmarks to validate RNAseq experiments with standard benchtop assays.

Hypothyroidism (HT) and hypoparathyroidism (HPT) are common endocrine complications in thalassemia major (TM) patients.

Colorectal disease is common throughout the world, but the spectrum of diagnoses across Africa remains largely unexplored. There is anecdotal evidence of changing colorectal disease but this has not been systematically investigated. The aim of this study was to enhance our insight into the spectrum of colonoscopic diagnoses in Zambia.

Background: Xerostomia is a very relevant and frequent complication of radiotherapy, causing the irradiated oral mucosa to be affected by bacterial, fungal and viral infections. Objective: The objective of this study was to evaluate a possible relationship between oral shedding of human herpesviruses and xerostomia in patients with squamous cell carcinoma of head and neck submitted to radio/chemotherapy. Methods: In this study, oral rinse samples were collected weekly from 20 patients during radiotherapy. The samples were submitted to PCR and enzymatic digestion for detection of human herpesviruses. Xerostomia was evaluated according to the Seminars in Radiation Oncology criteria. Results: There was a higher frequency of grade 1 xerostomia (51.4%), observed first in the 1st week of radiotherapy. In the 4th week of radiotherapy, all patients presented some degree of xerostomia. Analysis of herpesviruses showed oral shedding of EBV, HHV-6 and HHV-7 in all weeks. Considering all the periods, the highest frequency was in patients with EBV excretion (55.0%), which was significantly higher than that of other viruses. Conclusion: We observed that oral shedding of herpesviruses was not affected by xerostomia as there was a progression in their excretion, even with the evolution of xerostomia. This suggested that there is a local replication in the oral cavity that is not completely dependent of salivary excretion.

Objective: This single-centred study aims to evaluate the incidence, risk factors and treatment outcomes of a podiatry led, evidence-based diabetic foot ulcer (DFU) clinic. Research design and methods: Data from the DFU database and patient electronic health records were retrospectively collected from patients with new DFUs who were referred for treatment to the Department of Podiatry, Dasman Diabetes Institute, Kuwait, from 1 October 2014, to 31 December 2016. Patients were followed-up until healing occurred or until 6 months after the study end date, whichever came first. Results: All data were analysed using IBM SPSS version 24 software. Data were collected from 230 patients with 335 DFUs. Most DFUs (67%) were present for <3 months from the time of the first podiatry appointment. A total of 56% of DFUs were classified as neuropathic. Most (72%) DFUs healed, with a median healing time of 52.0 days. Chronic kidney disease (p = 0.001), retinopathy (p = 0.03), smoking (p = 0.02), ulcer location (p = 0.03), peripheral arterial disease (PAD) (p = 0.004) and osteomyelitis (p = 0.05) were found to have a meaningful association with DFU outcome. The number of days to heal was associated with ulcer classification (p = 0.005), bacterial infection (p = 0.002), osteomyelitis (p = < 0.001) and PAD (p = < 0.001). Conclusions: The incidence of new DFUs in our tertiary clinic is 3.4%. The incidence of diabetic foot ulceration, days to heal, healing rate and the risk factors influencing healing are in accordance with other multidisciplinary facilities with podiatry input.

The burden of communicable and non-communicable diseases in Sub-Saharan Africa poses a challenge in achieving quality healthcare. Although therapeutic drugs have generally improved health, their efficacy differs from individual to individual. Variability in treatment response is mainly because of genetic variants that affect the pharmacokinetics and pharmacodynamics of drugs.

Sorting nexin-1 (SNX1) is an important functional protein in cell endocytosis, efflux, protein sorting, cell signal transduction, etc; however, the expression, the role and clinical relevance of SNX1 have not been investigated in gastric cancer (GC). In this study, we first performed a bioinformatics investigation using the data obtained from The Cancer Genome Atlas (TCGA) database. The result showed that SNX1 mRNA levels were significantly lower in GC tissues than in paracancerous tissues. In a study of 150 cases of GC, including 60 cases with paired paracancerous and cancer tissues and 90 cases with detailed follow-up information, SNX1 expression was analyzed by immunohistochemistry. Our study on paired paracancerous and cancer tissues showed that SNX1 protein expression remarkably decreased in GC tissues (50/60, 83.33%). A study on 90 patients with detailed follow-up information showed that tumors with higher SNX1 protein level were correlated with better clinicopathologic stages (p = 0.0285), nodal status (p = 0.0286), smaller tumor sizes (p = 0.0294) and a better survival rate in patients with GC (p = 0.0245). Univariate analysis of the 90 patients with GC showed that low-level SNX1 was significantly correlated with decreased overall survival of GC patients (p = 0.008), and associated with a relatively higher cumulative hazard of death. Exogenous expression of SNX1 inhibited the growth, migration, invasion and promoted the apoptosis and enhanced the sensitivity of GC cells to the chemotherapeutic drug 5-Fluorouracil (5-Fu) in vitro, while knockdown of SNX1 by short hairpin RNA (shRNA) significantly promoted the growth, migration, invasion and reduced the apoptosis and the sensitivity of GC cells to 5-Fu. SNX1 also showed to influence the levels of epithelial-mesenchymal transition markers including Vimentin, Snail, and E-cadherin in GC cells in vitro. Taken together, we propose here that SNX1 serves as a tumor suppressor and prognostic marker that reduces tumor cell malignancy for GC.

Barley yellow dwarf virus-PAV (BYDV-PAV) is one of the major viruses causing a widespread and serious viral disease affecting cereal crops. To gain a better understanding of plant defence mechanisms of BYDV resistance genes (Bdv2 and RYd2) against BYDV-PAV infection, the differences in agronomical, biochemical and histological changes between susceptible and resistant wheat and barley cultivars were investigated. We found that root growth and total dry matter of susceptible cultivars showed greater reduction than that of resistant ones after infection. BYDV infected leaves in susceptible wheat and barley cultivars showed a significant reduction in photosynthetic pigments, an increase in the concentration of reducing sugar. The protein levels were also low in infected leaves. There was a significant increase in total phenol contents in resistant cultivars, which might reflect a protective mechanism of plants against virus infection. In phloem tissue, sieve elements (SE) and companion cells (CC) were severely damaged in susceptible cultivars after infection. It is suggested that restriction of viral movement in the phloem tissue and increased production of phenolic compounds may play a role in the resistance and defensive mechanisms of both Bdv2 and RYd2 against virus infection.

It is generally feasible to classify different species of vegetation based on remotely sensed images, but identification of different sub-species or even cultivars is uncommon. Tea trees (Camellia sinensis L.) have been proven to show great differences in taste and quality between cultivars. We hypothesize that hyperspectral remote sensing would make it possibly to classify cultivars of plants and even to estimate their taste-related biochemical components. In this study, hyperspectral data of the canopies of tea trees were collected by hyperspectral camera mounted on an unmanned aerial vehicle (UAV). Tea cultivars were classified according to the spectral characteristics of the tea canopies. Furthermore, two major components influencing the taste of tea, tea polyphenols (TP) and amino acids (AA), were predicted. The results showed that the overall accuracy of tea cultivar classification achieved by support vector machine is higher than 95% with proper spectral pre-processing method. The best results to predict the TP and AA were achieved by partial least squares regression with standard normal variant normalized spectra, and the ratio of TP to AA-which is one proven index for tea taste-achieved the highest accuracy (RCV = 0.66, RMSECV = 13.27) followed by AA (RCV = 0.62, RMSECV = 1.16) and TP (RCV = 0.58, RMSECV = 10.01). The results indicated that classification of tea cultivars using the hyperspectral remote sensing from UAV was successful, and there is a potential to map the taste-related chemical components in tea plantations from UAV platform; however, further exploration is needed to increase the accuracy.