The LHCGR gene encodes a G-protein coupled receptor that plays a pivotal role in sexual differentiation in males, ovarian development in females and in fertility via its interaction with luteinizing hormone and chorionic gonadotropin. Inactive variants of the LHCGR gene cause Leydig cell hypoplasia (LCH), which is a rare disease and one of the causes of disorder of sexual differentiation (DSD) in males. The aim of this work was to clarify the clinical and molecular characteristics of a 2.75 year old patient with type 1 LCH. Whole exome sequencing was performed for the patient family and variants in the LHCGR gene were validated by Sanger sequencing. Pathogenicity of the missense variant was evaluated by multiple in silico tools. Our Chinese patient, who exhibited DSD, had female external genitalia (normal labia majora and minora, external opening of urethra under the clitoris and blind-ended vagina) and bilateral testis tissues in the inguinal region. Genetic sequencing revealed compound heterozygous variants in the LHCGR gene in the patient, including a novel missense variant in exon 4 (c.349G>A, p.Gly117Arg) and a novel nonsense variant in exon 10 (c.878C>A, p.Ser293*). The missense variant is in the first leucine-rich repeat domain of the LHCGR protein, which is predicted to affect ligand recognition and binding affinity and thus protein function. The patient is molecularly and clinically diagnosed with type 1 LCH, which is caused by novel, compound heterozygous variants of the LHCGR gene. We believe this report will serve to expand the genotypic spectrum of LHCGR variants.

Although ankylosing spondylitis (AS) is a common, highly heritable arthropathy, the precise genetic mechanism underlying the disease remains elusive. Here, we investigate the disease-causing mutations in a large AS family with distinguished complexity, consisting of 23 patients covering four generations and exhibiting a mixed HLA-B27 (+) and (-) status. Linkage analysis with 32 members using three methods and whole-exome sequencing analysis with three HLA-B27 (+) patients, one HLA-B27 (-) patient, and one healthy individual did not identify a mutation common to all of the patients, strongly suggesting the existence of genetic heterogeneity in this large pedigree. However, if only B27-positive patients were analyzed, the linkage analysis located a 22-Mb region harboring the HLA gene cluster in chromosome 6 (LOD = 4.2), and the subsequent exome analysis identified two non-synonymous mutations in the TREML2 and IP6K3 genes. These genes were resequenced among 370 sporadic AS patients and 487 healthy individuals. A significantly higher mutation frequency of TREML2 was observed in AS patients (1.51% versus 0.21%). The results obtained for the AS pedigree and sporadic patients suggest that mutation of TREML2 is a major factor leading to AS for HLA-B27 (+) members in this large family and that TREML2 is also a susceptibility gene promoting the development of ankylosing spondylitis in HLA-B27 (+) individuals.

Oxidative stress is implicated in tissue inflammation, and plays an important role in the pathogenesis of immune-mediated nephritis. Using the anti-glomerular basement membrane antibody-induced glomerulonephritis (anti-GBM-GN) mouse model, we found that increased expression of glutathione S-transferase Mu 2 (GSTM2) was related to reduced renal damage caused by anti-GBM antibodies. Furthermore, mesenchymal stem cell (MSC)-based therapy has shed light on the treatment of immune-mediated kidney diseases. The aim of this study was to investigate if MSCs could be utilized as vehicles to deliver the GSTM2 gene product into the kidney and to evaluate its potential therapeutic effect on anti-GBM-GN.

MicroRNAs have been shown to be important regulators of immune homeostasis as patients with aberrant microRNA expression appeared to be more susceptible to autoimmune diseases. We recently found that miR-146a was up-regulated in activated B cells in response to rat acetylcholine receptor (AChR) α-subunit 97-116 peptide, and this up-regulation was significantly attenuated by AntagomiR-146a. Our data also demonstrated that silencing miR-146a with its inhibitor AntagomiR-146a effectively ameliorated clinical myasthenic symptoms in mice with ongoing experimental autoimmune myasthenia gravis. Furthermore, multiple defects were observed after miR-146a was knocked down in B cells, including decreased anti-R97-116 antibody production and class switching, reduced numbers of plasma cells, memory B cells and B-1 cells, and weakened activation of B cells. Previously, miR-146a has been identified as a nuclear factor-κB-dependent gene and predicted to base pair with the tumour necrosis factor receptor-associated factor 6 (TRAF6) and interleukin-1 receptor-associated kinase 1 (IRAK1) genes to regulate the immune response. However, our study proved that miR-146a inhibition had no effect on the expression of TRAF6 and IRAK1 in B cells. This result suggests that the function of miR-146a in B cells does not involve these two target molecules. We conclude that silencing miR-146a exerts its therapeutic effects by influencing the B-cell functions that contribute to the autoimmune pathogenesis of myasthenia gravis.

Late leaf spot (LLS) is a major foliar disease in peanut (A. hypogaea L.) worldwide, causing significant losses of potential yield in the absence of fungicide applications. Mutants are important materials to study the function of disease-related genes. In this study, the mutant line M14 was derived from cultivar Yuanza 9102 treated with EMS. Yuanza 9102 was selected from an interspecific cross of cultivar Baisha 1016 with A. diogoi, and is resistant to several fungal diseases. By contrast, the M14 was highly susceptible to late leaf spot. RNA-Seq analysis in the leaf tissues of the M14 and its wild type Yuanza 9102 under pathogen challenge showed 2219 differentially expressed genes including1317 up-regulated genes and 902 down-regulated genes. Of these genes, 1541, 1988, 1344, 643 and 533 unigenes were obtained and annotated by public protein databases of SwissPort, TrEMBL, gene ontology (GO), KEGG and clusters of orthologous groups (COG), respectively. Differentially expressed genes (DEGs) showed that expression of inducible pathogenesis-related (PR) proteins was significantly up-regulated; in the meantime DEGs related to photosynthesis were down-regulated in the susceptible M14 in comparison to the resistant WT. Moreover, the up-regulated WRKY transcription factors and down-regulated plant hormones related to plant growth were detected in the M14. The results suggest that down-regulated chloroplast genes, up-regulated WRKY transcription factors, and depressed plant hormones related to plant growth in the M14 might coordinately render the susceptibility though there was a significant high level of PRs. Those negative effectors might be triggered in the susceptible plant by fungal infection and resulted in reduction of photosynthesis and phytohormones and led to symptom formation.

Pathogenesis and treatment for diabetic neuropathy are still complex. A deficit of neurotrophic factors affecting Schwann cells is a very important cause of diabetic neuropathy. Neuritin is a newly discovered potential neurotrophic factor. In this study, we explored the effect of exogenous neuritin on survivability and functions of diabetic Schwann cells of rats with experimental diabetic neuropathy. Diabetic neuropathy was induced in rats. 12-week diabetic rats contrasted with non-diabetic normal rats had decreased levels of serum neuritin and slowed nerve conduction velocities (NCVs). Schwann cells isolated from these diabetic rats and cultured in high glucose showed reduced cell neuritin mRNA and protein and supernatant neuritin protein, increased apoptosis rates, increased caspase-3 activities and progressively reduced viability. In contrast, exogenous neuritin treatment reduced apoptosis and improved viability, with elevated Bcl-2 levels (not Bax) and decreased caspase-3 activities. Co-cultured with diabetic Schwann cells pre-treated with exogenous neuritin in high glucose media, and diabetic DRG neurons showed lessened decreased neurite outgrowth and supernatant NGF concentration occurring in co-culture of diabetic cells. Exogenous neuritin treatment ameliorated survivability and functions of diabetic Schwann cells of rats with diabetic neuropathy. Our study may provide a new mechanism and potential treatment for diabetic neuropathy.

Colorectal cancer (CRC) is considered to be a leading cause of cancer-related death. Centromere protein O (CENPO) can prevent the separation of sister chromatids and cell death after spindle injury. Nevertheless, the role of CENPO in CRC has not been reported. The expression level of CENPO in CRC was revealed by TCGA database and immunohistochemical (IHC) staining. Subsequently, the loss-of-function assays were performed to identified the role of CENPO in CRC in vitro and in vivo. Our data demonstrated that CENPO was highly expressed in CRC. The expression of CENPO was positively correlated with the deterioration of CRC. Moreover, CENPO knockdown inhibited the malignant phenotypes of CRC cells, which was characterized by slowed proliferation, cycle repression at G2, promotion of apoptosis, reduced migration and weakened tumorigenesis. Furthermore, CENPO knockdown downregulated the expression of N-cadherin, Vimentin, Snail, CCND1, PIK3CA and inhibited AKT phosphorylation in CRC cells. Moreover, the function of CENPO in regulating proliferation and apoptosis depended on p53. In summary, CENPO may play a promoting role in CRC through the epithelial mesenchymal transition (EMT) and PI3K/AKT signaling pathway, which can be regarded as a molecular therapeutic target for CRC.

Inflammatory bowel disease (IBD) is a chronic idiopathic disease characterized by inflammation-related epithelial barrier damage in the intestinal tract. Helminth infection reduces autoimmune disease symptoms through regulation of inflammatory responses based on hygiene theory. However, the underlying mechanisms remain unclear.

Preaxial polydactyly (PPD) is a common congenital hand malformation classified into four subtypes (PPD I-IV). Variants in the zone of polarizing activity regulatory sequence (ZRS) within intron 5 of the LMBR1 gene are linked to most PPD types. However, the genes responsible for PPD I and the underlying mechanisms are unknown.

The activity of one of the major catechins in Green Tea, the polyphenol (-)-epigallocatechin-3-gallate (EGCG), has been shown to have a variety of health benefits. Recent studies suggest that EGCG can modulate both the innate and adaptive arms of the immune system. The goal of the current studies was to examine the immunomodulatory effects and mechanisms of action of EGCG on experimental arthritis in mice.

Systemic lupus erythematosus (SLE) is a complex autoimmune syndrome characterized by various co-existing autoantibodies (autoAbs) in patients' blood. However, the full spectrum of autoAbs in SLE has not been comprehensively elucidated. In this study, a commercial platform bearing 9400 antigens (ProtoArray) was used to identify autoAbs that were significantly elevated in the sera of SLE patients. By comparing the autoAb profiles of SLE patients with those of healthy controls, we identified 437 IgG and 1213 IgM autoAbs that the expression levels were significantly increased in SLE (P < 0.05). Use of the ProtoArray platform uncovered over 300 novel autoAbs targeting a broad range of nuclear, cytoplasmic, and membrane antigens. Molecular interaction network analysis revealed that the antigens targeted by the autoAbs were most significantly enriched in cell death, cell cycle, and DNA repair pathways. A group of autoAbs associated with cell apoptosis and DNA repair function, including those targeting APEX1, AURKA, POLB, AGO1, HMGB1, IFIT5, MAPKAPK3, PADI4, RGS3, SRP19, UBE2S, and VRK1, were further validated by ELISA and Western blot in a larger cohort. In addition, the levels of autoAbs against APEX1, HMGB1, VRK1, AURKA, PADI4, and SRP19 were positively correlated with the level of anti-dsDNA in SLE patients. Comprehensive autoAb screening has identified novel autoAbs, which may shed light on potential pathogenic pathways leading to lupus.

Curcumin is known to have immunomodulatory potential in addition to anti-oxidant, anti-inflammatory and anti-carcinogenic effects. The aim of the present study is to investigate the therapeutic effects of curcumin on immune-mediated renal disease in an anti-glomerular basement membrane (GBM) model (representing acute kidney Injury, AKI) and murine lupus model (representing chronic kidney disease, CKD). In the AKI model, female anti-GBM 129/svj mice were administered with curcumin right before disease induction. In the CKD model, female MRL.lpr mice at the age of 8-10 weeks old were treated with curcumin or placebo via oral gavage daily for two months. After treatment, serum autoantibody levels, splenomegaly and spleen cellularity were reduced in murine lupus. Collectively, curcumin ameliorated kidney disease in the two mouse models with either acute or chronic nephritis, as marked by reduced proteinuria, blood urea nitrogen, glomerulonephritis, crescent formation, tubule-interstitial disease, and renal infiltration by lymphocytes. In addition, curcumin treatment reduced activation of the NFkB, MAPK, AKT and pBAD pathways either systemically, or within the inflamed kidneys. These findings suggest that natural food supplements could become an alternative approach to ameliorating immune-mediated kidney diseases.

As the main forms of carbohydrates, starch and sucrose play a vital role in the balance and coordination of various carbohydrates. Lanzhou lily is the most popular edible lily in China, mainly distributed in the central region of Gansu. To clarify the relationship between carbohydrate metabolism and bulb development of Lanzhou lily, so as to provide a basis for the promotion of the growth and development in Lanzhou lily and its important economic value, we studied lily bulbs in the squaring stage, flowering stage, half withering stage and withering stage. The plant height, fresh weight of mother and daughter bulbs continued to increase during the whole growth period and fresh weight of stem and leaf began to decrease in the half withering stage. The content of starch, sucrose and total soluble sugar in the lily mother bulb accumulated mostly in the flowering, withering and half withering stages, respectively. Starch, sucrose and total soluble sugar accumulated in the daughter bulb with the highest concentration during the withering stage. In the transcription level, sucrose synthase (SuSy1) and sucrose invertase (INV2) expressed the highest in squaring stage, and the expression was significantly higher in the mother bulb than in the daughter bulb. In flowering stage, the expression levels of soluble starch synthase (SSS1), starch-branching enzyme (SBE) and adenosine diphosphate-glucose pyrophosphorylase (AGP1) genes were higher in the mother bulb than in the daughter bulb. Altogether, our results indicate that starch and sucrose are important for the bulb growth and development of Lanzhou lily.

Hormonal drug therapy has been widely used in clinical practice for the treatment of progressive muscular dystrophy (PMD). Glucocorticoids, as a common drug in the clinical treatment of PMD, have been reported in several clinical studies.

Herein, an ease-of-use and highly sensitive origami-based "book" shaped three-dimensional electrochemical paper microdevice based on nucleic acid testing (NAT) methodology was developed for sample-to-answer detection of pathogens from whole blood and food samples. The whole steps of NAT, including sample preparation, amplification and detection, were performed by alternately folding the panels of the microdevice, just like flipping a book. The screen-printing electrodes were combined with wax-printing technology to construct a paper-based electrochemical unit to monitor Loop-mediated isothermal amplification (LAMP) reaction with an electrochemical strategy. After nucleic acid extraction and purification with the glass fiber, the LAMP reaction was performed for 45 min to amplify the extracted nucleic acid sequence, followed by the execution of the electrochemical interrogation reaction based on methylene blue (MB) and double-stranded LAMP amplicons. Starting with whole blood and food samples spiked with Salmonella typhimurium, this microdevice was successfully applied to identify pathogens from biological samples with satisfactory sensitivity and specificity. Therefore, the proposed origami-based "book" shaped three-dimensional paper microdevice has great potential for disease diagnosis, food safety analysis applications in the future.

Homoharringtonine (HHT) is commonly used for the treatment of Chinese adult AML, and all-trans retinoic acid (ATRA) has been verified in acute promyelocytic leukemia (APL). However, the efficacy and safety of HHT-based induction therapy have not been confirmed for childhood AML, and ATRA-based treatment has not been evaluated among patients with non-APL AML.

Mitochondrial abnormalities have been noted in lupus, but the causes and consequences remain obscure. Autophagy-related genes ATG5, ATG7 and IRGM have been previously implicated in autoimmune disease. We reasoned that failure to clear defective mitochondria via mitophagy might be a foundational driver in autoimmunity by licensing mitochondrial DNA-dependent induction of type I interferon. Here, we show that mice lacking the GTPase IRGM1 (IRGM homolog) exhibited a type I interferonopathy with autoimmune features. Irgm1 deletion impaired the execution of mitophagy with cell-specific consequences. In fibroblasts, mitochondrial DNA soiling of the cytosol induced cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-dependent type I interferon, whereas in macrophages, lysosomal Toll-like receptor 7 was activated. In vivo, Irgm1-/- tissues exhibited mosaic dependency upon nucleic acid receptors. Whereas salivary and lacrimal gland autoimmune pathology was abolished and lung pathology was attenuated by cGAS and STING deletion, pancreatic pathology remained unchanged. These findings reveal fundamental connections between mitochondrial quality control and tissue-selective autoimmune disease.

Paraquat (N,N0-dimethyl-4,40-bipyridinium dichloride;PQ) is a highly toxic pesticide, which usually leads to acute lung injury and subsequent development of pulmonary fibrosis. The exact mechanism underlying PQ-induced lung fibrosis remain largely unclear and as yet, no specific treatment drugs have been approved. Our study aimed to identify its potential mechanisms of PQ-induced fibrosis through a modeling study in vitro studies and bioinformatics analysis.

A lensless blood cell counting system integrating microfluidic channel and a complementary metal oxide semiconductor (CMOS) image sensor is a promising technique to miniaturize the conventional optical lens based imaging system for point-of-care testing (POCT). However, such a system has limited resolution, making it imperative to improve resolution from the system-level using super-resolution (SR) processing. Yet, how to improve resolution towards better cell detection and recognition with low cost of processing resources and without degrading system throughput is still a challenge. In this article, two machine learning based single-frame SR processing types are proposed and compared for lensless blood cell counting, namely the Extreme Learning Machine based SR (ELMSR) and Convolutional Neural Network based SR (CNNSR). Moreover, lensless blood cell counting prototypes using commercial CMOS image sensors and custom designed backside-illuminated CMOS image sensors are demonstrated with ELMSR and CNNSR. When one captured low-resolution lensless cell image is input, an improved high-resolution cell image will be output. The experimental results show that the cell resolution is improved by 4×, and CNNSR has 9.5% improvement over the ELMSR on resolution enhancing performance. The cell counting results also match well with a commercial flow cytometer. Such ELMSR and CNNSR therefore have the potential for efficient resolution improvement in lensless blood cell counting systems towards POCT applications.

Trehalose-6-phosphate synthase (TPS) is significant in the growth, development and stress resistance of plants. We identified the cucumber TPS family and its physicochemical properties, domains, gene structures, evolutionary relationships, gene locations, cis-acting elements, conserved motifs, and expression patterns using bioinformatics. Our results uncovered seven CsTPS genes in the cucumber genome and named CsTPS1-CsTPS7 according to their locations in the chromosomes. Seven CsTPS genes were randomly distributed in six cucumber chromosomes. Domain analysis showed that the TPS and TPP domains exist in all CsTPSs, and an additional hydrolase-3 domain exist in CsTPS3, CsTPS5 and CsTPS6. Phylogenetic analysis showed that TPS proteins from Arabidopsis, rice, soybean, and cucumber were divided into two subfamilies (Class I and Class II) and they were further divided into seven subgroups. TPS proteins from Arabidopsis and cucumber were grouped together, suggesting a close evolutionary relationship. Gene structure analysis indicated that most Class I genes contained 16-17 introns, while Class II genes (except CsTPS7) had two introns. Motif analysis showed that Class II genes had 10 complete conserved motifs, while Class I genes lacked motif 8 and motif 9. Furthermore, CsTPS genes possessed numerous cis-acting elements related to stress, hormone, and light response in the promoter regions. GO analysis indicated multiple functions for the CsTPS proteins. Expression analysis of CsTPS genes in different tissues found that they were expressed in roots, stems and leaves, with the highest expression levels in roots. The expression analysis of CsTPSs under different treatments showed that CsTPS genes may participate in the response to abiotic stress, plant hormones and sugar treatments.