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Sugarcane is an established industrial crop providing sugar, ethanol and biomass‐derived electricity worldwide. Cane sugar content is an important breeding target, but its improvement remains very slow in many breeding programmes. Biotechnology strategies to improve sucrose accumulation made little progress at the crop level, mainly due to the limited understanding of its regulation. miRNAs regulate many metabolic processes in plants. However, their roles and target genes associated with sugarcane sucrose accumulation remain unknown. Here, we conducted high‐throughput sequencing of transcriptome, small RNAs and degradome of leaves and stem of two early‐maturing sugarcane genotypes with contrasting sucrose content from the early to late stages of sucrose accumulation stages, which provided more insights into miRNA‐associated gene regulation during sucrose accumulation. The stem sucrose content in both genotypes increased steadily with time during sucrose accumulation stage. Transcriptome analysis identified 18,722 differentially expressed genes (DEGs) between both genotypes during sucrose accumulation. The major DEGs identified were involved in starch and sucrose metabolism, and photosynthesis. miRNA sequencing identified 563 known and 281 novel miRNAs from both genotypes during sucrose accumulation. Of these, 311 miRNAs were differentially expressed. A combined transcriptome and miRNA data analysis revealed differentially expressed miRNA‐target mRNA pairs related to sugar metabolism, of which 46 targets were transcription factors (TFs). miR172, miR164, miR396 and miR169 appear to regulate AP2/ERF, NAC, GRF and bZIP TF members associated with sugar metabolism. This is the first report of sugarcane miRNAs associated with sugar accumulation.

MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate the expression of targets genes by binding to the 3′-untranslated regions. They play vital roles in diverse biological processes, including the development of hepatic fibrosis (HF). HF is characterized by the accumulation of extracellular matrix (ECM) and hepatic stellate cells (HSCs) are considered a major cell type for producing ECM. Alteration of the HSC phenotype plays a crucial role in the HF pathological process. MiRNAs involved in various biological process, such as differentiation, apoptosis, migration, and their relevant signaling pathways, are expressed in HSCs; however, emerging evidence indicates that numerous miRNAs are abnormally expressed in activated HSCs. In this review, we summarize the categorization of miRNAs in HF and describe the relationships among them. We also discuss miRNAs recently discovered to be related to HF, and attempt to find potential miRNAs that may serve as novel biomarkers for use in HF treatment.

HLA-B*46:64 has one nucleotide change from HLA-B*46:01:01:01 where Histidine (113) is changed to Arginine. This article is protected by copyright. All rights reserved.

Dicistroviruses are members of a rapidly growing family of small RNA viruses. Related sequences have been discovered in many environmental samples, indicating that our knowledge about dicistrovirus diversity and host range is still limited. In this study, we performed a systematic search against the publicly available transcriptome database, and identified large numbers of dicistrovirus-like sequences in a wide variety of eukaryotic species. The origins of these sequences were 108 invertebrates (including 77 insect species belonging to 18 orders) and 11 plants, revealing new associations between dicistroviruses and hosts. Finally, 83 transcripts corresponding to nearly-complete viral genomes were retrieved from the RNA-seq data, of which most sequences showed limited similarity to known dicistroviruses and might present previously unreported virus species. Phylogenetic analysis suggested that horizontal virus transfer has occurred between diverse hosts and has important implications for dicistrovirus evolution. The results will provide new insight into the hidden diversity of the Dicistroviridae, and help us to better understand the viral evolution, host range and the possible way of transmission.

HLA-A*32:74 has one nucleotide change from HLA-A*32:01:01:01 where alanine (211) is changed to glutamate.

HLA-DRB1*15:123 has one nucleotide change from HLA-DRB1*15:01:01:01 where Threonine (90) is changed to Isoleucine.

HLA-A*31:97 differs by three nucleotide and two amino acid changes from HLA-A*31:01:02:01.

HLA-DRB1*08:76 is a novel allele differing by a single nucleotide from the HLA-DRB1*08:03:02 allele. This article is protected by copyright. All rights reserved.

The present study aimed to explore the biological functions and molecular mechanisms of the long non‑coding RNA VIM antisense RNA 1 (VIM‑AS1) in gastric cancer (GC). The expression of VIM‑AS1 was analyzed in tissues from patients with GC and GC cell lines by reverse transcription‑quantitative (RT‑q)PCR. The relationship between VIM‑AS1 expression and overall survival time of patients with GC was also assessed. To determine the biological functions of VIM‑AS1, Cell Counting Kit‑8 assay, colony formation assay, flow cytometry, wound healing assay and Transwell assay were employed. The targeting relationship among VIM‑AS1, microRNA (miR)‑8052 and frizzled 1 (FZD1) was verified by the dual luciferase reporter gene assay. The underlying molecular mechanism of VIM‑AS1 on GC was determined by RT‑qPCR and western blotting. In addition, tumor formation was detected in nude mice. The results of the present study demonstrated that VIM‑AS1 was highly expressed in GC tissues and cells. In addition, VIM‑AS1 expression was demonstrated to be closely related to the prognosis of patients with GC. Notably, silencing VIM‑AS1 inhibited the proliferation, migration and invasion, and enhanced apoptosis of AGS and HGC‑27 cells. Silencing VIM‑AS1 significantly increased the protein expression levels of cleaved caspase‑3, Bax and E‑cadherin, but decreased the protein expression levels of Bcl‑2, N‑cadherin, vimentin, matrix metalloproteinase (MMP)‑2, MMP‑9, β‑catenin, cyclin D1, C‑myc and FZD1. Additionally, silencing VIM‑AS1 inhibited tumor growth in nude mice. Cumulatively, the present study demonstrated that VIM‑AS1 may promote cell proliferation, migration, invasion and epithelial‑mesenchymal transition by regulating FDZ1 and activating the Wnt/β‑catenin pathway in GC.

Rheumatoid arthritis (RA) is a persistent autoimmune disease. Fibroblast-like synoviocytes (FLS) are a key component of invasive pannus and a pathogenetic mechanism in RA. Expression of bone morphogenetic protein 3 (BMP3) mRNA is reportedly decreased in the arthritic synovium. We previously showed that BMP3 expression is significantly downregulated in the synovial tissues of RA patients and models of adjuvant-induced arthritis (AIA). In the present study, we explored the association between BMP3 and FLS migration and secretion of proinflammatory factors in RA. We found that inhibition of BMP3 expression using BMP3 siRNA increased the proinflammatory chemokines and migration of FLS stimulated with TNF-α. Inhibition of BMP3 expression also increased expression of IL-6, IL-1β, IL-17A, CCL-2, CCL-3, VCAM-1, MMP-3, and MMP-9, but not TIMP-1, in AIA and RA FLS. Correspondingly, induction of BMP3 overexpression through intra-articular injection of ad-BMP3 diminished arthritis severity in AIA rats. We also found that BMP3 may inhibit activation of TGF-β1/Smad signaling. These data indicate that BMP3 may suppress the proliferation and migration of FLS via the TGF-β1/Smad signaling pathway.

Background: The immune checkpoint ligand, programmed cell death 1 ligand 1 (PD-L1), is expressed in various tumors and associated with response to drugs that target programmed cell death protein 1. Previous studies have estimated the level of PD-L1 expression among different stages of thymoma and thymic carcinoma to evaluate its potential use as a diagnostic factor; however, its varying expression level has been problematic. We conducted this meta-analysis of published literature to evaluate PD-L1 expression in thymomas and thymic carcinomas. Methods: We analyzed 12 studies that included 320 patients with type A/AB/B1 thymoma, 225 patients with type B2/B3 thymoma, and 180 patients with thymic carcinoma. Results: No difference in PD-L1 expression level was found between the B2/B3 vs C groups (odds ratio [OR], 0.67; 95% confidence interval [CI], 0.26, 1.76; p = 0.42). However, the heterogeneity was very high ( I2 = 78%), and a significant difference was found between groups A/AB/B1 and B2/B3 (OR, 0.22; 95% CI, 0.12, 0.41; p < 0.001), with a relatively low heterogeneity ( I2 = 55%). Conclusion: PD-L1 positivity might be a useful factor to differentiate type A/AB/B1 thymoma from type B2/B3 and thymic carcinoma. This result might be valuable for potential anti PD-L1 treatment in thymoma and thymic carcinoma.

We report acute antibody responses to SARS-CoV-2 in 285 patients with COVID-19. Within 19 days after symptom onset, 100% of patients tested positive for antiviral immunoglobulin-G (IgG). Seroconversion for IgG and IgM occurred simultaneously or sequentially. Both IgG and IgM titers plateaued within 6 days after seroconversion. Serological testing may be helpful for the diagnosis of suspected patients with negative RT-PCR results and for the identification of asymptomatic infections.

To observe the effects of electroacupuncture (EA) of different frequencies on transmission function, electromyography, nitric oxide synthase (NOS) content and interstitial cells of Cajal (ICC) expression of colon in rat models with slow transit constipation (STC). Of the 50 healthy male Wistar rats, 10 were randomly selected as a normal group and fed with ordinary diet, and the remaining 40 rats were fed with the diet added with the compound diphenoxylate at a dose of 8 mg/(kg·bw) each day for continuous 120 d. The 40 successfully established STC rat models were randomly divided into a model group, a low-frequency EA group (2 Hz), a high-frequency EA group (100 Hz), and a variable-frequency EA group (2 Hz/100 Hz), with 10 rats in each group. Rats in the normal and the model groups were not given any treatment; the low-frequency EA and the high-frequency EA groups were given EA at Tianshu (ST 25), Zusanli (ST 36) and Zhigou (TE 6) with continuous wave at the designated frequency, and the variable-frequency EA group received sparse-dense wave (2 Hz/100 Hz) EA at the same acupoints, once a day for a total of 15 d. After treatment, the colonic transmission function, electromyography, NOS content and ICC expression (calculated by the difference in the area of the C-kit positive cells) of the rats in each group were measured. For the colonic transmission function, compared with the normal group, the first black stool excretion durations of rats in the other groups were significantly prolonged (all P

Pulsatile GnRH release is essential for normal reproductive function. Kisspeptin secreting neurons found in the arcuate nucleus, known as KNDy neurons for co-expressing neurokinin B, and dynorphin, drive pulsatile GnRH release. Furthermore, gonadal steroids regulate GnRH pulsatile dynamics across the ovarian cycle by altering KNDy neurons' signalling properties. However, the precise mechanism of regulation remains mostly unknown. To better understand these mechanisms, we start by perturbing the KNDy system at different stages of the estrous cycle using optogenetics. We find that optogenetic stimulation of KNDy neurons stimulates pulsatile GnRH/LH secretion in estrous mice but inhibits it in diestrous mice. These in vivo results in combination with mathematical modelling suggest that the transition between estrus and diestrus is underpinned by well-orchestrated changes in neuropeptide signalling and in the excitability of the KNDy population controlled via glutamate signalling. Guided by model predictions, we show that blocking glutamate signalling in diestrous animals inhibits LH pulses, and that optic stimulation of the KNDy population mitigates this inhibition. In estrous mice, disruption of glutamate signalling inhibits pulses generated via sustained low-frequency optic stimulation of the KNDy population, supporting the idea that the level of network excitability is critical for pulse generation. Our results reconcile previous puzzling findings regarding the estradiol-dependent effect that several neuromodulators have on the GnRH pulse generator dynamics. Therefore, we anticipate our model to be a cornerstone for a more quantitative understanding of the pathways via which gonadal steroids regulate GnRH pulse generator dynamics. Finally, our results could inform useful repurposing of drugs targeting the glutamate system in reproductive therapy.

Yellow fever virus (YFV) is a re-emerging flavivirus, which can lead to severe clinical manifestations and high mortality, with no specific antiviral therapies available. The live-attenuated yellow fever vaccine 17D (YF17D) has been widely used for over eighty years. However, the emergence of yellow fever vaccine-associated viscerotropic disease (YFL-AVD) and yellow fever vaccine-associated neurotropic disease (YFL-AND) raised non-negligible concerns. Additionally, the attenuation mechanism of YF17D is still unclear. Thus, the development of convenient models is crucial to understand the mechanisms behind YF17D attenuation and its adverse effects. In this work, we generated a reporter YF17D expressing nano-luciferase (NLuc). In vitro and in vivo characterization demonstrated that the NLuc-YF17D shared similar biological properties with its parental strain and the NLuc activity can reflect viral infectivity reliably. Combined with in vivo bioluminescence imaging, a series of mice models of YF17D infection was established, which will be useful for the evaluation of antiviral medicines and novel vaccine candidates. Especially, we demonstrated that intraperitoneally (i.p.) infection of NLuc-YF17D in type I interferon receptor-deficient mice A129 resulted in outcomes resembling YEL-AVD and YEL-AND, evidenced by viral replication in multiple organs and invasion of the central neuronal system. Finally, in vitro and in vivo assays based on this reporter virus were established to evaluate the antiviral activities of validated antiviral agents. In conclusion, the bioluminescent reporter virus described herein provides a powerful platform to study YF17D attenuation and vaccine-associated diseases as well as to develop novel countermeasures against YFV.

An extracellular laccase (GLL) was purified from fermentation broth of the litter-decomposing fungus Gymnopus luxurians by four chromatography steps, which resulted in a high specific activity of 118.82 U/mg, purification fold of 41.22, and recovery rate of 42.05%. It is a monomeric protein with a molecular weight of 64 kDa and N-terminal amino acid sequence of AIGPV TDLHI, suggesting that GLL is a typical fungal laccase. GLL demonstrated an optimum temperature range of 55°C–65°C and an optimum pH 2.2 toward 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS). It displayed considerably high thermostability and pH stability with about 63% activity retained after 24 h at 50°C, and 86% activity retained after 24 h at pH 2.2, respectively. GLL was significantly enhanced in the presence of K+, Na+, and Mg2+ ions. It demonstrated Km of 539 μM and kcat/Km of 140 mM–1⋅s–1 toward ABTS at pH 2.2 and 37°C. Acetosyringone (AS) and syringaldehyde (SA) were the optimal mediators of GLL (0.4 U/ml) for dye decolorization with decolorization rates of about 60%–90% toward 11 of the 14 synthetic dyes. The optimum reaction conditions were determined to be mediator concentration of 0.1 mM, temperature range of 25°C –60°C, and pH 4.0. The purified laccase was the first laccase isolated from genus Gymnopus with high thermostability, pH stability, and effective decolorization toward dyes, suggesting that it has potentials for textile and environmental applications.

Rheumatoid arthritis (RA) is characterized by a tumor-like expansion of the synovium and subsequent destruction of adjacent articular cartilage and bone. In our previous work we showed that phosphatase and tension homolog deleted on chromosome 10 (PTEN) contributes to the activation of fibroblast-like synoviocytes (FLS) in adjuvant-induced arthritis (AIA), but the underlying mechanism is not unknown. In this study, we show that PTEN is downregulated while DNA methyltransferase (DNMT)1 is upregulated in FLS from RA patients and a rat model of AIA. DNA methylation of PTEN was increased by administration of tumor necrosis factor (TNF)-α in FLS of RA patients, as determined by chromatin immunoprecipitation and methylation-specific PCR. Treatment with the methylation inhibitor 5-azacytidine suppressed cytokine and chemokine release and FLS activation in vitro and alleviated paw swelling in vivo. PTEN overexpression reduced inflammation and activation of FLS via protein kinase B (AKT) signaling in RA, and intra-articular injection of PTEN-expressing adenovirus into the knee of AIA rats markedly reduced inflammation and paw swelling. Thus, PTEN methylation promotes the inflammation and activation of FLS in the pathogenesis of RA. These findings provide insight into the molecular basis of articular cartilage destruction in RA, and indicate that therapeutic strategies that prevent PTEN methylation may an effective treatment.

HLA-B*52:49N has one nucleotide change from HLA-B*52:01:01:01 where 601G (GAG) is changed to T(TAG).

Background RH1 is one of the most clinically important blood group antigens in the field of transfusion and in the prevention of fetal incompatibility. The molecular analysis and characterization of serologic weak D phenotypes is essential to ensuring transfusion safety. Methods Blood samples from a northeastern Chinese population were randomly screened for a serologic weak D phenotype. The nucleotide sequences of all 10 exons, adjacent flanking intronic regions, and partial 5′ and 3′ untranslated regions (UTRs) were detected for RHD genes. Predicted deleterious structural changes in missense mutations of serologicl weak D phenotypes were analyzed using SIFT, PROVEAN and PolyPhen2 software. The protein structure of serologic weak D phenotypes was predicted using Swiss-PdbViewer 4.0.1. Results A serologic weak D phenotype was found in 45 individuals (0.03%) among 132,479 blood donors. Seventeen distinct RHD mutation alleles were detected, with 11 weak D, four partial D and two DEL alleles. Further analyses resulted in the identification of two novel alleles (RHD weak D 1102A and 399C). The prediction of a three-dimensional structure showed that the protein conformation was disrupted in 16 serologic weak D phenotypes. Conclusions Two novel and 15 rare RHD alleles were identified. Weak D type 15, DVI Type 3, and RHD1227A were the most prevalent D variant alleles in a northeastern Chinese population. Although the frequencies of the D variant alleles presented herein were low, their phenotypic and genotypic descriptions add to the repertoire of reported RHD alleles. Bioinformatics analysis on RhD protein can give us more interpretation of missense variants of RHD gene.

Rheumatoid arthritis (RA) is characterized by tumor-like expansion of the synovium and the subsequent destruction of adjacent articular cartilage and bone. The latest studies proved phosphatase and tension homolog deleted on chromosome 10 (PTEN) might contribute to the surviving, proliferation and pro-inflammatory cytokines in RA. The purpose of this study was to explore the function and underlying mechanisms of PTEN in RA pro-inflammatory cytokines and chemokines of fibroblast-like synoviocytes (FLSs). Increased level of PTEN was observed in adjuvant-induced arthritis (AIA) FLSs in comparison to normal rats. Increased concentrations of pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β), chemokines (CCL-2 and CCL-3), VCAM-1 and VEGF-α expression were observed in FLSs with PTEN inhibitor bpv or PTEN-RNAi. Moreover, co-incubation FLSs with overexpression vector with PTEN-GV141 reduced the expression of pro-inflammatory cytokines, chemokines, VCAM-1 and VEGF-α in AIA. Interestingly, we also found DNA methylation could regulate PTEN expression and activation of AKT signaling was with a change of PTEN. Altogether, our findings in the present study suggested that PTEN might play a pivotal role during pro-inflammatory cytokines and chemokines of FLSs through activation of AKT signaling pathway. In addition, PTEN expression may be regulated by DNA methylation in the pathogenesis of AIA.

Arabidopsis thaliana ENO2 (AtENO2) plays an important role in plant growth and development. It encodes two proteins, a full-length AtENO2 and a truncated version, AtMBP-1, alternatively translated from the second start codon of the mRNA. The AtENO2 mutant (eno2- ) exhibited reduced leaf size, shortened siliques, a dwarf phenotype and higher sensitivity to abiotic stress. The objectives of this study were to analyze the regulatory network of the ENO2 gene in plant growth development and understand the function of AtENO2/AtMBP-1 to abiotic stresses. An eno2- /35S:AtENO2-GFP line and an eno2- /35S:AtMBP-1-GFP line of Arabidopsis were obtained. Results of sequencing by 454 GS FLX identified 578 upregulated and 720 downregulated differential expressed genes (DEGs) in a pairwise comparison (WT-VS-eno2- ). All the high-quality reads were annotated using the Gene Ontology (GO) terms. The DEGs with KEGG pathway annotations occurred in 110 pathways. The metabolic pathways and biosynthesis of secondary metabolites contained more DEGs. Moreover, the eno2- /35S:AtENO2-GFP line returned to the wild-type (WT) phenotype and was tolerant to drought and salt stresses. However, the eno2- /35S:AtMBP-1-GFP line was not able to recover the WT phenotype but it has a higher tolerance to drought and salt stresses. Results from this study demonstrate that AtENO2 is critical for the growth and development, and the AtMBP-1 coded by AtENO2 is important in tolerance of Arabidopsis to abiotic stresses.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths. Compound K, an active metabolite of ginsenosides, is reported to exhibit anti-cancer property in various types of human malignancies. The present study investigated the role of compound K on glucose metabolism in NSCLC cells and its underlying mechanism. Our study found that compound K dose-dependently inhibited the cell viability of NSCLC cells. Moreover, administration with compound K decreased glucose uptake and lactate secretion under normoxic and hypoxic conditions. Consistently, the expression of key enzymes (HK II, PDK1 and LDHA) involved in glucose metabolism were inhibited in compound K-treated tumor cells. In addition, compound K inhibited the expression of HIF-1α and its downstream gene GLUT1. On the contrary, overexpression of HIF-1α elevated metabolic reactions and partly attenuated the inhibitory role of compound K on NSCLC cell growth. These results demonstrate that compound K suppresses NSCLC cell growth via HIF-1α mediated metabolic alteration, contributing to novel anticancer therapy by targeting glucose metabolism.

NLRC5, a newly discovered member of the NLR family, has been reported to regulate immune responses and promote cell proliferation, migration, and invasion in hepatocellular carcinoma. However, to date, the potential regulatory roles and molecular mechanisms by which NLRC5 affects the development and progression of clear cell renal cell carcinoma (ccRCC) remain largely unknown. In this study, human clinical data from The Cancer Genome Atlas database revealed that increased NLRC5 expression was associated with advanced stage and poor prognosis in ccRCC patients. Moreover, experimental results showed that NLRC5 is aberrantly overexpressed in human ccRCC tissues and cell lines. Depletion of NLRC5 attenuated ccRCC cell proliferation, migration, and invasion and suppressed ccRCC growth in a nude mouse model. By contrast, overexpression of NLRC5 promoted the proliferation, migration, and invasion of ccRCC cells in vitro. Additionally, NLRC5 expression is not only positively correlated with β-catenin but also coordinates the activation of the downstream Wnt/β-catenin signalling pathway. Together, our data suggest that NLRC5 may be a potential therapeutic target for ccRCC therapy.

Exposure to psychosocial stress disrupts reproductive function and interferes with pulsatile luteinising hormone (LH) secretion in mammals. The posterodorsal sub-nucleus of the medial amygdala (MePD) is part of the limbic brain and is an upstream modulator of the reproductive axis as well as stress and anxiety states. Corticotropin releasing factor type-2 receptors (CRFR2) are activated in the presence of psychosocial stress together with an increased expression of the CRFR2 ligand Urocortin3 (Ucn3) in MePD of rodents. We investigate whether Ucn3 signalling in the MePD is involved in mediating the suppressive effect of psychosocial stress exposure on LH pulsatility. Firstly, we administered Ucn3 into the MePD and monitored the effect on pulsatile LH secretion in ovariectomised mice. Next, we delivered Astressin2B, a highly selective CRFR2 antagonist, intra-MePD in the presence of predator odor, 2,4,5-Trimethylthiazole (TMT) and examined the effect on LH pulses. Subsequently, we virally infected ovariectomised Ucn3-cre-tdTomato mice with inhibitory DREADDs targeting the MePD Ucn3 neurons while exposing the mice to TMT or restraint stress and examined the effect on LH pulsatility as well as corticosterone (CORT) release. Administration of Ucn3 into the MePD dose-dependently inhibited pulsatile LH secretion and intra-MePD administration of Astressin2B blocked the suppressive effect TMT on LH pulsatility. Additionally, DREADDs inhibition of MePD Ucn3 neurons blocked TMT and restraint stress-induced inhibition of LH pulses as well as CORT release in the presence of TMT. These results demonstrate for the first time that Ucn3 neurons in the MePD mediate psychosocial stress-induced suppression of the GnRH pulse generator and psychosocial stress-induced CORT secretion. Ucn3 signalling in the MePD plays a fundamental role in modulating the hypothalamic-pituitary-ganadal and hypothalamic-pituitary-adrenal axes, and this brain locus may represent a nodal centre in the crosstalk between the reproductive and stress axes.

Pulsatile GnRH release is essential for normal reproductive function. Kisspeptin secreting neurons found in the arcuate nucleus, known as KNDy neurons for co-expressing neurokinin B, and dynorphin, drive pulsatile GnRH release. Furthermore, gonadal steroids regulate GnRH pulsatile dynamics across the ovarian cycle by altering KNDy neurons’ signalling properties. However, the precise mechanism of regulation remains mostly unknown. To better understand these mechanisms we start by perturbing the KNDy system at different stages of the estrous cycle using optogenetics. We find that optogenetic stimulation of KNDy neurons stimulates pulsatile GnRH/LH secretion in estrous mice but inhibits it in diestrous mice. These in-vivo results in combination with mathematical modelling suggest that the transition between estrus and diestrus is underpinned by well-orchestrated changes in neuropeptide signalling and in the excitability of the KNDy population controlled via glutamate signalling. Guided by model predictions, we show that blocking glutamate signalling in diestrous animals inhibits LH pulses, and that optic stimulation of the KNDy population mitigates this inhibition. In estrous mice, disruption of glutamate signalling inhibits pulses generated via sustained low-frequency optic stimulation of the KNDy population, supporting the idea that the level of network excitability is critical for pulse generation. Our results reconcile previous puzzling findings regarding the estradiol-dependent effect that several neuromodulators have on the GnRH pulse generator dynamics. Therefore, we anticipate our model to be a cornerstone for a more quantitative understanding of the pathways via which gonadal steroids regulate GnRH pulse generator dynamics. Finally, our results could inform useful repurposing of drugs targeting the glutamate system in reproductive therapy.

The challenge of decoding information about complex diseases hidden in huge number of single nucleotide polymorphism (SNP) genotypes is undertaken based on five dbGaP studies. Current genome-wide association studies have successfully identified many high-risk SNPs associated with diseases, but precise diagnostic models for complex diseases by these or more other SNP genotypes are still unavailable in the literature. We report that lung cancer, breast cancer and prostate cancer as the first three top cancers worldwide can be predicted precisely via 240–370 SNPs with accuracy up to 99% according to leave-one-out and 10-fold cross-validation. Our findings (1) confirm an early guess of Dr. Mitchell H. Gail that about 300 SNPs are needed to improve risk forecasts for breast cancer, (2) reveal an incredible fact that SNP genotypes may contain almost all information that one wants to know, and (3) show a hopeful possibility that complex diseases can be precisely diagnosed by means of SNP genotypes without using phenotypical features. In short words, information hidden in SNP genotypes can be extracted in efficient ways to make precise diagnoses for complex diseases.

HLA-B*55:71 has one nucleotide change from HLA-B*55:02:01:01 where histidine (3) is changed to tyrosine.

Neuroendocrine axes display a remarkable diversity of dynamic signaling processes relaying information between the brain, endocrine glands, and peripheral target tissues. These dynamic processes include oscillations, elastic responses to perturbations, and plastic long term changes observed from the cellular to the systems level. While small transient dynamic changes can be considered physiological, larger and longer disruptions are common in pathological scenarios involving more than one neuroendocrine axes, suggesting that a robust control of hormone dynamics would require the coordination of multiple neuroendocrine clocks. The idea of apparently different axes being in fact exquisitely intertwined through neuroendocrine signals can be investigated in the regulation of stress and fertility. The stress response and the reproductive cycle are controlled by the Hypothalamic-Pituitary-Adrenal (HPA) axis and the Hypothalamic-Pituitary-Gonadal (HPG) axis, respectively. Despite the evidence surrounding the effects of stress on fertility, as well as of the reproductive cycle on stress hormone dynamics, there is a limited understanding on how perturbations in one neuroendocrine axis propagate to the other. We hypothesize that the links between stress and fertility can be better understood by considering the HPA and HPG axes as coupled systems. In this manuscript, we investigate neuroendocrine rhythms associated to the stress response and reproduction by mathematically modeling the HPA and HPG axes as a network of interlocked oscillators. We postulate a network architecture based on physiological data and use the model to predict responses to stress perturbations under different hormonal contexts: normal physiological, gonadectomy, hormone replacement with estradiol or corticosterone (CORT), and high excess CORT (hiCORT) similar to hypercortisolism in humans. We validate our model predictions against experiments in rodents, and show how the dynamic responses of these endocrine axes are consistent with our postulated network architecture. Importantly, our model also predicts the conditions that ensure robustness of fertility to stress perturbations, and how chronodisruptions in glucocorticoid hormones can affect the reproductive axis' ability to withstand stress. This insight is key to understand how chronodisruption leads to disease, and to design interventions to restore normal rhythmicity and health.

Neuroendocrine axes display a remarkable diversity of dynamic signalling processes relaying information between the brain, endocrine glands, and peripheral target tissues. These dynamic processes include oscillations, elastic responses to perturbations, and plastic long term changes observed from the cellular to the systems level. While small transient dynamic changes can be considered physiological, larger and longer disruptions are common in pathological scenarios involving more than one neuroendocrine axes, suggesting that a robust control of hormone dynamics would require the coordination of multiple neuroendocrine clocks. The idea of apparently different axes being in fact exquisitely intertwined through neuroendocrine signals can be investigated in the regulation of stress and fertility. The stress response and the reproductive cycle are controlled by the Hypothalamic-Pituitary-Adrenal (HPA) axis and the Hypothalamic-Pituitary-Gonadal (HPG) axis, respectively. Despite the evidence surrounding the effects of stress on fertility, as well as of the reproductive cycle on stress hormone dynamics, there is a limited understanding on how perturbations in one neuroendocrine axis propagate to the other. We hypothesize that the links between stress and fertility can be better understood by considering the HPA and HPG axes as coupled systems. In this manuscript, we investigate neuroendocrine rhythms associated to the stress response and reproduction by mathematically modelling the HPA and HPG axes as a network of interlocked oscillators. We postulate a network architecture based on physiological data and use the model to predict responses to stress perturbations under different hormonal contexts: normal physiological, gonadectomy, hormone replacement with estradiol or corticosterone (CORT), and high excess CORT (hiCORT) similar to hypercortisolism in humans. We validate our model predictions against experiments in rodents, and show how the dynamic responses of these endocrine axes are consistent with our postulated network architecture. Importantly, our model also predicts the conditions that ensure robustness of fertility to stress perturbations, and how chronodisruptions in glucocorticoid hormones can affect the reproductive axis’ ability to withstand stress. This insight is key to understand how chronodisruption leads to disease, and to design interventions to restore normal rhythmicity and health.

HLA-B*15:01:39 has one synonymous nucleotide change from HLA-B*15:01:01:01 at nucleotide 117 (residue 15 Proline).

HLA-A*31:73 has one nucleotide change from HLA-A*31:01:02:01 where Serine (71) is changed to Alanine.

HLA-A*31:72 has one nucleotide change from HLA-A*31:01:02:01, where histidine (188) is changed to arginine.

Background Bombay and para-Bombay phenotypes, which arise from gene mutations of α-1,2-fucosyltransferase FUT1, are very rare in Chinese population. A para-Bombay phenotype Chinese individual with two novel FUT1 mutations was reported here. Study design and methods The peripheral blood and saliva samples of the proband and her family members were collected after informed consent. ABO and H blood group phenotyping was performed by haemagglutination methods. ABO genotype was determined by PCR-SSP kit. A, B, and H antigens in saliva were detected by a hemagglutination inhibition test. Fragments encompassing the full coding region of FUT1 and FUT2 genes were PCR amplified and sequenced. Allelic sequences were validated by cloning and sequencing individual colonies. Results The serologic reaction results of the proband revealed that A, B, and H antigen were absent on RBCs, but B and H antigen were presented in saliva, and the serum contains anti-H. The proband was assigned as B/O1 by ABO genotyping. Two new heterozygous mutations of FUT1 gene, c.508dupT and c.787A>C, were identified through direct sequencing of PCR-amplified products. TA cloning and sequencing confirmed that two novel mutations were on different alleles. FUT2 gene sequence of the proband is consistent with standard. The other family members of the proband showed normal phenotypes of ABO blood group and their genotypes are consistent with phenotypes. Conclusion Two novel FUT1 alleles, with the previously not reported mutations c.508dupT and c.787C, respectively, are responsible for the para-Bombay phenotype detected in the sample from the proband.

Background The Am phenotype, which arises from mutations of the α-1,3-N-acetylgalactosaminyltransferase gene, is rare in the Chinese population. The present study focuses on a novel mutation with the Am phenotype in a Chinese individual. Study design and methods The sample with ABO blood group discrepancy was analyzed by serologic techniques. The full coding and flanking regions of the ABO gene, including the Intron 1 transcription factor-binding site, were identified through direct sequencing of polymerase chain reaction (PCR)-amplified products. PCR products of Exons 6 and 7 were validated to isolate the ABO gene haplotypes by cloning and sequencing individual colonies. The impact of the novel mutation on enzyme function was predicted with Polymorphism Phenotyping algorithm V2 and bioinformatic software programs. Results The serologic characteristics of ABO blood typing showed the rare Am phenotype. The c.467C/T and c.912C/A heterozygous sites in Exon 7 were identified by direct sequencing analysis. Further TA cloning and sequencing revealed that the patient carried an ABO*O.01.01 allele and a novel ABO*A allele. The new allele sequence had one nucleotide alteration (C>A) at position 912 on the background of the ABO*A1.02 allele. The c.912C>A mutation was predicted to be "probably damaging" and "deleterious" by PolyPhen-2 and PROVEAN algorithms, respectively. Conclusion A novel mutation c.912C>A in α-1,3-N-acetylgalactosaminyltransferase gene resulting in Am phenotype was identified in a Chinese individual.

Epidermal growth factor receptor- tyrosine kinase inhibitors (EGFR-TKIs) have shown promise against non-small cell lung cancers (NSCLCs) in clinics but the utility is often short-lived because of T790M mutations in EGFR that help evade TKIs’ action. Osimertinib is the third and latest generation TKI that targets EGFRs with T790M mutations. However, there are already reports on acquired resistance against Osimertinib. Recent work has revealed the role that miRNAs, particularly tumor suppressor let-7c, play in the invasiveness and acquired resistance of NSCLCs, but the mechanistic details, particularly in Osimertinib resistance, remain elusive. Using two cells lines, H1975 (endogenous T790M mutation) and HCC827-T790M (with acquired T790M mutation), we found that let-7c is a regulator of EMT, as well as it affects CSC phenotype. In both the cell lines, transfection with pre-let-7c led to reversal of EMT as studied through EMT markers e-cadherin and ZEB1. This resulted in reduced proliferation and invasion. Conversely, reduced expression of let-7c through anti-let-7c transfections significantly increased proliferation and invasion of lung cancer cells. Expression of let-7c was functionally relevant as EMT correlated with resistance to Osimertinib. High let-7c expression reversed EMT and made cells sensitive to Osimertinib, and vice versa. WNT1 and TCF-4 were found to be two targets of let-7c which were epigenetic suppressed by let-7c through increased methylation. In vivo, pre-let-7c inhibited while anti-let-7c potentiated tumor growth and WNT1 and TCF-4 were downregulated in xenografts with pre-let-7c. Silencing of both WNT1 and TCF-4 resulted in potentiation of Osimertinib action. Our results suggest an important role of let-7c in regulating EMT and the resulting Osimertinib resistance in T790M NSCLCs. More clinical studies need to be performed to fully understand the translational relevance of this novel mechanism.

Endogenous viral elements (EVEs), derived from all major types of viruses, have been discovered in many eukaryotic genomes, representing “fossil records” of past viral infections. The endogenization of nudiviruses has been reported in several insects, leading to the question of whether genomic integration is a common phenomenon for these viruses. In this study, genomic assemblies of insects and other arthropods were analyzed to identify endogenous sequences related to Nudiviridae. A total of 359 nudivirus-like genes were identified in 43 species belonging to different groups; however, none of these genes were detected in the known hosts of nudiviruses. A large proportion of the putative EVEs identified in this study encode intact open reading frames or are transcribed as mRNAs, suggesting that they result from recent endogenization of nudiviruses. Phylogenetic analyses of the identified EVEs and inspections of their flanking regions indicated that integration of nudiviruses has occurred recurrently during the evolution of arthropods. This is the first report of a comprehensive screening for nudivirus-derived EVEs in arthropod genomes. The results of this study demonstrated that a large variety of arthropods, especially hemipteran and hymenopteran insects, have previously been or are still infected by nudiviruses. These findings have greatly extended the host range of Nudiviridae and provide new insights into viral diversity, evolution, and host–virus interactions.

BackgroundWe aim to investigate the profile of acute antibody response in COVID-19 patients, and provide proposals for the usage of antibody test in clinical practice.MethodsA multi-center cross-section study (285 patients) and a single-center follow-up study (63 patients) were performed to investigate the feature of acute antibody response to SARS-CoV-2. A cohort of 52 COVID-19 suspects and 64 close contacts were enrolled to evaluate the potentiality of the antibody test.ResultsThe positive rate for IgG reached 100% around 20 days after symptoms onset. The median day of seroconversion for both lgG and IgM was 13 days after symptoms onset. Seroconversion of IgM occurred at the same time, or earlier, or later than that of IgG. IgG levels in 100% patients (19/19) entered a platform within 6 days after seroconversion. The criteria of ‘IgG seroconversion’ and ‘> 4-fold increase in the IgG titers in sequential samples’ together diagnosed 82.9% (34/41) of the patients. Antibody test aided to confirm 4 patients with COVID-19 from 52 suspects who failed to be confirmed by RT-PCR and 7 patients from 148 close contacts with negative RT-PCR.ConclusionIgM and IgG should be detected simultaneously at the early phase of infection. The serological diagnosis criterion of seroconversion or the ‘>; 4-fold increase in the IgG titer’ is suitable for a majority of COVID-19 patients. Serologic test is helpful for the diagnosis of SARS-CoV-2 infection in suspects and close contacts.

Kisspeptin within the arcuate nucleus of the hypothalamus is a critical neuropeptide in the regulation of reproduction. Together with neurokinin B and dynorphin A, arcuate kisspeptin provides the oscillatory activity that drives the pulsatile secretion of gonadotrophin-releasing hormone (GnRH), and therefore luteinising hormone (LH) pulses, and is considered to be a central component of the GnRH pulse generator. It is well established that the amygdala also exerts an influence over gonadotrophic hormone secretion and reproductive physiology. The discovery of kisspeptin and its receptor within the posterodorsal medial amygdala (MePD) and our recent finding showing that intra-MePD administration of kisspeptin or a kisspeptin receptor antagonist results in increased LH secretion and decreased LH pulse frequency, respectively, suggests an important role for amygdala kisspeptin signalling in the regulation of the GnRH pulse generator. To further investigate the function of amygdala kisspeptin, the present study used an optogenetic approach to selectively stimulate MePD kisspeptin neurones and examine the effect on pulsatile LH secretion. MePD kisspeptin neurones in conscious Kiss1-Cre mice were virally infected to express the channelrhodopsin 2 protein and selectively stimulated by light via a chronically implanted fibre optic cannula. Continuous stimulation using 5 Hz resulted in an increased LH pulse frequency, which was not observed at the lower stimulation frequencies of 0.5 and 2 Hz. In wild-type animals, continuous stimulation at 5 Hz did not affect LH pulse frequency. These results demonstrate that selective activation of MePD Kiss1 neurones can modulate hypothalamic GnRH pulse generator frequency.

Aberrated glucose metabolism is a key future of cancer cells. Unlike normal cells, tumor cells favor glycolysis even in the presence of sufficient oxygen. Pyruvate kinase (PK), a key glucose metabolic enzyme, converts phosphoenolpyruvate (PEP) to pyruvate by transferring the high-energy phosphate group to adenosine diphosphate (ADP) to produce adenosine triphosphate (ATP). Pyruvate kinase M2 (PKM2), one of the four isozyme of PK, which universally expressed in rapidly proliferating cells such as embryonic cells and cancer cells. Recent years, more and more research suggested PKM2 plays a crucial role in cancer progression through both metabolic and non-metabolic pathways. On the one hand, the middle product of glycolysis, such as amino acids, nucleotides, lipids is necessary to rapid growth of cancer cells. On the other hand, PKM2 supports tumor growth through regulating the expression of gene that involved in cell proliferation, migration and apoptosis. In this article, we review the recent advances to further understand the regulation and function of PKM2 in tumorigenesis. Given its multiple effects on cancer, PKM2 may be a potential target for cancer diagnosis and treatment.

Macrophages play a crucial role in the progression of hepatic fibrosis (HF). In macrophages, epigenetic mechanisms are increasingly being recognized as crucial controllers of their phenotype. However, the functions of macrophage DNA methylation in experimental models of hepatic fibrosis have not been fully addressed. Here, we analyzed isolated hepatic macrophages DNA methylation from CCL4-induced (4 weeks) mice using reduced representation bisulfite sequencing (RRBS). We identified and validated the methylation status of 26 gene promoter regions associated with CpG islands. We further investigated the function of PSTPIP2 in HF by hepatic-adeno-associated virus (AAV9)-PSTPIP2 overexpression. The molecular mechanisms underlying PSTPIPS2-regulated HF were further explored in mice and RAW264.7 cell line. RRBS results show hypermethylation of PSTPIP2 (chr18: 77,843,840-77,843,968) in the 5'-UTR region. PSTPIP2 expression was significantly decreased in isolated hepatic macrophages from CCL4-induced mice. PSTPIP2 hypermethylation is mediated by the methyltransferases DNMT3a and DNMT3b in LPS-induced RAW264.7 cell line. Further investigation indicated that specific overexpression of PSTPIP2 in C57BL/6 mice reduced the inflammatory response and ameliorated liver fibrosis. These data indicated that hypermethylation of PSTPIP2 caused a mixed induction of hepatic classical macrophage (M1) and alternative macrophage (M2) biomarkers in CCL4-induced HF mice. Furthermore, overexpression of PSTPIP2 inhibited the expression of M1 markers by suppressing STAT1 activity, and enhanced the expression of M2 markers by promoting STAT6 activity. In contrast, knockdown of PSTPIP2 promoted M1 polarization and suppressed M2 polarization in vitro. Adding PSTPIP2 expression alleviates liver fibrosis and hepatic inflammation in mice by regulating macrophage polarization.

HLA-A*30:72 has one nucleotide change from HLA-A*30:01:01:01 where isoleucine (95) is changed to threonine.

Acute liver injury (ALI) is characteristic of abrupt hepatic dysfunction and inflammatory response. Activaion of Kupffer cells (KCs) plays a central role in the pathogenesis of ALI. Since the High Mobility Group A protein2 (HMGA2) occurs as a driver at critical stage of hepatocellular carcinoma, herein, we investigated the role of HMGA2 in macrophage activation during ALI. Our study found that the expression of HMGA2 decreased dramatically both in KCs isolated from the liver in mice with ALI and in LPS-induced RAW264.7 cell lines. Moreover, loss- and gain-of-function studies suggested that HMGA2 could enhance the expression of pro-inflammatory cytokines including TNF-α, IL-6 and IL-1β. These results indicated that HMGA2 may play an essential role in macrophage activation during ALI. Additionally, our results showed the expression of HMGA2 was up-regulated when LPS-induced RAW264.7 cells were treated with 5-aza-2-deoxycytidine. Furthermore, silencing of DNMT1, DNMT3a, DNMT3b could respectively prevent the down-expression of HMGA2 in LPS-induced RAW264.7 cells. In conclusion, HMGA2 promotes the release of pro-inflammatory cytokines through NF-κB pathway, and the dysregulation of HMGA2 may involve with hypermethylation.

Objective To explore the effect of moxibustion at “Shenque” ( CV 8) on the immune system of rats taking long-term exhaustive exercise. Method Thirty male SD rats were randomly divided into blank group, model group and moxibustion group with 10 rats in each group. Except the rats in blank group, all the rats were established into long-term exhaustive models through swimming again and again. Mild moxibustion at CV 8 for 15 min was carried out in the rats in moxibustion group after modeling. The treatment was conducted once every other day, and treatment for 10 times was needed. The exhaustive duration for each time was recorded, the levels of serum IgA, IgG, IgM and ACP were detected 24 h after the 10th exhaustive exercise, and the histomorphological changes of spleen were observed. Immunoturbidimetry was adopted for detecting the IgA level, and ELISA method was used for detecting the levels of IgG, IgM and ACP. Results The common exhaustive duration in moxibustion group was longer than that in model group, however, the time difference was statistically significant after the 5th exhaustive exercise ( P P P P Conclusion Moxibustion at CV 8 can improve the levels of immunoglobulin (IgG, IgA, IgM) of tired body for a long time, decrease the ACP level, and repair the damaged spleen tissues.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease, in which pathogenesis is not clear. Many research demonstrated that fibroblast-like synoviocytes (FLSs) play a key role in RA pathogenesis, join in the cartilage injury and hyperplasia of the synovium, and contribute to the release of inflammatory cytokines. We used adjuvant arthritis (AA) rats as RA animal models. The methyl-CpG-binding protein 2 (MeCP2) enables the suppressed chromatin structure to be selectively detected in AA FLSs. Overexpression of this protein leads to an increase of integral methylation levels. Some research has confirmed the hedgehog (Hh) signaling pathway plays an important role in RA pathogenesis; furthermore, patched 1 (PTCH1) is a negative fraction of Hh signaling pathway. We used 5-aza-2'-deoxycytidine (5-azadc) as DNA methylation inhibitor. In our research, we found MeCP2 reduced PTCH1 expression in AA FLSs; 5-azadc obstructed the loss of PTCH1 expression. 5-Azadc, treatment of AA FLSs, also blocks the release of inflammatory cytokines. In order to probe the potential molecular mechanism, we assumed the epigenetic participation in the regulation of PTCH1. Results demonstrated that PTCH1 hypermethylation is related to the persistent FLS activation and inflammation in AA rats. Knockdown of MeCP2 using small-interfering RNA technique added PTCH1 expression in AA FLSs. Our results indicate that DNA methylation may offer molecule mechanisms, and the reduced PTCH1 methylation level could regulate inflammation through knockdown of MeCP2. Graphical Abstract PTCH1 is an inhibitory protein of the Hedgehog signaling pathway. Increased expression of PTCH1 can inhibit the expression of Gli1 and Shh, thereby inhibiting the activation of Hedgehog signaling pathway. Inactivated Hedgehog signaling pathway inhibits the secretion of IL-6 and TNF-α. MeCP2 mediates hypermethylation of PTCH1 gene and decreases the expression of PTCH1 protein, thus activating Hedgehog signaling pathway and increasing secretion of IL-6 and TNF-α.

Fertility critically depends on the gonadotropin-releasing hormone (GnRH) pulse generator, a neural construct comprised of hypothalamic neurons coexpressing kisspeptin, neurokoinin-B and dynorphin. Here, using mathematical modeling andin vivooptogenetics we reveal for the first time how this neural construct initiates and sustains the appropriate ultradian frequency essential for reproduction. Prompted by mathematical modeling, we show experimentally using female estrous mice that robust pulsatile release of luteinizing hormone, a proxy for GnRH, emerges abruptly as we increase the basal activity of the neuronal network using continuous low-frequency optogenetic stimulation. Further increase in basal activity markedly increases pulse frequency and eventually leads to pulse termination. Additional model predictions that pulsatile dynamics emerge from nonlinear positive and negative feedback interactions mediated through neurokinin-B and dynorphin signaling respectively are confirmed neuropharmacologically. Our results shed light on the long-elusive GnRH pulse generator offering new horizons for reproductive health and wellbeing.SIGNIFICANCE STATEMENTThe gonadotropin-releasing hormone (GnRH) pulse generator controls the pulsatile secretion of the gonadotropic hormones LH and FSH and is critical for fertility. The hypothalamic arcuate kisspeptin neurons are thought to represent the GnRH pulse generator, since their oscillatory activity is coincident with LH pulses in the blood; a proxy for GnRH pulses. However, the mechanisms underlying GnRH pulse generation remain elusive. We developed a mathematical model of the kisspeptin neuronal network and confirmed its predictions experimentally, showing how LH secretion is frequency-modulated as we increase the basal activity of the arcuate kisspeptin neuronsin vivousing continuous optogenetic stimulation. Our model provides a quantitative framework for understanding the reproductive neuroendocrine system and opens new horizons for fertility regulation.

Azithromycin (AZM) is a widely used antibiotic, with additional antiviral and anti-inflammatory properties that remain poorly understood. Although Zika virus (ZIKV) poses a significant threat to global health, there are currently no vaccines or effective therapeutics against it. Herein, we report that AZM effectively suppresses ZIKV infection in vitro by targeting a late stage in the viral life cycle. Besides that, AZM upregulates the expression of host type I and III interferons and several of their downstream interferon-stimulated genes (ISGs) in response to ZIKV infection. In particular, we found that AZM upregulates the expression of MDA5 and RIG-I, pathogen recognition receptors (PRRs) induced by ZIKV infection, and increases the levels of phosphorylated TBK1 and IRF3. Interestingly, AZM treatment upregulates phosphorylation of TBK1, without inducing phosphorylation of IRF3 by itself. These findings highlight the potential use of AZM as a broad antiviral agent to combat viral infection and prevent ZIKV associated devastating clinical outcomes, such as congenital microcephaly.

HLA-B*52:01:24 has one synonymous nucleotide change from HLA-B*52:01:01:01 at nucleotide 384 (codon 104 Glycine).

Maternal environmental factors such as diet have profound effects on offspring development and later health. The hypothalamic-pituitary-adrenal (HPA) axis is an important stress neuroendocrine system that is subject to programming by early life challenges. The present study was further to investigate whether maternal high fat diet (HFD) exposure during rat pregnancy and lactation can alter the HPA axis activity in adult male offspring. We observed that maternal HFD consumption exerted long-term effects on the basal activity of the HPA axis in adult offspring, with increased mean plasma corticosterone levels that result from elevated steroid pulse frequence and pulse amplitude. More importantly, maternal HFD offspring displayed enhanced corticosterone responses to restraint (1 h) and lipopolysaccharide (25 μg/kg, iv) but not insulin-induced hypoglycemia (0.3U/kg, iv) stress, suggesting a stressor-specific effect of maternal diet on the hyperresponsiveness of the HPA axis to stress. Additionally, maternal HFD exposure markedly attenuated the habituation of HPA responses to repeated restraint stress. These findings demonstrate that perinatal HFD exposure has a potent and long-lasting influence on development of neuroendocrine regulatory mechanisms. Maternal HFD consumption significantly increased basal corticotropin-releasing factor (CRF) mRNA expression in the paraventricular nucleus; nevertheless, similar increments in CRF mRNA levels following restraint were observed between maternal HFD offspring and control rats. Furthermore, the medial and central nuclei of amygdala played a pivotal role in maternal HFD-induced sensitization of the HPA response to psychological and systemic stress, respectively, suggesting that different neural pathways may mediate maternal HFD-induced HPA hyperresponsivity to different types of stressors. Take together, the long-term effects of maternal HFD challenge on the central regulation of the HPA axis, therefore, expose the adult offspring to greater HPA function throughout lifespan, in stressor-specific and region-specific manner.

HLA-A*11:01:46 has one synonymous nucleotide change from HLA-A*11:01:01:01 at nucleotide 807 (codon 245 Alanine).