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Immune checkpoint inhibitors (ICIs) achieve a milestone in cancer treatment. Despite the great success of ICI, ICI therapy still faces a big challenge due to heterogeneity of tumor, and therapeutic response is complicated by possible immune-related adverse events (irAEs). Therefore, it is critical to assess the systemic immune response elicited by ICI therapy to guide subsequent treatment regimens. Positron emission tomography (PET) molecular imaging is an optimal approach in cancer diagnosis, treatment effect evaluation, follow-up, and prognosis prediction. PET imaging can monitor metabolic changes of immunocytes and specifically identify immuno-biomarkers to reflect systemic immune responses. Here, we briefly review the application of PET molecular imaging to date of systemic immune responses following ICI therapy and the associated rationale.

Gigahertz hard X-ray imaging presents an unprecedented challenge to both timing and spatial resolutions for inorganic scintillator-based front imagers. A beam test with 30-keV X-rays from the Advanced Photon Source (APS) showed that 5-mm BaF2 plates resolve well 30-keV X-ray septuplets of 27-ps width and 2.83-ns spacing. Pixelated crystal screens with a pitch down to $400~\mu \text{m}$ were fabricated by mechanic slicing for BaF2, BaF2:Y, and LYSO crystals. Their spatial resolution and detection efficiency for hard X-rays are defined by the pitch and thickness, respectively. Thicker monolithic crystal screens show poorer spatial resolution, which may be improved using a small optical aperture with a loss in both efficiency and dynamic range for hard X-rays. Future plans include pursuing smaller crystal pitches by laser slicing and research and development on novel ultrafast inorganic scintillators.

ObjectiveThe strong genetic contribution of the major histocompatibility complex (MHC) region to rheumatoid arthritis (RA) has been generally attributed to human leukocyte antigen (HLA)-DRB1. However, due to the high polymorphisms and linkage disequilibrium within MHC, it is difficult to define novel and/or independent genetic risks using conventional HLA genotyping or chip-based microarray technology. This study aimed to identify novel RA risk variants by performing deep sequencing for MHC.MethodsWe first conducted target sequencing for the entire MHC region in 357 anticitrullinated protein antibodies (ACPA)-positive patients with RA and 1001 healthy controls, and then performed HLA typing in an independent case–control cohort consisting of 1415 samples for validation. All study subjects were Han Chinese. Genetic associations for RA susceptibility and severity were analysed. Comparative modelling was constructed to predict potential functions for the newly discovered RA association variants.ResultsHLA-DQα1:160D conferred the strongest and independent susceptibility to ACPA-positive RA (p=6.16×10−36, OR=2.29). DRβ1:37N had an independent protective effect (p=5.81×10−16, OR=0.49). As predicted by comparative modelling, the negatively charged DQα1:160D stabilises the dimer of dimers, thus may lead to an increased T cell activation. The negatively charged DRβ1:37N encoding alleles preferentially bind with epitope P9 arginine, thus may result in a decreased RA susceptibility.ConclusionsWe provide the first evidence that HLA-DQα1:160D, instead of HLA-DRB1*0405, is the strongest and independent genetic risk for ACPA-positive RA in Han Chinese. Our study also illustrates the value of deep sequencing for fine-mapping disease risk variants in the MHC region.

There is growing interest in studying the genetic contributions to longevity, but limited relevant genes have been identified. In this study, we performed a genetic association study of longevity in a total of 15,651 Chinese individuals. Novel longevity loci, BMPER (rs17169634; p = 7.91 × 10−15) and TMEM43/XPC (rs1043943; p = 3.59 × 10−8), were identified in a case–control analysis of 11,045 individuals. BRAF (rs1267601; p = 8.33 × 10−15) and BMPER (rs17169634; p = 1.45 × 10−10) were significantly associated with life expectancy in 12,664 individuals who had survival status records. Additional sex‐stratified analyses identified sex‐specific longevity genes. Notably, sex‐differential associations were identified in two linkage disequilibrium blocks in the TOMM40/APOE region, indicating potential differences during meiosis between males and females. Moreover, polygenic risk scores and Mendelian randomization analyses revealed that longevity was genetically causally correlated with reduced risks of multiple diseases, such as type 2 diabetes, cardiovascular diseases, and arthritis. Finally, we incorporated genetic markers, disease status, and lifestyles to classify longevity or not‐longevity groups and predict life span. Our predictive models showed good performance (AUC = 0.86 for longevity classification and explained 19.8% variance of life span) and presented a greater predictive efficiency in females than in males. Taken together, our findings not only shed light on the genetic contributions to longevity but also elucidate correlations between diseases and longevity., This genetic association study of longevity on 15,651 Chinese individuals (3,448 nonagenarians and 2,509 centenarians) identified two novel human longevity loci. Two novel longevity loci, BMPER (rs17169634; p = 7.91 × 10−15) and TMEM43/XPC (rs1043943; p = 3.59 × 10−8) reached genome‐wide significance. Interestingly, gender differential associations revealed two linkage disequilibrium blocks on TOMM40/APOE region. In addition, our predictive models showed good performance (AUC = 0.86 for longevity classification and explained 19.8% variances of life span), and higher efficiencies in females than males. These findings provide potential strategies for improving healthy aging.

Background Aging is closely associated with the occurrence and development of many complex diseases such as cardiovascular conditions, type 2 diabetes, gastrointestinal (GI) and renal diseases. Detecting changes as early as possible in the human body due to aging is thus crucial significant to potentially mitigate its impacts on physical health. Methods Here, we present a comprehensive metagenome association study and serum metabolomics profiling in a registry Guangxi-Longevity cohort aged from 20–111 years (n=151) and Kunming cohort ages ranging from 20–80 years (n=80). Results We identified uremic toxins as key factors in serum metabolomics highly associated with aging, and this finding has been validated in an independent Kunming-Aging cohort aged from 20–80 years (n=80). We also observed that aging-associated systemic inflammation levels were positively associated with uremic toxins. Moreover, the increased Escherichia coli, Odoribacter splanchnicus, Bilophila wadsworthia and Parabacteroides spp. abundances were related to serum levels of uremic toxins, and the accumulating rate of uremic toxins and specific microbial species was robustly much slower in centenarians than in nonagenarians. We further investigated the frailty and health status in long-living individuals aged above 90 years, and found that the frailty status might be a putative extreme aging phenomenon characterized by novel uremic toxin accumulation patterns. Conclusions Our findings reveal novel potential links between gut microbiota alterations, uremic toxins and aging, and highlight the preponderance of gut microbiota and serum metabolism in aging.

Panic disorder (PD) is an acute paroxysmal anxiety disorder with poorly understood pathophysiology. The dorsal periaqueductal gray (dPAG) is involved in the genesis of PD. However, the downstream neurofunctional changes of the dPAG during panic attacks have yet to be evaluated in vivo. In this study, optogenetic stimulation to the dPAG was performed to induce panic-like behaviors, and in vivo positron emission tomography (PET) imaging with 18F-flurodeoxyglucose (18F-FDG) was conducted to evaluate neurofunctional changes before and after the optogenetic stimulation. Compared with the baseline, post-optogenetic stimulation PET imaging demonstrated that the glucose metabolism significantly increased (P < 0.001) in dPAG, the cuneiform nucleus, the cerebellar lobule, the cingulate cortex, the alveus of the hippocampus, the primary visual cortex, the septohypothalamic nucleus, and the retrosplenial granular cortex but significantly decreased (P < 0.001) in the basal ganglia, the frontal cortex, the forceps minor corpus callosum, the primary somatosensory cortex, the primary motor cortex, the secondary visual cortex, and the dorsal lateral geniculate nucleus. Taken together, these data indicated that in vivo PET imaging can successfully detect downstream neurofunctional changes involved in the panic attacks after optogenetic stimulation to the dPAG.

The strong genetic contribution of the major histocompatibility complex (MHC) to rheumatoid arthritis (RA) susceptibility has been generally attributed to HLA-DRB1. However, due to the high linkage disequilibrium in the MHC region, it is difficult to define the ‘real’ or/and additional independent genetic risks using the conventional HLA genotyping or chip-based microarray technology. By the capture sequencing of entire MHC region for discovery and HLA-typing for validation in 2,773 subjects of Han ancestry, we identified HLA-DQα1:160D as the strongest independent genetic risk for anti-citrullinated protein antibodies (ACPA)-positive RA in Han population (P = 6.16 × 10−36, OR=2.29). Further stepwise conditional analysis revealed that DRβ1:37N has an independent protective effect on ACPA–positive RA (P = 5.81 × 10−16, OR=0.49). The DQα1:160 coding allele DQA1*0303 displayed high impact on joint radiographic severity, especially in patients with early disease and smoking (P = 3.02 × 10−5). Interaction analysis by comparative molecular modeling revealed that the negative charge of DQα1:160D stabilizes the dimer of dimers, leading to an increased T cell activation. The electrostatic potential surface analysis indicated that the negative charged DRβ1:37N encoding alleles could bind with epitope P9 arginine, thus may result in a decreased RA susceptibility.In this study, we provide the first evidence that HLA-DQA1, instead of HLA-DRB1, is the strongest and independent genetic risk for ACPA-positive RA in Chinese Han population. Our study also illustrates the value of MHC deep sequencing for fine mapping disease risk variants in the MHC region.

Genetically modified (GM) crops have brought various economic benefits but may also have adversely affected soil microorganisms. To examine whether transgenic high-methionine soybean ZD91 alters the bacterial community structure in the rhizosphere, we performed a 2-year follow-up study using the transgenic high-methionine soybean cultivar ZD91 and wild type cultivar ZD. The community composition and the relative abundance of bacteria in rhizosphere soil were determined by sequencing of the 16S rRNA amplicon. Our results indicated that transgenic soybean ZD91 had no significantly effects on rhizosphere bacterial communities. Instead, the plant growth stage and year appeared to have a stronger effect on bacterial communities. Our findings therefore provided reliable scientific evidence for potential commercial cultivation of cultivar ZD91.

To decrease the flue-oil and flue-gas for the aluminum melting furnace, a novel heavy oil burner was development, which includes secondary air injection technology and premixed combustion. In this study, on-site experiment shows that the flame is very clean and eddy, and has a large contact area with the aluminum. The fuel consumption is about 55 kg-heavy oil/t-aluminum which decreasing 35% fuel compare with the traditional burner. Moreover, for flue-gas, the O 2 and NO x are decreased, however, CO is increased.

Background Mutations of PKD1 and PKD2 accounted for the most cases of autosomal dominant polycystic kidney disease (ADPKD). The presence of the large transcript, numerous exons and complex reiterated regions within the gene has significantly complicated the analysis of PKD1 with routine PCR-based approaches. Methods We developed a strategy to analyze both the PKD1/PKD2 genes simultaneously using targeted next-generation sequencing (NGS). All coding exons plus the flanking sequences of PKD1 and PKD2 genes from probands were captured, individually barcoded and followed by HiSeq2000 sequencing. The candidate variants were validated by using classic Sanger sequencing. PKD1-specific primers were designed to amplify the replicated areas of PKD1 gene. Results Five novel variations and one known mutation in PKD1 gene were detected in five familial and one sporadic Chinese ADPKD patients. Through pedigree and bioinformatic analysis, five of them were identified as pathogenic mutations (p.G1319R, p.Y3781*, p.W4122*, p.Val700Glyfs*14, and p.Leu3656Trpfs*28) and one was as polymorphism (p.T2420I). Conclusions Our result showed that targeted capture and NGS technology were effective for the gene testing of ADPKD disorder. Mutation study of PKD1 and PKD2 genes in Chinese patients may contribute to better understanding of the genetic diversity between different ethnic groups and enrich the mutation database in Asian population.

Tuberous sclerosis complex is an autosomal dominant disorder characterized by hamartomas in multiple organ systems. Mutations in the 2 large genes TSC1 and TSC2 have been demonstrated to be associated with tuberous sclerosis complex by various mutation screening methods. Targeted next-generation sequencing for genetic analysis is performed in the current study and is proved to be less cost, labor, and time consuming compared with Sanger sequencing. Two de novo and 1 recurrent TSC2 mutation in patients with tuberous sclerosis complex were revealed. Clinical details of patients were described and the underlying mechanism of the 2 novel TSC2 mutations, c.245G>A(p.W82X) and c.5405_5408dupACTT(p.P1803Lfs*25), were discussed. These results added to variability of TSC mutation spectrum and suggest that targeted next-generation sequencing could be the primary choice over Sanger sequencing in future tuberous sclerosis complex genetic counseling.

Trichloroethylene induced hypersensitivity syndrome is dose-independent and potentially life threatening disease, which has become one of the serious occupational health issues and requires intensive treatment. To discover the genetic risk factors and evaluate the performance of risk prediction model for the disease, we conducted genomewide association study and replication study with total of 174 cases and 1761 trichloroethylene-tolerant controls. Fifty seven SNPs that exceeded the threshold for genome-wide significance (P −8) were screened to relate with the disease, among which two independent SNPs were identified, that is rs2857281 at MICA (odds ratio, 11.92; Pmeta = 1.33 × 10−37) and rs2523557 between HLA-B and MICA (odds ratio, 7.33; Pmeta = 8.79 × 10−35). The genetic risk score with these two SNPs explains at least 20.9% of the disease variance and up to 32.5-fold variation in inter-individual risk. Combining of two SNPs as predictors for the disease would have accuracy of 80.73%, the area under receiver operator characteristic curves (AUC) scores was 0.82 with sensitivity of 74% and specificity of 85%, which was considered to have excellent discrimination for the disease and could be considered for translational application for screening employees before exposure.

Optical coherence tomography images may be distorted by motion artifacts in dynamic imaging, so it may lead to misdiagnosis in clinical diagnosis. Motion artifacts correction has become an urgent issue in optical coherence tomography imaging.Firstly, using the improved complex nonlinear diffusion preprocessing filtering reduced the noise of the sequence images, then using the image mass center aligned the distortion data in the Y direction, finally, using the method of deviation average corrected motion artifacts along the Y direction.After correction, the motion artifacts in the longitudinal 2D images and the 3D image disappeared, the surface of the 2D and the 3D image became more smooth, the structure between layers of the images got clear and distinct, retinal en-face single slice image was sharp, and the fundus tissue structure could be observed.The algorithm of correction makes the physical structure of the retinal display truly after motion artifacts correction.

We carried out metagenomic shotgun sequencing and a metagenome-wide association study (MGWAS) of fecal, dental and salivary samples from a cohort of individuals with rheumatoid arthritis (RA) and healthy controls. Concordance was observed between the gut and oral microbiomes, suggesting overlap in the abundance and function of species at different body sites. Dysbiosis was detected in the gut and oral microbiomes of RA patients, but it was partially resolved after RA treatment. Alterations in the gut, dental or saliva microbiome distinguished individuals with RA from healthy controls, were correlated with clinical measures and could be used to stratify individuals on the basis of their response to therapy. In particular, Haemophilus spp. were depleted in individuals with RA at all three sites and negatively correlated with levels of serum autoantibodies, whereas Lactobacillus salivarius was over-represented in individuals with RA at all three sites and was present in increased amounts in cases of very active RA. Functionally, the redox environment, transport and metabolism of iron, sulfur, zinc and arginine were altered in the microbiota of individuals with RA. Molecular mimicry of human antigens related to RA was also detectable. Our results establish specific alterations in the gut and oral microbiomes in individuals with RA and suggest potential ways of using microbiome composition for prognosis and diagnosis.

Using the algorithm on the layered structure of the retina and quantitative analysis of the automatic segmentation technique is the key to the early diagnosis of glaucoma and other retinopathy on optical coherence tomography. Existing methods require high quality image and have low reliability. This paper used the improved complex nonlinear diffuse filtering and other methods to solve this problem.This paper includes algorithm such as automatic threshold, improved complex nonlinear diffusion filtering, morphological operations and peak detection. Use the method for the segmentation of 20 retinal layers images which acquired on the self-builder OCT system, the boundary of inner limiting membrane(ILM), outer nuclear layer(ONL), the photoreceptor segments(IS/ OS) and the RPE_ChCap layer are detected accurately. At last, the photoreceptor layer thickness is measured.The results of segmentation and measurement are good corresponded with expert manual segmentation and measurements, retinal foveal measurements data is consistent with Zeiss Stratus OCT central retinal thickness 212+/-20 micro m.The algorithm proposed is prospective applied to clinical diagnosis of retinal diseases.

Previous studies have shown that methionine from root exudates affects the rhizosphere bacterial population involved in soil nitrogen fixation. A transgenic line of Zigongdongdou soybean cultivar (ZD91) that expresses Arabidopsis cystathionine γ-synthase resulting in an increased methionine production was examined for its influence to the rhizosphere bacterial population. Using 16S rRNA gene-based pyrosequencing analysis of the V4 region and DNA extracted from bacterial consortia collected from the rhizosphere of soybean plants grown in an agricultural field at the pod-setting stage, we characterized the populational structure of the bacterial community involved. In total, 87,267 sequences (approximately 10,908 per sample) were analyzed. We found that Acidobacteria, Proteobacteria, Bacteroidetes, Actinobacteria, Chloroflexi, Planctomycetes, Gemmatimonadetes, Firmicutes, and Verrucomicrobia constitute the dominant taxonomic groups in either the ZD91 transgenic line or parental cultivar ZD, and that there was no statistically significant difference in the rhizosphere bacterial community structure between the two cultivars.

The nature and changes of active substances at the surface of fresh and aged Cu-Cr impregnated carbon were examined by XPS in the paper. The result shows that at the surface of fresh sample there exist several Cu(II)-Cr(VI) compounds (A, B and C) and a little Cr(III) compound (D). A and B are two kinds of active substances for destroying CNCl and C is formed from the deterioration of A and B. In a humid environment, both A and B change into C and E, but the deactivation rate of B is higher than that of A. In an acidic environment (e.g., CO2), B is easily reduced to Cr(III)(D) and A is almost not affected. That is, B is very sensitive to an acidic environment; its basicity is stronger than that of A. When the humid air contaminated with CNCl flowed through the impregnated carbon, A and B are deactivated, parts of them change into C, and the others change into Cr(III)(CrCl3 and Cr2O3).

To better coordinate the interaction of inhalation and aerosol release, an intelligent adapter (IA) was developed for metered dose inhalers (MDIs). The adapter included three main units: a signal acquisition device, a micro-control-unit (MCU), and an actuation mechanism. To fully study the effectiveness of the intelligent adapter, an inhalation simulation experiment was done, and two bands of MDI were used for the experiment. The results indicated that, when inhalation, the intelligent adapter can press down the MDI automatically; moreover, this intelligent adapter could achieve an aerosol-release time Tr of 0.4 s for MDI A and 0.60 s for MDI B, which compares very well with the existing pure mechanical systems at 0.8 s and 1.0 s.