[The measurements of the similarity of dynamic brain functional network].

Brain functional network changes over time along with the process of brain development, disease, and aging. However, most of the available measurements for evaluation of the difference (or similarity) between the individual brain functional networks are for charactering static networks, which do not work with the dynamic characteristics of the brain networks that typically involve a long-span and large-scale evolution over the time. The current study proposes an index for measuring the similarity of dynamic brain networks, named as dynamic network similarity (DNS). It measures the similarity by combining the "evolutional" and "structural" properties of the dynamic network. Four sets of simulated dynamic networks with different evolutional and structural properties (varying amplitude of changes, trend of changes, distribution of connectivity strength, range of connectivity strength) were generated to validate the performance of DNS. In addition, real world imaging datasets, acquired from 13 stroke patients who were treated by transcranial direct current stimulation (tDCS), were used to further validate the proposed method and compared with the traditional similarity measurements that were developed for static network similarity. The results showed that DNS was significantly correlated with the varying amplitude of changes, trend of changes, distribution of connectivity strength and range of connectivity strength of the dynamic networks. DNS was able to appropriately measure the significant similarity of the dynamics of network changes over the time for the patients before and after the tDCS treatments. However, the traditional methods failed, which showed significantly differences between the data before and after the tDCS treatments. The experiment results demonstrate that DNS may robustly measure the similarity of evolutional and structural properties of dynamic networks. The new method appears to be superior to the traditional methods in that the new one is capable of assessing the temporal similarity of dynamic functional imaging data.

Association between peroxisome proliferator-activated receptor γ gene polymorphism and susceptibility to northwest dryness syndrome.

OBJECTIVE: To investigate the relationship between gene polymorphism of peroxisome proliferator- activated receptor (PPAR) and susceptibility to northwest dryness syndrome (NDS). METHODS: The polymorphisms of 11 PPARγ gene loci rs10510418, rs12633551, rs1373640, rs17036188, rs2921190, rs4135247, rs4135275, rs4135283, rs6768587, rs709156, and rs7615916 were detected in 249 patients with NDS and 260 patients with non-NDS (control group) by using Snapshot single-nucleotide polymorphism typing technology. RESULTS: All locus detections were in accordance with Hardy-Weinberg equilibrium test. Compared with the control group, rs2921190 genotype frequency showed statistical difference in the NDS group (P < 0.05). Two-two comparison result showed that CC genotype frequency in the NDS group was higher than that in the control group. CT and TT genotype distribution frequencies showed differences between the two groups. The rare allele frequency in the NDS group was lower than that of the control group (P < 0.01). Multi-factor logistic regression analysis showed that the age and genotype entered the regression equation. The subjects in the age bracket 30-55 and 45-45 were 1.796 and 1.561 times likely, respectively, than those in other age brackets to contract NDS,. The patients with CC genotype was only 0.524 times likely than those with CT/TT genotype to suffer from NDS. CONCLUSION: PPARγ gene rs2921190 polymorphism was correlated with the susceptibility to NDS.

[Prevalence of acute coronary heart disease among farmers in Panyu, Guangzhou: a 20-year population-based study].

OBJECTIVE: To monitor the incidence change of acute coronary heart events in the all-ages farmers in Panyu District, Guangzhou City during 1991-2001 and 2010-2011. METHODS: The surveillance on the same defined population as that from the PRC-USA cooperative epidemiologic project on the cardiovascular and pulmonary diseases 30-year ago was carried out in Panyu, Guangzhou in 1991-2001 and 2010-2011. The crude incidence of acute coronary events and the age-standardized incidence rate were calculated by the year, gender and age, and standardized with the world standard population age distribution. Incidences at the two different periods were compared. The annual average changing rate of the incidence was obtained by the regression analysis methods. RESULTS: In the 11 consecutive years of 1991-2001, a upward trend on the incidence of acute coronary events among the farmers in women in Panyu District was found (P < 0.05). The incidence of the acute coronary events in the year of 2010-2011 was significantly higher than that in the year of 1991 to 2001 [34.06 per 100 000 (age-adjusted rate as 28.50 per 100 000) versus 16.14 per 100 000 (age-adjusted rate as 16.57 per 100 000), P < 0.05]. The age-adjusted rate increased by 83.04%. Peak incidence of acute coronary events in males was noticed in 75-79 age group, and in 80-84 age group in females. Comparing to the period of 1991-2001, the largest incidence increases appeared in the age groups of 35-39 and 75-79 years in males, while in the age groups of 50-54 and 65-69 years in females. Up to 47.37% (36/76) events occurred on the age group older than 75 years, raised by 40.44% comparing to that in 1991-2001 (33.73%, 56/166). CONCLUSIONS: The incidence of acute coronary events among farmers in Panyu District is at middle or low level of China but there is an increasing trend in acute coronary incidence from 1991 to 2011. Our results suggest that the prevention and treatment on acute coronary syndrome should be strengthened, and especially on the age group with the largest increase of disease incidence.

Microstructure Evolution and Strengthening Mechanism of Dual-Phase Mg-8.3Li-3.1Al-1.09Si Alloys during Warm Rolling.

In this study, the rolling process of the warm-rolled duplex-phase Mg-8.3Li-3.1Al-1.09Si alloy and the strengthening mechanism of as-rolled Mg-Li alloy were investigated. The highest ultimate tensile strength (UTS, 323.66 ± 19.89 MPa) could be obtained using a three-pass rolling process with a 30% thickness reduction for each pass at 553 K. The strength of the as-rolled LAS831 alloy is determined by a combination of second-phase strengthening, grain refinement strengthening, dislocation strengthening, and load-transfer reinforcement. Of these factors, dislocation strengthening, which is caused by strain hardening of the α-Mg phase, can produce a good strengthening effect but also cause a decrease in plasticity. The Mg2Si phase is broken up into particles or strips during the rolling process. After three passes, the AlLi particles were transformed into an AlLi phase, and the Mg2Si particles and nanosized AlLi particles strengthened the second phase to form a hard phase. The average size of the DRXed ß-Li grains decreased with each successive rolling pass, and the average size of recrystallized grains in the three-pass-rolled LAS831 alloy became as low as 0.27 µm. The interface between the strip-like Mg2Si phase and the α-Mg phase is characterized by semicoherent bonding, which can promote the transfer of tensile and shear forces from the matrix to the strip-like Mg2Si phase, thereby improving the strength of the matrix and thus strengthening the LAS831 alloy.

Improved magnetic resonance myelin water imaging using multi-channel denoising convolutional neural networks (MCDnCNN).

Background: Myelin water imaging (MWI) is powerful and important for studying and diagnosing neurological and psychiatric diseases. In particular, myelin water fraction (MWF) is derived from MWI data for quantifying myelination. However, MWF estimation is typically sensitive to noise. Improving the accuracy of MWF estimation based on WMI data acquired using a magnetic resonance (MR) multiple gradient recalled echo (mGRE) imaging sequence is desired. Methods: The proposed method employs a recently introduced the multi-channel denoising convolutional neural networks (MCDnCNN). Five different MCDnCNN models, denoted as Delevel1, Delevel2, Delevel3, Delevel4 and DelevelMix corresponding to five noise levels (Level1, Level2, Level3, Level4 and LevelMix), were trained using the data of the first echo of the mGRE brain images acquired from 15 healthy human subjects. Using simulated noisy data that employed a hollow cylinder model, we first evaluated the improvement in estimating MWF based on data denoised by the five different MCDnCNNs, by comparing the MWF maps calculated from the denoised data with ground truth. Next, we again evaluated the improvement using real-world in vivo datasets of 11 human participants acquired using the mGRE sequence. The datasets were first denoised by five different MCDnCNNs (Delevel1, 2, 3, 4 and DelevelMix), and subsequently their MWF maps were calculated and compared with the MWF maps directly calculated from the raw mGRE images without being denoised. Results: Experiments using the simulation data denoised by the appropriate MCDnCNN models showed that the standard deviation (SD) of the absolute error (AE) of the derived MWF results was significantly reduced (maximal reduction =15.5%, Level3 simulated noisy data, orientation angle =0, all the five MCDnCNN models). In the test using in vivo data, estimating MWF based on data particularly denoised by the appropriate MCDnCNN models was found to be the best, compared to otherwise not using the appropriate models. The results demonstrated that the appropriate MCDnCNN models may permit high-quality MWF mapping, i.e., substantial reduction of random variation in estimating MWF-maps while preserving accuracy and structural details. Conclusions: Appropriate MCDnCNN models as proposed may improve both the accuracy and precision in estimating MWF maps, thereby making it a more clinically feasible alternative.

Comparison of H7N9 and H9N2 influenza infections in mouse model unravels the importance of early innate immune response in host protection.

The outcome of infection with influenza A virus is determined by a complex virus-host interaction. A new H7N9 virus of avian origin crossed the species barrier to infect humans, causing high mortality and emerged as a potential pandemic threat. The mechanisms underlying the virulence and pathogenicity of H7N9 virus remains elusive. H7N9 virus originated from a genetic assortment that involved the avian H9N2 virus, which was the donor of the six internal genes. Unlike the H7N9 virus, the H9N2 virus caused only mild phenotype in infected mice. In this study, we used the mouse infection model to dissect the difference in the host response between the H7N9 and H9N2 viruses. Through analyzing transcriptomics of infected lungs, we surprisingly found that the H9N2 infection elicited an earlier induction of innate immunity than H7N9 infection. This finding was further corroborated by an immunohistochemical study demonstrating earlier recruitment of macrophage to the H9N2-infected lung than the H7N9-infected lung, which could occur as early as 6 hours post infection. In contrast, H7N9 infection was characterized by a late, strong lung CD8+ T cell response that is more robust than H9N2 infection. The different pattern of immune response may underlie more severe lung pathology caused by H7N9 infection compared to H9N2 infection. Finally, we could show that co-infection of the H9N2 virus protected mice from the challenge of both H7N9 and PR8 viruses, thereby strengthening the importance of the induction of an early innate immunity in the host's defense against influenza infection. Collectively, our study unraveled a previously unidentified difference in host response between H7N9 and H9N2 infection and shed new insight on how virus-host interaction shapes the in vivo outcome of influenza infection.

Granulocytic myeloid-derived suppressor cells increase infection risk via the IDO/IL-10 pathway in patients with hepatitis B virus-related liver failure.

Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) results in high susceptibility to infection. Although granulocytic myeloid-derived suppressor cells (gMDSC) are elevated in patients with HBV-ACLF, their role in HBV-ACLF pathogenesis is unknown. To elucidate the mechanism of gMDSC expansion and susceptibility to infection in HBV-ACLF patients, we analyzed the proportion of gMDSC in the peripheral blood and organ tissues of patients with HBV-ACLF and an ACLF mouse model established by continuous injection (eight times) of Concanavalin by flow cytometry and immunohistochemistry. We found that the proportion of gMDSC increased significantly in the blood and liver of patients with HBV-ACLF. This increase was positively correlated with disease severity, prognosis, and infection. gMDSC percentages were higher in peripheral blood, liver, spleen, and bone marrow than control levels in the ACLF mouse model. Immunofluorescence revealed that the gMDSC count increased in the liver of patients with HBV-ACLF as well as in the liver and spleen of ACLF mice. We further exposed peripheral blood monocyte cells from healthy donors to plasma from HBV-ACLF patients, recombinant cytokines, or their inhibitor, and found that TNF-α led to gMDSC expansion and significant upregulation of indoleamine 2, 3-dioxygenase (IDO), while blocking TNF-α signaling decreased gMDSC. Moreover, we detected proliferation and cytokine secretion of T lymphocytes when purified gMDSC was co-cultured with Pan T cells or IDO inhibitor and found that TNF-α-induced gMDSC inhibited T cell proliferation and interferon-γ production through the IDO signaling pathway. Lastly, the ability of gMDSC to phagocytose bacteria was low in patients with HBV-ACLF. Our findings elucidate HBV-ACLF pathogenesis and provide potential therapeutic targets.

A genetic variant in IL-6 lowering its expression is protective for critical patients with COVID-19.

Critical coronavirus disease 2019 (COVID-19) is associated with high mortality and potential genetic factors have been reported to be involved in the development of critical COVID-19. We performed a genome-wide association study to identify the genetic factors responsible for developing critical COVID-19. 632 critical patients with COVID-19 and 3021 healthy controls from the Chinese population were recruited. First, we identified a genome-wide significant difference of IL-6 rs2069837 (p = 9.73 × 10-15, OR = 0.41) between 437 critical patients with COVID-19 and 2551 normal controls in the discovery cohort. When replicated these findings in a set of 195 patients with critical COVID-19 and 470 healthy controls, we detected significant association of rs2069837 with COVID-19 (p = 8.89 × 10-3, OR = 0.67). This variant surpassed the formal threshold for genome-wide significance (combined p = 4.64 × 10-16, OR = 0.49). Further analysis revealed that there was a significantly stronger expression of IL-6 in the serum from patients with critical COVID-19 than in that from patients with asymptomatic COVID-19. An in vitro assay showed that the A to G allele changes in rs2069837 within IL-6 obviously decreased the luciferase expression activity. When analyzing the effect of this variant on the IL-6 in the serum based on the rs2069837 genotype, we found that the A to G variation in rs2069837 decreased the expression of IL-6, especially in the male. Overall, we identified a genetic variant in IL-6 that protects against critical conditions with COVID-19 though decreasing IL-6 expression in the serum.

Dynamic blood single-cell immune responses in patients with COVID-19.

The 2019 coronavirus disease (COVID-19) outbreak caused by the SARS-CoV-2 virus is an ongoing global health emergency. However, the virus' pathogenesis remains unclear, and there is no cure for the disease. We investigated the dynamic changes of blood immune response in patients with COVID-19 at different stages by using 5' gene expression, T cell receptor (TCR), and B cell receptors (BCR) V(D)J transcriptome analysis at a single-cell resolution. We obtained single-cell mRNA sequencing (scRNA-seq) data of 341,420 peripheral blood mononuclear cells (PBMCs) and 185,430 clonotypic T cells and 28,802 clonotypic B cells from 25 samples of 16 patients with COVID-19 for dynamic studies. In addition, we used three control samples. We found expansion of dendritic cells (DCs), CD14+ monocytes, and megakaryocytes progenitor cells (MP)/platelets and a reduction of naïve CD4+ T lymphocytes in patients with COVID-19, along with a significant decrease of CD8+ T lymphocytes, and natural killer cells (NKs) in patients in critical condition. The type I interferon (IFN-I), mitogen-activated protein kinase (MAPK), and ferroptosis pathways were activated while the disease was active, and recovered gradually after patient conditions improved. Consistent with this finding, the mRNA level of IFN-I signal-induced gene IFI27 was significantly increased in patients with COVID-19 compared with that of the controls in a validation cohort that included 38 patients and 35 controls. The concentration of interferon-α (IFN-α) in the serum of patients with COVID-19 increased significantly compared with that of the controls in an additional cohort of 215 patients with COVID-19 and 106 controls, further suggesting the important role of the IFN-I pathway in the immune response of COVID-19. TCR and BCR sequences analyses indicated that patients with COVID-19 developed specific immune responses against SARS-CoV-2 antigens. Our study reveals a dynamic landscape of human blood immune responses to SARS-CoV-2 infection, providing clues for therapeutic potentials in treating COVID-19.

A Systemic Prime-Intrarectal Pull Strategy Raises Rectum-Resident CD8+ T Cells for Effective Protection in a Murine Model of LM-OVA Infection.

As the entry sites of many pathogens such as human immunodeficiency virus (HIV), mucosal sites are defended by rapidly reacting resident memory T cells (TRM). TRMs represent a special subpopulation of memory T cells that persist long term in non-lymphoid sites without entering the circulation and provide the "sensing and alarming" role in the first-line defense against infection. The rectum and vagina are the two primary mucosal portals for HIV entry. However, compared to vaginal TRM, rectal TRM is poorly understood. Herein, we investigated the optimal vaccination strategy to induce rectal TRM. We identified an intranasal prime-intrarectal boost (pull) strategy that is effective in engaging rectal TRM alongside circulating memory T cells and demonstrated its protective efficacy in mice against infection of Listeria monocytogenes. On the contrary, the same vaccine delivered via either intranasal or intrarectal route failed to raise rectal TRM, setting it apart from vaginal TRM, which can be induced by both intranasal and intrarectal immunizations. Moreover, intramuscular prime was also effective in inducing rectal TRM in combination with intrarectal pull, highlighting the need of a primed systemic T cell response. A comparison of different pull modalities led to the identification that raising rectal TRM is mainly driven by local antigen presence. We further demonstrated the interval between prime and boost steps to be critical for the induction of rectal TRM, revealing circulating recently activated CD8+ T cells as the likely primary pullable precursor of rectal TRM. Altogether, our studies lay a new framework for harnessing rectal TRM in vaccine development.

IFN-κ suppresses the replication of influenza A viruses through the IFNAR-MAPK-Fos-CHD6 axis.

Type I interferons (IFNs) are the first line of defense against viral infection. Using a mouse model of influenza A virus infection, we found that IFN-κ was one of the earliest responding type I IFNs after infection with H9N2, a low-pathogenic avian influenza A virus, whereas this early induction did not occur upon infection with the epidemic-causing H7N9 virus. IFN-κ efficiently suppressed the replication of various influenza viruses in cultured human lung cells, and chromodomain helicase DNA binding protein 6 (CHD6) was the major effector for the antiviral activity of IFN-κ, but not for that of IFN-α or IFN-ß. The induction of CHD6 required both of the type I IFN receptor subunits IFNAR1 and IFNAR2, the mitogen-activated protein kinase (MAPK) p38, and the transcription factor c-Fos but was independent of signal transducer and activator of transcription 1 (STAT1) activity. In addition, we showed that pretreatment with IFN-κ protected mice from lethal influenza viral challenge. Together, our findings identify an IFN-κ-specific pathway that constrains influenza A virus and provide evidence that IFN-κ may have potential as a preventative and therapeutic agent against influenza A virus.

AXL promotes Zika virus infection in astrocytes by antagonizing type I interferon signalling.

Zika virus (ZIKV) is associated with neonatal microcephaly and Guillain-Barré syndrome1,2. While progress has been made in understanding the causal link between ZIKV infection and microcephaly3-9, the life cycle and pathogenesis of ZIKV are less well understood. In particular, there are conflicting reports on the role of AXL, a TAM family kinase receptor that was initially described as the entry receptor for ZIKV10-22. Here, we show that while genetic ablation of AXL protected primary human astrocytes and astrocytoma cell lines from ZIKV infection, AXL knockout did not block the entry of ZIKV. We found, instead, that the presence of AXL attenuated the ZIKV-induced activation of type I interferon (IFN) signalling genes, including several type I IFNs and IFN-stimulating genes. Knocking out type I IFN receptor α chain (IFNAR1) restored the vulnerability of AXL knockout astrocytes to ZIKV infection. Further experiments suggested that AXL regulates the expression of SOCS1, a known type I IFN signalling suppressor, in a STAT1/STAT2-dependent manner. Collectively, our results demonstrate that AXL is unlikely to function as an entry receptor for ZIKV and may instead promote ZIKV infection in human astrocytes by antagonizing type I IFN signalling.

Characterization of rifampin-resistant isolates of Mycobacterium tuberculosis from Sichuan in China.

Rifampin is a key component of standard short-course first-line therapy against Mycobacterium tuberculosis, and rifampin resistance of this pathogen has been reported to be related to rpoB gene mutations. The objective of this study was to characterize the rpoB gene mutations in rifampin-resistant M. tuberculosis isolates circulated in Sichuan. Sequencing of rpoB gene and spoligotyping were performed on 268 randomly selected isolates from January 2008 to May 2010. The results indicated that 207 (97.2%) rifampin-resistant isolates had mutations at 26 codons in the amplified region with 50 different genotypes, while 1 (1.8%) of 55 susceptible isolates had a nonsense mutation. The most common mutations were in codon 531 (55.9%), 526 (16.4%), 516 (10.3%) and 511 (8.9%). Among the 213 resistant isolates, 150 (70.4%) belonged to the Beijing family and mutation at codon 531 (TCG→TTG) was associated with Beijing genotype (χ(2), 9.8305; p, 0.0017). It is demonstrated that the frequency of 511 (CTG→CCG) mutations in Sichuan was higher than in other provinces of China, as well as other geographic regions worldwide. It is suggested that only a small portion (2.7%) of rifampin-resistant Beijing genotype isolates in Sichuan be spread by clonal expansion during the study period.