Since the World Health Assembly endorsed a plan to completely eradicate polio in 1988, the large-scale use of the attenuated oral poliovirus vaccine （OPV） has drastically decreased the number of ...polio cases. However, the OPV vaccine brings rare but serious adverse consequences, especially in the Type 2 vaccine strains.
Variations in coastline geometry caused by coastal engineering affect tides, storm surges, and storm tides. Three cluster land reclamation projects have been planned for construction in the Jiaojiang ...Estuary during the period from 2011 to 2023. They will cause significant changes in coastline geometry. In this study, a surge-tide coupled model was established based on a three-dimensional finite-volume coastal ocean model （FVCOM）. A series of numerical experiments were carried out to investigate the effects of variations in coastline geometry on tides, storm surges, and storm tides. This model was calibrated using data observed at the Haimen and Ruian gauge stations and then used to reproduce the tides, storm surges, and storm tides in the Jiaojiang Estuary caused by Typhoon Winnie in 1997. Results show that the high tide level, peak storm surge, and high storm tide level at the Haimen Gauge Station increased along with the completion of reclamation projects, and the maximum increments caused by the third project were 0.13 m, 0.50 m, and 0.43 m, respectively. The envelopes with maximum storm tide levels of 7.0 m and 8.0 m inside the river mouth appeared to move seaward, with the latter shifting 1.8 km, 3.3 km, and 4.4 km due to the first project, second project, and third project, respectively. The results achieved in this study contribute to reducing the effects of, and preventing storm disasters after the land reclamation in the Jiaojiang Estuary.
Background
Congenital heart disease (CHD) frequently manifests as a complex phenotype and approximately one‐third of cases may be caused by genetic factors. BCOR, an X‐linked gene encoding the ...corepressor of BCL6, has been demonstrated to be closely involved in human heart development. However, whether BCOR variants represent the genetic etiology underlying CHD needs further investigation.
Methods
We performed whole exome sequencing on CHD nuclear families and identified a candidate gene, BCOR, by robust bioinformatic analysis and medical literature searches. Targeted DNA sequencing of the candidate gene was conducted and then the association between variants and the risk of developing CHD was analyzed. The effects of BCOR mutations on gene expression, localization, protein interaction, and signaling pathways were evaluated in vitro.
Results
We identified a BCOR hemizygous missense variant (c.1448C>T, p.Pro483Leu) in a male proband presented with CHD/heterotaxy. Sanger sequencing confirmed that this variant was inherited from his asymptomatic mother. Interestingly, through literature searches, we observed another novel BCOR hemizygous missense variant (c.1619G>A, p.Arg540Gln) in a CHD patient with heterotaxy, supporting the pathogenic evidence of BCOR variants. Functional experiments conducted in vitro revealed that the variant p.Pro483Leu altered the subcellular localization of BCOR protein, disrupted its interaction with BCL6, and significantly promoted cell proliferation, whereas the variant p.Arg540Gln displayed no obvious effects. Nevertheless, transcriptional analysis revealed that down‐regulation of BCOR substantially enhanced the activities of mitogen‐activated protein and phosphoinositide 3‐kinase‐AKT signaling pathways, which are closely attributed to heart development. Targeted sequencing of 932 sporadic CHD patients enriched nine variants of BCOR predicted as likely rare and damaging and a septal defect was present in 81.8% (9/11) of them, including the two probands, which was consistent with the possible phenotype caused by BCOR defects.
Conclusions
The findings of the present study indicate that variants in BCOR may predispose individuals to CHD in the Chinese Han population.
We identified two BCOR missense variants (c.1448C>T and c.1619G>A) in two nuclear families. Functional experiments performed in vitro revealed the pathogenicity of two variants. Targeted sequencing in congenital heart disease (CHD) patients enriched nine variants of BCOR predicted as likely rare and damaging and the septal defect occupied the vast majority of cardiac‐related phenotypes. Our findings indicated that variants in BCOR may predispose individuals to CHD in the Chinese Han population.
Objectives
The objectives of this study were to analyze the relationship between serum globulin levels and immune restoration and HIV reservoir size during long‐term antiretroviral therapy (ART).
...Methods
We enrolled 13 patients living with HIV who had been receiving ART for 5 years. We measured levels of serum globulin, cell‐associated (CA) HIV DNA and RNA, and p24 antibody at 0, 1, 3, and 5 years of ART. CD38 and human leukocyte antigen – DR isotype (HLA‐DR) were used as activation markers for T‐cell activation. Serum concentrations of the inflammatory cytokines interferon gamma‐inducible protein (IP)‐10 and soluble CD163 (sCD163) were detected by enzyme‐linked immunosorbent assay. We analyzed the relationship between serum globulin levels, HIV reservoir size, immune restoration, T‐cell immune activation, and inflammatory levels during long‐term ART.
Results
Our data showed that serum globulin levels in people living with HIV were higher than in healthy controls and significantly decreased during the first year of ART. Serum globulin levels during long‐term ART were positively correlated with CA HIV DNA, CA HIV RNA, p24 antibody levels, and CD8+ T‐cell counts and negatively correlated with CD4+ T‐cell counts and CD4/CD8 ratios. Moreover, serum globulin levels were positively correlated with CD4+ and CD8+ T‐cell activation and the concentrations of inflammatory biomarkers IP‐10 and sCD163 during long‐term ART.
Conclusions
Our findings suggest that serum globulin levels may be associated with HIV reservoir size and immune restoration during long‐term ART.
Background
Congenital heart disease (CHD) is a class of cardiovascular defects that includes septal defects, outflow tract abnormalities, and valve defects. Human homolog of Drosophila headcase ...(HECA) is a novel cell cycle regulator whose role in CHD has not been elucidated. This is the first study to determine the frequency of HECA mutations in patients with CHD and the association between HECA variants and CHD.
Methods
In this study, we identified a candidate gene, HECA, by whole‐exome sequencing of an atrial septal defect family. To investigate the association between HECA variants and CHD risk, targeted exon sequencing was conducted in 689 individuals with sporadic CHD. We further analyzed the effect of HECA gene abnormalities on cardiomyocyte phenotype behavior and related signaling pathways by Western blotting, reverse transcription‐quantitative polymerase chain reaction, and scratch assay.
Results
We found a novel de novo mutation, c.409_410insA (p. W137fs), in the HECA gene and identified five rare deleterious variants that met the filtering criteria in 689 individuals with sporadic CHD. Fisher's exact test revealed a significant association between HECA variations and CHD compared with those in gnomADv2‐East Asians(p = 0.0027). Further functional analysis suggested that the variant p. W137fs resulted in a deficiency of the normal HECA protein, and HECA deficiency altered AC16 cell cycle progression, increased cell proliferation, and migration, and promoted the activation of the PDGF‐BB/PDGFRB/AKT pathway.
Conclusions
Our study identified HECA and its six rare variants, expanding the spectrum of genes associated with CHD pathogenesis in the Chinese population.
In this study, we identified a candidate gene HECA and its six rare variants, and Fisher's exact test reveals a significant association of HECA variations with CHD, comparing with those in gnomADv2‐East Asian. Further functional analysis suggested that the variant p.W137fs resulted in the deficiency of the normal HECA protein, and HECA deficiency altered AC16 cell cycle progression, increase cell proliferation and migration, and promoted activation of the PDGF‐BB/PDGFRB/AKT pathway.
Immune deficiency is one of the hallmarks of HIV infection and a major cause of adverse outcomes in people living with HIV (PLWH). Long‐lived memory CD8+ T cells (LLMCs) are essential executors of ...long‐term protective immunity; however, the generation and maintenance of LLMCs during chronic HIV infection are not well understood. In the present study, we analyzed circulating LLMCs in healthy controls (HCs) and PLWH with different disease statuses, including treatment naïve patients (TNs), complete responders (CRs), and immunological nonresponders (INRs). We found that both TNs and INRs showed severely compromised LLMCs compared with HCs and CRs, respectively. The decrease of LLMCs in TNs correlated positively with the reduction of their precursors, namely memory precursor effector T cells (MPECs), which might be associated with elevated pro‐inflammatory cytokines. Strikingly, INRs showed an accumulation of MPECs, which exhibited diminished responsiveness to interleukin 7 (IL‐7), thereby indicating abrogated differentiation into LLMCs. Moreover, in vitro studies showed that treatment with dexamethasone could improve the IL7‐phosphorylated (p)‐signal transducer and activator of transcription (STAT5) response by upregulating the expression of the interleukin 7 receptor (IL‐7Rα) on MPECs in INRs. These findings provide insights that will encourage the development of novel therapeutics to improve immune function in PLWH.
The loss of LLMCs is mainly attributed to poor MPEC maintenance in TNs, but is caused by differentiation failure of MPECs in INRs. IP‐10 serves as a determinant factor for MPEC survival in TNs, while impaired IL‐7 responsiveness of MPECs accounts for the differential defects in INRs.
The viral reservoir is the major hurdle in developing and establishing an HIV cure. Understanding factors affecting the size and decay of this reservoir is crucial for the development of therapeutic ...strategies. Recent work highlighted that CD8+ T cells are involved in the control of viral replication in ART-treated HIV-1-infected individuals, but how CD8+ T cells sense and restrict the HIV reservoir are not fully understood. Here, we demonstrate that a population of unconventional CD45RA+, PanKIR+, and/or NKG2A+ virtual memory CD8+ T cells (T
cells), which confer rapid and robust protective immunity against pathogens, plays an important role in restraining the HIV DNA reservoir in HIV-1-infected patients with effective ART. In patients undergoing ART, T
cells negatively correlate with HIV DNA and positively correlate with circulating IFN-α2 and IL-15. Moreover, T
cells constitutively express high levels of cytotoxic granule components, including granzyme B, perforin and granulysin, and demonstrate the capability to control HIV replication through both cytolytic and noncytolytic mechanisms. Furthermore, by using an ex vivo system, we showed that HIV reactivation is effectively suppressed by T
cells through KIR-mediated recognition. This study suggests that T
cells are a promising target to predict posttreatment virological control and to design immune-based interventions to reduce the reservoir size in ART-treated HIV-1-infected individuals.
Objectives
The study aimed to investigate the incidence of and risk factors for liver damage in patients with human immunodeficiency virus type‐1 (HIV‐1) mono‐infection receiving antiretroviral ...therapy (ART).
Methods
We retrospectively analyzed the clinical data of patients who were diagnosed with HIV‐1 infection and initiated ART from January to December 2017. Among them, 382 patients with HIV‐1 mono‐infection and normal baseline liver function were included in the analysis. The incidence of liver damage at each follow‐up point, and possible risk factors for liver damage were evaluated via COX regression survival analyses.
Results
The overall incidence of liver damage (grade I–IV) was 27.23% (interquartile range IQR: 26.38%–28.72%). Grade I liver damage was most common and accounted for 22.13% of cases (IQR: 21.06%–24.04%), while grade II liver damage accounted for 3.40% of cases (IQR: 3.19%–4.26%). COX regression and survival analyses revealed that baseline body mass index (BMI), alanine aminotransferase (ALT) level, CD4+ T cell count, HIV‐1 viral load, and the antiretroviral regimen were significantly correlated with the occurrence of liver damage. Moreover, baseline ALT levels and HIV‐1 viral load were identified as independent risk factors for liver damage in patients with HIV‐1 mono‐infection.
Conclusion
Liver damage is common in patients with HIV‐1 mono‐infection undergoing ART. Patients with risk factors for liver damage should be well‐informed before the initiation of ART, and liver function should be closely monitored during ART even in patients with normal liver function before ART.
Congenital heart disease (CHD) is the most common congenital birth defect, with a prevalence of 8.98‰ of all live births in China. PTPN11 has been known to be closely involved in heart developments. ...In this research, we carried out whole-exome sequencing in nine CHD families and identified eight rare deleterious missense variants of PTPN11 gene in nine probands by stringently filtering criteria. Sanger sequencing of these probands and their unaffected familiar members revealed that six damaging variants were de novo in seven CHD families. Then, targeted sequencing was used to assess the PTPN11 exon variants in 672 sporadic CHD cases and 399 unrelated controls and identified 7 deleterious missense variants in 8 patients. Fisher’s exact test reveals a significant association of PTPN11 variations with CHD (P=0.0289). We observed the distribution of different subtypes in CHD patients with PTPN11 variants and found atrial septal defect (ASD) is a prominent phenotype (58.8%, 10/17). In vitro functional assays revealed that the predicted PTPN11 variants disturb RAS-mitogen-activated protein kinase signaling activity by influencing the phosphorylation level of pathway proteins and increasing the proliferation and migration abilities of cardiomyocytes to different extents. Our findings demonstrated that PTPN11 variants were associated with increased risk of CHD development and may be served as an important susceptible genetic event for CHD, especially the ASD subphenotype.
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