A vaccine capable of stimulating protective antiviral antibody responses is needed to curtail the global AIDS epidemic caused by HIV-1. Although rarely elicited during the course of natural infection ...or upon conventional vaccination, the membrane-proximal ectodomain region (MPER) of the HIV-1 glycoprotein of Mr 41,000 (gp41) envelope protein subunit is the target of 3 such human broadly neutralizing antibodies (BNAbs): 4E10, 2F5, and Z13e1. How these BNAbs bind to their lipid-embedded epitopes and mediate antiviral activity is unclear, but such information might offer important insight into a worldwide health imperative. Here, EPR and NMR techniques were used to define the manner in which these BNAbs differentially recognize viral membrane-encrypted residues configured within the L-shaped helix-hinge-helix MPER segment. Two distinct modes of antibody-mediated interference of viral infection were identified. 2F5, like 4E10, induces large conformational changes in the MPER relative to the membrane. However, although 4E10 straddles the hinge and extracts residues W672 and F673, 2F5 lifts up residues N-terminal to the hinge region, exposing L669 and W670. In contrast, Z13e1 effects little change in membrane orientation or conformation, but rather immobilizes the MPER hinge through extensive rigidifying surface contacts. Thus, BNAbs disrupt HIV-1 MPER fusogenic functions critical for virus entry into human CD4 T cells and macrophages either by preventing hinge motion or by perturbing MPER orientation. HIV-1 MPER features important for targeted vaccine design have been revealed, the implications of which extend to BNAb targets on other viral fusion proteins.
Highlights • History of Dendritic cell discovery as a member of mononuclear phagocyte system. • Recent discoveries of dendritic cell development and its transcriptional regulation. • Debate and open ...questions about dendritic cell development.
The widely used air plasma sprayed thermal barrier coatings (TBCs) in industrial gas turbine engines are limited by its durability. The failure of plasma sprayed TBCs in thermal cycling is usually ...induced by the spallation of ceramic coating within the ceramic coating near the top coat/bond coat interface. In this research, a multilayered ceramic coating architecture is introduced comprised of the layers of segmentation cracks, porous and dense. The segmented yttria stabilized zirconia (YSZ) layer was deposited at the substrate temperature of 750°C without any artificial cooling, which resulted in the formation of YSZ layer with obvious columnar crystal structure and segmentation cracks. And a dense top YSZ layer was also included on the top to restrain the penetration of oxygen and the molten calcium–magnesium–alumina-silicate (CMAS) glass deposits. Additionally, the conventional porous YSZ coating was preserved in order to get the low thermal conductivity. The thermal cycling tests show that the lifetime of the multilayered TBCs increases by a factor of 2 compared with that of the conventional one, which could attribute to the high strain tolerance and fracture toughness of the segmented and columnar microstructure. Oxidation resistance and CMAS corrosion resistance are also better for the multilayered TBCs compared with that of the conventional one, due to the suppression function of dense top YSZ layer. It is potential to obtain the high performance TBCs by adjusting plasma spraying.
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•A multilayered architecture is introduced, including segmentation cracking, porous and dense layer.•The thermal cycling lifetime of the multilayered TBCs is higher than the conventional one.•It is potential to obtain the high performance TBCs by adjusting plasma spraying.
Androgen receptor (AR) has essential roles during prostate cancer progression. With genome-wide AR-binding sites mapped to high resolution, studies have recently reported AR as a transcriptional ...repressor. How AR inhibits gene expression and how this contributes to prostate cancer, however, are incompletely understood. Through meta-analysis of microarray data, here we nominate nephroblastoma overexpressed (NOV) as a top androgen-repressed gene. We show that NOV is directly suppressed by androgen through the AR. AR occupies the NOV enhancer and communicates with the NOV promoter through DNA looping. AR activation recruits the polycomb group protein EZH2, which subsequently catalyzes histone H3 lysine 27 tri-methylation around the NOV promoter, thus leading to repressive chromatin remodeling and epigenetic silencing. Concordantly, AR and EZH2 inhibition synergistically restored NOV expression. NOV is downregulated in human prostate cancer wherein AR and EZH2 are upregulated. Functionally, NOV inhibits prostate cancer cell growth in vitro and in vivo. NOV reconstitution reverses androgen-induced cell growth and NOV knockdown drives androgen-independent cell growth. In addition, NOV expression is restored by hormone-deprivation therapies in mice and prostate cancer patients. Therefore, using NOV as a model gene we gained further understanding of the mechanisms underlying AR-mediated transcriptional repression. Our findings establish a tumor-suppressive role of NOV in prostate cancer and suggest that one important, but previously underestimated, manner by which AR contributes to prostate cancer progression is through inhibition of key tumor-suppressor genes.
Serological markers are important in the diagnosis of rheumatoid arthritis (RA) and other connective tissues diseases This study explored the clinical value of collagen triple helix repeat ...containing-1 (CTHRC1) and 14-3-3η protein, compared to routine markers, in the diagnosis of RA.
We recruited 103 RA patients, 105 non-RA patients (osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus) and 59 healthy controls. CTHRC1, 14-3-3η, anti-cyclic citrullinated peptide antibody (anti-CCP), anti-mutated citrullinated vimentin antibody (anti-MCV), rheumatoid factor and erythrocyte sedimentation rate (ESR) levels were measured, and their diagnostic value for RA evaluated and compared.
All laboratory indices were elevated in RA (P < 0.05). Of these, anti-MCV had the highest sensitivity (86.4%) and anti-CCP the highest specificity (94.5%). The areas under the curve (AUC) of CTHRC1, 14-3-3η, anti-CCP, anti-MCV, rheumatoid factor and ESR were 0.84, 0.81, 0.89, 0.91, 0.85 and 0.77 respectively (all P < 0.01). Anti-CCP and anti-MCV were the most valuable in the diagnosis of RA. The combination of anti-CCP and anti-MCV had the maximum Youden index, followed by the combination of anti-CCP and 14-3-3η. Binary logistic regression analysis showed that 14-3-3η had the largest odds ratio value (95% CI) at 5.1 (2.1-12.5) for RA.
CTHRC1 and 14-3-3η are promising serological indicators of RA, and when combined with anti-CCP, anti-MCV and ESR, can improve the diagnosis of this disease.
Summary
Our objective was to investigate the associations between polymorphisms in Wnt pathway genes and peak bone mineral density (BMD) and body composition in young Chinese men. Our study ...identified that
WNT5B
and
CTNNBL1
for both BMD and body composition, and
WNT4
and
CTNNB1
gene polymorphisms contribute to the variation in BMD and body composition in young Chinese men, respectively.
Introduction
Our objective was to investigate the associations between polymorphisms in
WNT4
,
WNT5B
,
WNT10B
,
WNT16
,
CTNNB1
, and
CTNNBL1
genes and peak bone mineral density (BMD), lean mass (LM), and fat mass (FM) in young Chinese men.
Methods
Using SNPscan
TM
kits, 51 single-nucleotide polymorphisms (SNPs) located in the 6 genes were genotyped in a total of 1214 subjects from 399 Chinese nuclear families. BMD, total lean mass (TLM), and total fat mass (TFM) were measured using dual energy X-ray absorptiometry (DXA). The associations between the 51 SNPs and peak BMD and body composition including the TLM, percentage lean mass (PLM), TFM, percentage fat mass (PFM), and the body mass index (BMI) were analyzed through quantitative transmission disequilibrium tests (QTDTs).
Results
For peak BMD, we found significant within-family associations of rs2240506, rs7308793, and rs4765830 in the
WNT5B
gene and rs10917157 in the
WNT4
gene with the lumbar spine BMD (all
P
< 0.05). We detected an association of rs11830202, rs3809269, rs1029628, and rs6489301 in the
WNT5B
gene and rs2293303 in the
CTNNB1
gene with body composition (all
P
< 0.05). For the
CTNNBL1
gene, six SNPs (rs6126098, rs6091103, rs238303, rs6067647, rs8126174, and rs4811144) were associated with peak BMD of the lumbar spine, femoral neck, or total hip (all
P
< 0.05). Furthermore, two of the six SNPs (rs8126174 and rs4811144) were associated with body composition.
Conclusions
This study identified
WNT5B
and
CTNNBL1
for peak BMD and body composition in males from the Han Chinese ethnic group, and the results suggest a site-specific gene regulation. The
WNT4
and
CTNNB1
gene polymorphisms contribute to the variation in peak BMD and body composition, respectively.
Surgery for acute type A aortic dissection in octogenarians is justified Tang, Gilbert H.L., MD, MSc; Malekan, Ramin, MD; Yu, Cindy J., NP ...
Journal of thoracic and cardiovascular surgery/The Journal of thoracic and cardiovascular surgery/The journal of thoracic and cardiovascular surgery,
03/2013, Letnik:
145, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Objective Surgery in octogenarians with acute type A aortic dissection is commonly avoided or denied because of the high surgical morbidity and mortality reported in elderly patients. We sought to ...compare clinical and quality of life outcomes between octogenarians and those aged less than 80 years who underwent surgical repair at New York Medical College. Methods A total of 101 cases of acute type A aortic dissection repair between July 2005 and December 2011 were retrospectively analyzed, comparing 21 octogenarians with 80 concurrent patients aged less than 80 years. All patients underwent corrective surgery (ascending/hemiarch replacement in 71; Bentall in 22; David procedure in 2; Wheat procedure in 4; total arch replacement in 2) using deep hypothermic circulatory arrest. During follow-up, the RAND 36-Item Short Form Health Survey Questionnaire was used to assess quality of life. Results Octogenarians (average, 85 years; range, 80-91 years) were compared with the younger group (average, 60 years; range, 30-79 years). The 2 groups had similar preoperative characteristics, but the younger group experienced more malperfusion (40% vs 9%, P = .002), were more likely to have undergone a Bentall procedure (26% vs 5%, P = .04), and had longer circulatory arrest times (20 ± 7 minutes vs 16 ± 9 minutes, P = .03). The overall hospital mortality was 9% (9/101). Among octogenarians, there were no hospital deaths, no late deaths during follow-up (mean, 17 months; range, 1-59 months), and emotional health scores were better than those of the younger patients ( P = .04). Conclusions Surgery for acute type A aortic dissection should be offered to octogenarians because excellent surgical and quality of life outcomes can be achieved even in this elderly population.
To evaluate the association between computed tomography (CT)-based imaging variables at the time of admission and haemorrhagic transformation (HT) after intravenous thrombolysis (IVT).
One hundred ...and eight patients who were treated with IVT for acute ischaemic stroke (AIS) during January 2021 to July 2023 were analysed retrospectively. The infarct location was classified as cortical or subcortical in accordance with the Alberta Stroke Program Early CT Score (ASPECTS) system. Logistic regression and receiver operating characteristic curve analyses were performed to determine the relationship between ischaemic variables and HT.
Of the total, 18 (16.7%) patients had HT and seven (6.5%) had symptomatic intracerebral haemorrhage (sICH). Multivariate analysis revealed that cortical ASPECTS was independently associated with HT (odds ratio OR, 0.197; 95% confidence interval CI, 0.076–0.511; p=0.001) and cortical ASPECTS was independently associated with sICH (OR, 0.066; 95% CI, 0.009–0.510; p=0.009). To predict HT and sICH, cortical ASPECTS (HT area under the curve AUC = 0.881, sICH AUC = 0.971) provided a higher AUC compared with ASPECTS (HT AUC = 0.850, sICH AUC = 0.918).
Cortical ASPECTS seen on CT at the time of admission is associated with HT and sICH after IVT.
Ternary homogeneous nucleation (THN) of H2 SO4 , NH3 and H2 O has been used to explain new particle formation in various atmospheric regions, yet laboratory measurements of THN have failed to ...reproduce atmospheric observations. Here, we report first laboratory observations of THN made under conditions relevant to the lower troposphere (H2 SO4 of 106 -107 cm-3 , NH3 of 0.08-20 ppbv, and a temperature of 288 K). Our observations show that NH3 can enhance atmospheric H2 SO4 aerosol nucleation and the enhancement factor (EF) in nucleation rate (J) due to NH3 (the ratio of J measured with vs. without NH3 ) increases linearly with increasing NH3 and increases with decreasing H2 SO4 and RH. Two chemical ionization mass spectrometers (CIMS) are used to measure H2 SO4 and NH3 , as well as possible impurities of amines in the nucleation system. Aerosol number concentrations are measured with a water condensation counter (CPC, TSI 3786). The slopes of Log J vs. Log H2 SO4 , Log J vs. Log RH, and Log J vs. Log NH3 are 3-5, 1-4, and 1, respectively. These slopes and the threshold of H2 SO4 required for the unity nucleation vary only fractionally in the presence and absence of NH3 . These observations can be used to improve aerosol nucleation models to assess how man-made SO2 and NH3 affect aerosol formation and CCN production at the global scale.
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