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Organic proteins are attractive owing to their unique optical properties, remarkable mechanical characteristics, and biocompatibility. Manufacturing multifunctional structures on organic protein films is essential for practical applications; however, the controllable fabrication of specific structures remains challenging. Herein, we propose a strategy for creating specific structures on silk film surfaces by modulating the bulging and ablation of organic materials. Unique surface morphologies such as bulges and craters with continuously varying diameters were generated based on the controlled ultrafast laser-induced crystal-form transition and plasma ablation of the silk protein. Owing to the anisotropic optical properties of the bulge/crater structures with different periods, the fabricated organic films can be used for large-scale inkless color printing. By simultaneously engineering bulge/crater structures, we designed and demonstrated organic film-based optical functional devices that achieves holographic imaging and optical focusing. This study provides a promising strategy for the fabrication of multifunctional micro/nanostructures that can broaden the potential applications of organic materials.

The lack of success in clinical trials for HIV vaccines highlights the need to explore novel strategies for vaccine development. Research on highly exposed seronegative (HESN) HIV-resistant Kenyan female sex workers revealed naturally protective immunity is correlated with a focused immune response mediated by virus-specific CD8 T cells. Further studies indicated that the immune response is unconventionally focused on highly conserved sequences around HIV viral protease cleavage sites (VPCS). Thus, taking an unconventional approach to HIV vaccine development, we designed lipid nanoparticles loaded with mRNA that encodes multi-epitopes of VPCS (MEVPCS-mRNA LNP), a strategic design to boost antigen presentation by dendritic cells, promoting effective cellular immunity. Furthermore, we developed a novel cold-chain compatible mRNA LNP formulation, ensuring long-term stability and compatibility with cold-chain storage/transport, widening accessibility of mRNA LNP vaccine in low-income countries. The in-vivo mouse study demonstrated that the vaccinated group generated VPCS-specific CD8 memory T cells, both systemically and at mucosal sites of viral entry. The MEVPCS-mRNA LNP vaccine-induced CD8 T cell immunity closely resembled that of the HESN group and displayed a polyfunctional profile. Notably, it induced minimal to no activation of CD4 T cells. This proof-of-concept study underscores the potential of the MEVPCS-mRNA LNP vaccine in eliciting CD8 T cell memory specific to the highly conserved multiple VPCS, consequently having a broad coverage in human populations and limiting viral escape mutation. The MEVPCS-mRNA LNP vaccine holds promise as a candidate for an effective prophylactic HIV vaccine.

Abstract Objective To compare the computed tomography (CT) images of patients with locally advanced gastric cancer (GC) before and after neoadjuvant chemotherapy (NAC) in order to identify CT features that could predict pathological response to NAC. Methods We included patients with locally advanced GC who underwent gastrectomy after NAC from September 2016 to September 2021. We retrieved and collected the patients’ clinicopathological characteristics and CT images before and after NAC. We analyzed CT features that could differentiate responders from non-responders and established a logistic regression equation based on these features. Results We included 97 patients (69 [71.1%] men; median [range] age, 60 [26–75] years) in this study, including 66 (68.0%) responders and 31 (32.0%) non-responders. No clinicopathological variable prior to treatment was significantly associated with pathological response. Out of 16 features, three features (ratio of tumor thickness reduction, ratio of reduction of primary tumor attenuation in arterial phase, and ratio of reduction of largest lymph node attenuation in venous phase) on logistic regression analysis were used to establish a regression equation that demonstrated good discrimination performance in predicting pathological response (area under receiver operating characteristic curve 0.955; 95% CI, 0.911–0.998). Conclusion Logistic regression equation based on three CT features can help predict the pathological response of patients with locally advanced GC to NAC.

Glycosaminoglycans (GAGs) are long linear polysaccharides found in every mammalian tissue. Previously thought only to be involved in cellular structure or hydration, GAGs are now known to be involved in cell signaling and protein modulation in cellular adhesion, growth, proliferation, and anti-coagulation. In this study, we showed that GAGs have an inhibitory effect on the IL-1β-stimulated mRNA expression of IL-6 and IL-8. Exogenous heparin (p < 0.0001), heparan (p < 0.0001), chondroitin (p < 0.049), dermatan (p < 0.0027), and hyaluronan (p < 0.0005) significantly reduced the IL-1β-induced IL-8 mRNA expression in HeLa cells. Exogenous heparin (p < 0.0001), heparan (p < 0.0001), and dermatan (p < 0.0027) also significantly reduced IL-1β-induced IL-6 mRNA expression in HeLa cells, but exogenous chondroitin and hyaluronan had no significant effect. The exogenous GAGs may reduce the transcription of these inflammatory cytokines through binding to TILRR, a co-receptor of IL-1R1, and block/reduce the interactions of TILRR with IL-1R1.

Purpose The aim of this study was to compare the effectiveness and outcomes of percutaneous ablation guided by ultrasonography (US) and computed tomography (CT) in colorectal liver oligometastases (CLOM). Methods This study included patients with CLOM treated with percutaneous ablation from January 2008 to January 2021 in this observational study. Only lesions visualized on both CT and US images were further analyzed according to whether patients’ initial ablation treatments utilized US guidance or CT guidance. The Kaplan-Meier method was used to estimate local tumor progression (LTP)–free survival after propensity score matching (PSM). The LTP-free survival and treatment-related outcomes were compared between these two groups. Results PSM identified 116 patients from each group, with 269 and 238 lesions in the USguided and CT-guided groups, respectively. US-guided ablation had a shorter average procedure time and lower cost than CT-guided ablation (27.54±12.06 minutes vs. 32.70±13.88 minutes, P=0.003; $2,175.13±618.17 vs. $2,455.49±710.25, P=0.002). For patients >60 years of age, the cumulative LTP rate at 1 year was lower in the US-guided group than in the CT-guided group (17.8% vs. 25.1%, P=0.038). For patients with perivascular liver lesions, the cumulative LTP rate at 1 year was lower in the US-guided group (14.4% vs. 28.2%, P=0.040). Conclusion For patients whose age is >60 years or who have perivascular liver lesions, USguided ablation is better than CT-guided ablation, with a shorter treatment time and lower costs when both ablation methods are feasible for patients.

Abstract This research work proposes an equivalent approach modelling the peculiar hysteretic behavior of passive variable friction damper, for engineers who call for a simplified way to simulate such damper in anti-earthquake engineering practice with acceptable accuracy. This approach models the special nonlinear behavior of the damper via paralleling 3 basic link elements that commonly built-in commercially available structural analysis software, instead of developing direct hysteretic model that demands for both post development functionality on software side and programming skill on engineer side. The mathematical derivation and analytical geometric equating work are comprehensively conducted. The numerical accuracy of analysis output yielded using equivalent model is digitally verified against the one yielded using generic FEM simulation of the same damper subject to several loading cases. Code-automated optimization workflow for yielding product-wise modelling parameters is developed that is convenient and straightforward for application by engineers without requirement of high expertise, which is demonstrated by generating optimized parameters to equivalently model tested specimen. Article highlights Passive variable friction damper can be modelled by assembling friction spring, elastic spring and wen model into parallel. Code-automated optimization process can locate the most ideal modelling parameters combination in predefined numeral fields. Hysteretic behaviors yielded from equivalent modelling approach match well corresponding ones from generic FEA simulation.

The author wishes to make the following corrections to this paper [...]

PURPOSEWe aimed to explore the feasibility and clinical effectiveness of percutaneous CT-guided iodine-125 (¹²⁵I) brachytherapy combined with chemotherapy for the treatment of patients with unresectable or locally advanced pancreatic carcinoma (PC).METHODSWe retrospectively reviewed 66 patients with Stage III and IV PC who had received chemotherapy. A total of 35 (53%) patients receiving 125I brachytherapy and chemotherapy (gemcitabine + cisplatin, GP) were classified as Group A, and 31 (47%) patients who received GP chemotherapy alone were categorized as Group B. The evaluated indications were local control rate (LCR), local progression-free survival (LPFS), overall survival (OS), treatment-related complications, and the degree of symptom relief. Kaplan-Meier curves, log-rank test and Cox regression models were generated and used for further analysis to identify predictors of outcomes.RESULTSThe median follow-up time was 6.00±0.84 months. The 1-, 3-, 6-, 12- and 18-month LCRs for Group A were 100% (35/35), 89.3% (25/28), 71.4% (15/21), 37.5% (3/8) and 33.3% (1/3), respectively; and those for Group B were 87.1% (27/31), 69.6% (16/23), 41.2% (7/17), 14.3% (1/7) and 0% (0/3), respectively. The LCR differed at 1-, 3- and 6-months (P = 0.032; P = 0.009; P = 0.030; respectively). The median LPFS was 7.00±0.30 months and 5.00±0.75 months for Groups A and B (P = 0.023), respectively; however, the median OS of the groups were not significantly different (8.00±0.77 months vs. 6.00±1.04 months. P = 0.917). No life-threatening complications occurred during or after the procedures. Patients in Group A experienced better pain control and relief of abdominal distension than those in Group B.CONCLUSIONCT-guided 125I brachytherapy is a feasible, safe, and valuable treatment for patients with unresectable PC.

Summary: Background: TILRR (Toll-like Interleukin-1 Receptor Regulator) is a modulator of many genes in NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling. It promotes the production of inflammatory mediators and the migration of immune cells. Recently, we showed that TILRR protein circulates in human blood. Thus, it could influence systemic inflammation. Systemic and mucosal inflammations increase the susceptibility to HIV infection. In this study, we analyzed the TILRR protein levels of the archived plasma samples of women enrolled in the Pumwani cohort to determine whether the plasma TILRR protein levels before seroconversion are correlated with differential risk of HIV seroconversion. Methods: TILRR protein of 941 archived HIV negative plasma samples from 390 women who were HIV negative at the cohort enrollment was quantified with an in-house developed multiplex bead array method. Proinflammatory cytokines/chemokines were measured using a 14-plex bead array method. Spearman rank correlation analysis was used to determine the correlation between plasma TILRR protein and proinflammatory cytokines/chemokines. Kaplan-Meier survival analysis was conducted to evaluate whether the median plasma TILRR protein levels correlate with increased risk of HIV seroconversion. Findings: The level of plasma TILRR protein was positively correlated with plasma IL-1β (rho: 0.2593, p

Abstract Background Due to the unique anatomical location of retroperitoneal metastatic lymph nodes, current treatment options are limited. This study was designed to explore the clinical efficacy and prognostic factors of CT-guided 125I brachytherapy for the treatment of retroperitoneal metastatic lymph nodes. Methods We retrospectively evaluated 92 patients received 125I brachytherapy for retroperitoneal metastatic lymph nodes. A layered Cox proportional hazards model was established to filter out the independent factors affecting local tumor progression-free survival (LTPFS). Results The median LTPFS was 8 months. Metastatic lymph node with uniform density (p-0.009), clear boundaries (p-0.011), regular morphology (P

Background: We examined associations between NFκB1 polymorphisms and influenza A (H1N1) clinical outcomes in Canadian. Methods: A total of thirty-six Caucasian patients admitted to the intensive care unit (ICU) in hospitals in Canada were recruited during the 2009 H1N1 pandemic. Genomic DNA was extracted from the whole blood samples. The NFkB1 gene was targeted for genotyping using next-generation sequencing technology—Roche 454. Results: A total of 136 single nucleotide polymorphisms (SNPs) were discovered within the NFκB1 gene. Among them, 63 SNPs were significantly enriched in patients admitted in the ICU (p < 0.05) compared with the British Caucasian population in the 1000 Genomes study. These enriched SNPs are mainly intron variants, and only two are exon SNPs from the non-transcribing portion of the NFκB1 gene. Conclusions: Genetic variations in the NFκB1 gene could influence clinical outcomes of pandemic H1N1 infections. Our findings showed that sequence variations of the NFκB1 gene might influence patient response to influenza infection.

Natural immunity against HIV has been observed in many individuals in the world. Among them, a group of female sex workers enrolled in the Pumwani sex worker cohort remained HIV uninfected for more than 30 years despite high-risk sex work. Many studies have been carried out to understand this natural immunity to HIV in the hope to develop effective vaccines and preventions. This review focuses on two such examples. These studies started from identifying immunogenetic or genetic associations with resistance to HIV acquisition, and followed up with an in-depth investigation to understand the biological relevance of the correlations of protection, and to develop and test novel vaccines and preventions.

Abstract Iodine‐125 (125I) brachytherapy, a promising form of radiotherapy, is increasingly applied in the clinical treatment of a wide range of solid tumors. However, the extremely hypoxic microenvironment in solid tumors can cause hypoxia‐induced radioresistance to 125I brachytherapy, resulting in therapeutic inefficacy. In this study, the aim is to sensitize hypoxic areas in solid tumors using ultrasound‐activated oxygen microbubbles for 125I brachytherapy. A modified emulsion freeze‐drying method is developed to prepare microbubbles that can be lyophilized for storage and easily reconstituted in situ before administration. The filling gas of the microbubbles is modified by the addition of sulfur hexafluoride to oxygen such that the obtained O2/SF6 microbubbles (OS MBs) achieve a much longer half‐life (>3×) than that of oxygen microbubbles. The OS MBs are tested in nasopharyngeal carcinoma (CNE2) tumor‐bearing mice and oxygen delivery by the OS MBs induced by ultrasound irradiation relieve hypoxia instantly. The post‐treatment results of brachytherapy combined with the ultrasound‐triggered OS MBs show a greatly improved therapeutic efficacy compared with brachytherapy alone, illustrating ultrasound‐mediated oxygen delivery with the developed OS MBs as a promising strategy to improve the therapeutic outcome of 125I brachytherapy in hypoxic tumors.

COVID-19 has greatly affected public health and world economy. In this study, we analyzed 129 full-length genomes of SARS-CoV-2 viruses of a Canadian population during early phase of the pandemic. Phylogenetic analysis revealed three major paths of transmission of SARS-CoV-2 viruses into Canada. Twenty-one substitutions that have frequencies greater than 3% of viral population were identified. Analysis of these substitutions indicated that P1427I (ORF1b), Y1464C (ORF1b), and Q57H (ORF3a) might affect functions of the corresponding SARS-CoV-2 encoded proteins. Additionally, we found the evidence of positive selection on the ORF3a and codon 614 of Spike protein, suggesting the viral components responsible for host entry and activation of inflammation response were targeted by host immune responses. The study showed genomic variation and evolution of SARS-CoV-2 in a Canadian population. These information may help develop preventive strategies and be used for further study of SARS-CoV-2 pathogenesis and therapeutics development.

Studies have shown that vaccine vectors and route of immunization can differentially activate different arms of the immune system. However, the effects of different HIV vaccine immunogens on mucosal inflammation have not yet been studied. Because mucosal sites are the primary route of HIV infection, we evaluated the cervico-vaginal inflammatory cytokine and chemokine levels of Mauritian cynomolgus macaques following immunization and boost using two different SIV vaccine immunogens. The PCS vaccine delivers 12 20-amino acid peptides overlapping the 12 protease cleavage sites, and the Gag/Env vaccine delivers the full Gag and full Env proteins of simian immunodeficiency virus. We showed that the PCS vaccine prime and boosts induced short-lived, lower level increases of a few pro-inflammatory/chemotactic cytokines. In the PCS-vaccine group only the levels of MCP-1 were significantly increased above the baseline (P = 0.0078, Week 6; P = 0.0078, Week 17; P = 0.0234; Week 51) following multiple boosts. In contrast, immunizations with the Gag/Env vaccine persistently increased the levels of multiple cytokines/chemokines. In the Gag/Env group, higher than baseline levels were consistently observed for IL-8 (P = 0.0078, Week 16; P = 0.0078, Week 17; P = 0.0156, Week 52), IL-1β (P = 0.0234, Week 16; P = 0.0156, Week 17; P = 0.0156, Week 52), and MIP-1α (P = 0.0313, Week 16; P = 0.0156, Week 17; P = 0.0313, Week 52). Over time, repeated boosts altered the relative levels of these cytokines between the Gag/Env and PCS vaccine group. 18 weeks after final boost with a higher dosage, IP-10 levels (P = 0.0313) in the Gag/Env group remained higher than baseline. Thus, the influence of vaccine immunogens on mucosal inflammation needs to be considered when developing and evaluating candidate HIV vaccines.

TILRR has been identified as an important modulator of inflammatory responses. It is associated with NF-κB activation, and inflammation. Our previous study showed that TILRR significantly increased the expression of many innate immune responsive genes and increased the production of several pro-inflammatory cytokines/chemokines by cervical epithelial cells. In this study, we evaluated the effect of TILRR-induced pro-inflammatory cytokines/chemokines on the migration of immune cells. The effect of culture supernatants of TILRR-overexpressed cervical epithelial cells on the migration of THP-1 monocytes and MOLT-4 T-lymphocytes was evaluated using Transwell assay and a novel microfluidic device. We showed that the culture supernatants of TILRR-overexpressed HeLa cells attracted significantly more THP-1 cells (11–40%, p = 0.0004–0.0373) and MOLT-4 cells (14–17%, p = 0.0010–0.0225) than that of controls. The microfluidic device-recorded image analysis showed that significantly higher amount with longer mean cell migration distance of THP-1 (p < 0.0001–0.0180) and MOLT-4 (p < 0.0001–0.0025) cells was observed toward the supernatants of TILRR-overexpressed cervical epithelial cells compared to that of the controls. Thus, the cytokines/chemokines secreted by the TILRR-overexpressed cervical epithelial cells attracted immune cells, such as monocytes and T cells, and may potentially influence immune cell infiltration in tissues.

Background There has been no prospective or retrospective studies reporting the comparison outcome between surgery and ablation for resectable-ablative (lesions could be treated by resection or complete ablation) colorectal liver oligometastases (CLOM). The purpose of this study was to compare the efficacy and prognostic difference in patients who underwent R0 resection vs. complete ablation within the resectable-ablative CLOM criteria. Methods From January 2008 to May 2018, a total of 2,367 patients diagnosed with colorectal liver metastases were included in this observational study. The metastasis was characterized by only limited to liver with number ≤5, size ≤5 cm, and resectable-ablative (lesions could be treated by resection or complete ablation). The evaluated indications, including liver progression-free survival (LPFS), overall survival (OS), survival rates, pattern and number of recurrences, and complications, were compared by using propensity score matching (PSM). The Kaplan−Meier curves were generated, and a log-rank test was performed. The Cox regression model was used for univariate and multivariate analyses to identify predictors of outcomes. Results A total of 421 consecutive patients were eligible for this study, with 250 and 171 undergoing R0 resection and complete ablation, respectively. PSM identified 145 patients from each group. The 1-, 3-, 5- and 8-year OS rates in the resection group and the ablation group were 95.8% vs. 95.0%, 69.8% vs. 60.1%, 53.6% vs. 42.5%, and 45.1% vs. 32.9% (p = 0.075), respectively. The median LPFS in the resection group was significantly longer than that in the ablation group (35 months vs. 15 months, p = 0.011). No statistical difference was found in LPFS between the two groups when comparing ≤3 cm liver metastases. For liver metastasis >3 cm, the median LPFS in the resection group and ablation group was 11 months and 5 months, respectively (p = 0.001). In terms of high risk of clinical risk score (CRS), the resection group showed longer LPFS than the ablation group (median 18 months vs. 10 months, p = 0.043). Conclusion For patients within the CLOM criteria suggesting that liver metastases were resectable as well as ablative, resection could result in longer liver recurrence-free survival than ablation in cases with size >3 cm or high risk of CRS. But for ≤3 cm liver metastases, their treatment efficacies were comparable.

Background: We analyzed the prevalence of pre-antiretroviral therapy (ART) drug resistance mutations (DRMs) in a Kenyan population. We also examined whether host HLA class I genes influence the development of pre-ART DRMs. Methods: The HIV-1 proviral DNAs were amplified from blood samples of 266 ART-naïve women from the Pumwani Sex Worker cohort of Nairobi, Kenya using a nested PCR method. The amplified HIV genomes were sequenced using next-generation sequencing technology. The prevalence of pre-ART DRMs was investigated. Correlation studies were performed between HLA class I alleles and HIV-1 DRMs. Results: Ninety-eight percent of participants had at least one DRM, while 38% had at least one WHO surveillance DRM. M184I was the most prevalent clinically important variant, seen in 37% of participants. The DRMs conferring resistance to one or more integrase strand transfer inhibitors were also found in up to 10% of participants. Eighteen potentially relevant (p < 0.05) positive correlations were found between HLA class 1 alleles and HIV drug-resistant variants. Conclusions: High levels of HIV drug resistance were found in all classes of antiretroviral drugs included in the current first-line ART regimens in Africa. The development of DRMs may be influenced by host HLA class I-restricted immunity.

FREM1 (Fras-related extracellular matrix 1) and its splice variant TILRR (Toll-like interleukin-1 receptor regulator) have been identified as integral components of innate immune systems. The potential involvement of FREM1 in HIV-1 (human immunodeficiency virus 1) acquisition was suggested by a genome-wide SNP (single nucleotide polymorphism) analysis of HIV-1 resistant and susceptible sex workers enrolled in the Pumwani sex worker cohort (PSWC) in Nairobi, Kenya. The studies showed that the minor allele of a FREM1 SNP rs1552896 is highly enriched in the HIV-1 resistant female sex workers. Subsequent studies showed that FREM1 mRNA is highly expressed in tissues relevant to mucosal HIV-1 infection, including cervical epithelial tissues, and TILRR is a major modulator of many genes in the NF-κB signal transduction pathway. In this article, we review the role of FREM1 and TILRR in modulating inflammatory responses and inflammation, and how their influence on inflammatory responses of cervicovaginal tissue could enhance the risk of vaginal HIV-1 acquisition.

PURPOSE: To evaluate whether intravoxel incoherent motion (IVIM)–related parameters could be used to differentiate malignant from benign focal liver lesions (FLLs) and to improve diagnostic efficiency. METHODS: Seventy-four patients with 75 lesions, including 51 malignant FLLs and 24 benign FLLs, underwent liver 3.0-T magnetic resonance imaging for routine examination sequences. IVIM diffusion-weighted imaging (DWI) with 11 b values (0-800 s/mm2) was also acquired concurrently. Apparent diffusion coefficient (ADCtotal) and IVIM-derived parameters, such as the pure diffusion coefficient (D), the pseudodiffusion coefficient (D⁎), and the perfusion fraction (f), were calculated and compared between the two groups. A receiver operating characteristic curve analysis was performed to assess their diagnostic value. RESULTS: ADCtotal, D, and f were significantly lower in the malignant group than in the benign group, whereas D⁎ did not show a statistical difference. D had a larger area under the curve value (0.968) and higher sensitivity (92.30%) for differentiation. CONCLUSION: IVIM is a useful method to differentiate malignant and benign FLLs. The D value showed higher efficacy to detect hepatic solid lesions.

The Singapore Genome Variation projects characterized the genetics of Singapore’s Chinese, Malay, and Indian populations. The Singapore Integrative Omics Study introduced here goes further in providing multi-omic measurements in individuals from these populations, including genetic, transcriptome, lipidome, and lifestyle data, and will facilitate the study of common diseases in Asian communities.

Abstract HIV preferentially infects activated CD4+ T cells and mutates rapidly. The classical vaccine approach aimed to generate broad immune responses to full HIV proteins largely failed to address the potential adverse impact of increased number of activated CD4+ T cells as viral targets. Learning from natural immunity observed in a group of HIV resistant Kenyan female sex workers, we are testing a novel vaccine approach. It focuses immune response to the highly conserved sequences surrounding the HIV protease cleavage sites (PCS) to disrupt viral maturation, while limiting excessive immune activation. Our pilot studies using nonhuman primate SIV infection models suggest that this approach is feasible and promising.

PURPOSE:We aimed to explore whether intravoxel incoherent motion (IVIM)-related parameters of hepatocellular carcinoma (HCC) and focal nodular hyperplasia (FNH) demonstrate differences that could be used to differentiate and improve diagnostic efficiency.METHODS:A total of 27 patients, including 22 with HCC and 5 with FNH, underwent liver 3.0 T magnetic resonance imaging for routine sequences. They were concurrently examined by IVIM diffusion-weighted imaging (DWI) scanning with 11 different b values (0–800 s/mm2). IVIM-derived parameters, such as pure diffusion coefficient (D), pseudo-diffusion coefficient (D*), perfusion fraction (f), and apparent diffusion coefficient (ADCtotal), were quantified automatically by post-processing software and compared between HCC and FNH groups. A receiver operating characteristic (ROC) curve was then created to predict their diagnostic value.RESULTS:D* was weak in terms of reproducibility among the other parameters. ADCtotal, D, and D* were significantly lower in the HCC group than in the FNH group, while f did not show a significant difference. ADCtotal and D had the largest area under the curve values (AUC; 0.915 and 0.897, respectively) and similarly high efficacy to differentiate the two conditions.CONCLUSION:IVIM provides a new modality to differentiate the HCC and FNH. ADCtotal and D demonstrated outstanding and comparable diagnosing utility.

TILRR (Toll-like interleukin-1 receptor regulator), a transcript variant of FREM1, is a novel regulatory component, which stimulates innate immune responses through binding to IL-1R1 (Interleukin-1 receptor, type 1) and TLR (Toll-like receptor) complex. However, it is not known whether TILRR expression influences other genes in the NFκB signal transduction and pro-inflammatory responses. Our previous study identified FREM1 as a novel candidate gene in HIV-1 resistance/susceptibility in the Pumwani Sex worker cohort. In this study, we investigated the effect of TILRR overexpression on expression of genes in the NFκB signaling pathway in vitro. The effect of TILRR on mRNA expression of 84 genes related to NFκB signal transduction pathway was investigated by qRT-PCR. Overexpression of TILRR on pro-inflammatory cytokine/chemokine(s) secretion in cell culture supernatants was analyzed using Bioplex multiplex bead assay. We found that TILRR overexpression significantly influenced expression of many genes in HeLa and VK2/E6E7 cells. Several cytokine/chemokine(s), including IL-6, IL-8 (CXCL8), IP-10, MCP-1, MIP-1β, and RANTES (CCL5) were significantly increased in the cell culture supernatants following TILRR overexpression. Although how TILRR influences the expression of these genes needs to be further studied, we are the first to show the influence of TILRR on many genes in the NFκB inflammatory pathways. The NFκB inflammatory response pathways are extremely important in microbial infection and pathogenesis, including HIV-1 transmission. Further study of the role of TILRR may identify the novel intervention targets and strategies against HIV infection.

In order to investigate the corrosion performance on intersecting and longitudinal surfaces of unoxidized and oxidized directionally solidified superalloys, Ni-base directionally solidified superalloy DZ125 and Co-base directionally solidified superalloy DZ40M were selected. Oxidation behavior on both alloys with different orientations was investigated at 1050℃ at different times, simulating the oxidation process of vanes or blades in service; subsequent electrochemical performance in 3.5%NaCl aqueous solution was studied on two orientations of unoxidized and oxidized alloys, simulating the corrosion process of superalloy during downtime. The results show that grain boundaries and sub-boundaries of directionally solidified superalloys are susceptible to corrosion and thus longitudinal surface with lower area fraction of grain boundaries has higher corrosion resistance. Compared to intersecting surface of alloys, the structure of grain boundaries of longitudinal surface is less conducive to diffusion and thus the oxidation rate on longitudinal surface is lower. Formation of oxide layers on alloys after short-time oxidation provides protective effect and enhances the corrosion resistance.

The laboratory plays a crucial role in science education. However, teacher education for pre-service teachers' design performance in the laboratory is still challenging. This study paved the way for redesigning traditional laboratory teaching into a student-centered approach: inquiry-based design thinking (IBDT). To investigate the impact of the IBDT approach on students' design performance of science experiments, 25 pre-service science teachers participated in a series of laboratory activities guided by the IBDT approach in a teacher education program in this study. Mixed research methods were employed to collect and analyze students' responses to pre- and post-surveys, their designed artifacts, and self-reflection reports. The overall positive results were obtained except for students' performance in art design, organization of the materials, and the gap between students' understanding of theories and their practices/practical skills. The findings will inform the laboratory instruction in teacher education in science or science-oriented Science-Technology-Engineering-Mathematics (STEM) education.

HIV mutates rapidly and infects CD4+ T cells, especially when they are activated. A vaccine targeting conserved, essential viral elements while limiting CD4+ T cell activation could be effective. Learning from natural immunity observed in a group of highly HIV-1 exposed seronegative Kenyan female sex workers, we are testing a novel candidate HIV vaccine targeting the 12 viral protease cleavage sites (PCSs) (the PCS vaccine), in comparison with a vaccine targeting full-length Gag and Env (the Gag/Env vaccine) in a Mauritian cynomolgus macaque/SIV model. In this study we evaluated these vaccines for induction of mucosal antibodies to SIV immunogens at the female genital tract. Bio-Plex and Western blot analyses of cervicovaginal lavage samples showed that both the PCS and Gag/Env vaccines can elicit mucosal IgG antibody responses to SIV immunogens. Significantly higher increase of anti-PCS antibodies was induced by the PCS vaccine than by the Gag/Env vaccine (p

Cynomolgus macaques are an increasingly important nonhuman primate model for HIV vaccine research. SIV-free animals without pre-existing anti-SIV immune responses are generally needed to evaluate the effect of vaccine-induced immune responses against the vaccine epitopes. Here, in order to select such animals for vaccine studies, we screened 108 naïve female Mauritian cynomolgus macaques for natural (baseline) antibodies to SIV antigens using a Bio-Plex multiplex system. The antigens included twelve 20mer peptides overlapping the twelve SIV protease cleavage sites (-10/+10), respectively (PCS peptides), and three non-PCS Gag or Env peptides. Natural antibodies to SIV antigens were detected in subsets of monkeys. The antibody reactivity to SIV was further confirmed by Western blot using purified recombinant SIV Gag and Env proteins. As expected, the immunization of monkeys with PCS antigens elicited anti-PCS antibodies. However, unexpectedly, antibodies to non-PCS peptides were also induced, as shown by both Bio-Plex and Western blot analyses, while the non-PCS peptides do not share sequence homology with PCS peptides. The presence of natural and vaccine cross-inducible SIV antibodies in Mauritian cynomolgus macaques should be considered in animal selection, experimental design and result interpretation, for their best use in HIV vaccine research.

Within the Pumwani sex worker cohort, a subgroup remains seronegative, despite frequent exposure to HIV-1; some of them seroconverted several years later. This study attempts to identify viral variations in 5’LTR-leader sequences (5’LTR-LS) that might contribute to the late seroconversion. The 5’LTR-LS contains sites essential for replication and genome packaging, viz, primer binding site (PBS), major splice donor (SD), and major packaging signal (PS). The 5’LTR-LS of 20 late seroconverters (LSC) and 122 early seroconverters (EC) were amplified, cloned, and sequenced. HelixTree 6.4.3 was employed to classify HIV subtypes and sequence variants based on seroconversion status. We find that HIV-1 subtypes A1.UG and D.UG were overrepresented in the viruses infecting the LSC (P < 0.0001). Specific variants of PBS (Pc < 0.0001), SD1 (Pc < 0.0001), and PS (Pc < 0.0001) were present only in the viral population from EC or LSC. Combinations of PBS [PBS-2 (Pc < 0.0001) and PBS-3 (Pc < 0.0001)] variants with specific SD sequences were only seen in LSC or EC. Combinations of A1.KE or D with specific PBS and SD variants were only present in LSC or EC (Pc < 0.0001). Furthermore, PBS variants only present in LSC co-clustered with PBS references utilizing tRNAArg; whereas, the PBS variants identified only in EC co-clustered with PBS references using tRNALys3 and its variants. This is the first report that specific PBS, SD1, and PS sequence variants within 5’LTR-LS are associated with HIV-1 seroconversion, and it could aid designing effective anti-HIV strategies.

HLA class II antigens are central in initiating antigen-specific CD4+ T cell responses to HIV-1. Specific alleles have been associated with differential responses to HIV-1 infection and disease among adults. This study aims to determine the influence of HLA class II genes and their interactive effect on mother-child perinatal transmission in a drug naïve, Mother-Child HIV transmission cohort established in Kenya, Africa in 1986. Our study showed that DRB concordance between mother and child increased risk of perinatal HIV transmission by three fold (P = 0.00035/Pc = 0.0014, OR: 3.09, 95%CI, 1.64-5.83). Whereas, DPA1, DPB1 and DQB1 concordance between mother and child had no significant influence on perinatal HIV transmission. In addition, stratified analysis showed that DRB1*15:03+ phenotype (mother or child) significantly increases the risk of perinatal HIV-1 transmission. Without DRB1*15:03, DRB1 discordance between mother and child provided 5 fold protection (P = 0.00008, OR: 0.186, 95%CI: 0.081-0.427). However, the protective effect of DRB discordance was diminished if either the mother or the child was DRB1*15:03+ phenotype (P = 0.49-0.98, OR: 0.7-0.99, 95%CI: 0.246-2.956). DRB3+ children were less likely to be infected perinatally (P = 0.0006, Pc = 0.014; OR:0.343, 95%CI:0.183-0.642). However, there is a 4 fold increase in risk of being infected at birth if DRB3+ children were born to DRB1*15:03+ mother compared to those with DRB1*15:03- mother. Our study showed that DRB concordance/discordance, DRB1*15:03, children's DRB3 phenotype and their interactions play an important role in perinatal HIV transmission. Identification of genetic factors associated with protection or increased risk in perinatal transmission will help develop alternative prevention and treatment methods in the event of increases in drug resistance of ARV.

We examined the effect of HLA class I haplotypes on HIV-1 seroconversion and disease progression in the Pumwani sex worker cohort. This study included 595 HIV-1 positive patients and 176 HIV negative individuals. HLA-A, -B, and -C were typed to 4-digit resolution using sequence-based typing method. HLA class I haplotype frequencies were estimated using PyPop 32-0.6.0. The influence of haplotypes on time to seroconversion and CD4+ T cell decline to

Multiple genome-wide association studies (GWAS) have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although in generally small samples. Under the auspices of the International Collaboration for the Genomics of HIV, we have combined the genome-wide single nucleotide polymorphism (SNP) data collected by 25 cohorts, studies, or institutions on HIV-1 infected individuals and compared them to carefully matched population-level data sets (a list of all collaborators appears in Note S1 in Text S1). After imputation using the 1,000 Genomes Project reference panel, we tested approximately 8 million common DNA variants (SNPs and indels) for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6 × 10⁻¹¹). However, restricting analysis to individuals with a known date of seroconversion suggested that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed no evidence for genetic influence on HIV-1 acquisition (with the exception of CCR5Δ32 homozygosity). Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size.

In the title homochiral mononuclear compound, [Zn(NO3)2(C6H12N4O2)2], the ZnII atom is located on a twofold rotation axis and coordinated by two N atoms from two ligands and two O atoms from two NO3− anions, adopting a distorted tetrahedral coordination geometry. The compound is enantiomerically pure and corresponds to the S diastereoisomer, with the optical activity originating from the chiral ligand. In the crystal, molecules are connected into three-dimensional supramolecular networks through O—H...O, O—H...N and N—H...O hydrogen bonds.

As of February 2012, 50 circulating recombinant forms (CRFs) have been reported for HIV-1 while one CRF for HIV-2. Also according to HIV sequence compendium 2011, the HIV sequence database is replete with 414,398 sequences. The fact that there are CRFs, which are an amalgamation of sequences derived from six or more subtypes (CRF27_cpx (cpx refers to complex) is a mosaic with sequences from 6 different subtypes besides an unclassified fragment), serves as a testimony to the continual divergent evolution of the virus with its approximate 1% per year rate of evolution, and this phenomena per se poses tremendous challenge for vaccine development against HIV/AIDS, a devastating disease that has killed 1.8 million patients in 2010. Here, we explore the interaction between HIV-1 and host genetic variation in the context of HIV/AIDS and antiretroviral therapy response.

To identify novel biomarkers for HIV-1 resistance, including pathways that may be critical in anti-HIV-1 vaccine design, we carried out a gene expression analysis on blood samples obtained from HIV-1 highly exposed seronegatives (HESN) from a commercial sex worker cohort in Nairobi and compared their profiles to HIV-1 negative controls. Whole blood samples were collected from 43 HIV-1 resistant sex workers and a similar number of controls. Total RNA was extracted and hybridized to the Affymetrix HUG 133 Plus 2.0 micro arrays (Affymetrix, Santa Clara CA). Output data was analysed through ArrayAssist software (Agilent, San Jose CA). More than 2,274 probe sets were differentially expressed in the HESN as compared to the control group (fold change ≥1.3; p value ≤0.0001, FDR

CD4+ T cells orchestrate immunity against viral infections, but their importance in HIV infection remains controversial. Nevertheless, comprehensive studies have associated increase in breadth and functional characteristics of HIV-specific CD4+ T cells with decreased viral load. A major challenge for the identification of HIV-specific CD4+ T cells targeting broadly reactive epitopes in populations with diverse ethnic background stems from the vast genomic variation of HIV and the diversity of the host cellular immune system. Here, we describe a novel epitope selection strategy, PopCover, that aims to resolve this challenge, and identify a set of potential HLA class II-restricted HIV epitopes that in concert will provide optimal viral and host coverage. Using this selection strategy, we identified 64 putative epitopes (peptides) located in the Gag, Nef, Env, Pol and Tat protein regions of HIV. In total, 73% of the predicted peptides were found to induce HIV-specific CD4+ T cell responses. The Gag and Nef peptides induced most responses. The vast majority of the peptides (93%) had predicted restriction to the patient's HLA alleles. Interestingly, the viral load in viremic patients was inversely correlated to the number of targeted Gag peptides. In addition, the predicted Gag peptides were found to induce broader polyfunctional CD4+ T cell responses compared to the commonly used Gag-p55 peptide pool. These results demonstrate the power of the PopCover method for the identification of broadly recognized HLA class II-restricted epitopes. All together, selection strategies, such as PopCover, might with success be used for the evaluation of antigen-specific CD4+ T cell responses and design of future vaccines.

HIV-1 is grouped phylogenetically into clades, which may impact rates of HIV-1 disease progression. Clade D infection in particular has been shown to be more pathogenic. Here we confirm in a Nairobi-based prospective female sex worker cohort (1985-2004) that Clade D (n = 54) is associated with a more rapid CD4 decline than clade A1 (n = 150, 20.6% vs 13.4% decline per year, 1.53-fold increase, p = 0.015). This was independent of "protective" HLA and country of origin (p = 0.053), which in turn were also independent predictors of the rate of CD4 decline (p = 0.026 and 0.005, respectively). These data confirm that clade D is more pathogenic than clade A1. The precise reason for this difference is currently unclear, and requires further study. This is first study to demonstrate difference in HIV-1 disease progression between clades while controlling for protective HLA alleles.

Pyrosequencing technology has the potential to rapidly sequence HIV-1 viral quasispecies without requiring the traditional approach of cloning. In this study, we investigated the utility of ultra-deep pyrosequencing to characterize genetic diversity of the HIV-1 gag quasispecies and assessed the possible contribution of pyrosequencing technology in studying HIV-1 biology and evolution.HIV-1 gag gene was amplified from 96 patients using nested PCR. The PCR products were cloned and sequenced using capillary based Sanger fluorescent dideoxy termination sequencing. The same PCR products were also directly sequenced using the 454 pyrosequencing technology. The two sequencing methods were evaluated for their ability to characterize quasispecies variation, and to reveal sites under host immune pressure for their putative functional significance. A total of 14,034 variations were identified by 454 pyrosequencing versus 3,632 variations by Sanger clone-based (SCB) sequencing. 11,050 of these variations were detected only by pyrosequencing. These undetected variations were located in the HIV-1 Gag region which is known to contain putative cytotoxic T lymphocyte (CTL) and neutralizing antibody epitopes, and sites related to virus assembly and packaging. Analysis of the positively selected sites derived by the two sequencing methods identified several differences. All of them were located within the CTL epitope regions.Ultra-deep pyrosequencing has proven to be a powerful tool for characterization of HIV-1 genetic diversity with enhanced sensitivity, efficiency, and accuracy. It also improved reliability of downstream evolutionary and functional analysis of HIV-1 quasispecies.

BACKGROUND: Infection by the pandemic influenza A (H1N1/09) virus resulted in significant pathology among specific ethnic groups worldwide. Natural Killer (NK) cells are important in early innate immune responses to viral infections. Activation of NK cells, in part, depend on killer-cell immunoglobulin-like receptors (KIR) and HLA class I ligand interactions. To study factors involved in NK cell dysfunction in overactive immune responses to H1N1 infection, KIR3DL1/S1 and KIR2DL2/L3 allotypes and cognate HLA ligands of H1N1/09 intensive-care unit (ICU) patients were determined. METHODOLOGY AND FINDINGS: KIR3DL1/S1, KIR2DL2/L3, and HLA -B and -C of 51 H1N1/09 ICU patients and 105 H1N1-negative subjects (St. Theresa Point, Manitoba) were characterized. We detected an increase of 3DL1 ligand-negative pairs (3DL1/S1(+) Bw6(+) Bw4(-)), and a lack of 2DL1 HLA-C2 ligands, among ICU patients. They were also significantly enriched for 2DL2/L3 ligand-positive pairs (PVA, P=0.024, Pc=0.047; Odds Ratio:2.563, CI95%:1.109-5.923), 3DL1*00101 (Ab>VA, PSTh, P=0.034, Pc=0.268), and 3DL1*029 (Ab>STh, P=0.039, Pc=0.301). Aboriginal patients ligand-positive for 3DL1/S1 and 2DL1 had the lowest probabilities of death (R(d)) (R(d)=28%), compared to patients that were 3DL1/S1 ligand-negative (R(d)=52%) or carried 3DL1*029 (R(d)=52%). Relative to Caucasoids (CA), two allotypes were enriched among non-aboriginal ICU patients (NAb): 3DL1*00401 (NAb>CA, P

West Nile virus (WNV) infection is asymptomatic in most individuals, with a minority developing symptoms ranging from WNV fever to serious neuroinvasive disease. This study investigated the impact of host HLA on the outcome of WNV disease.A cohort of 210 non-Hispanic mostly white WNV(+) subjects from Canada and the U.S. were typed for HLA-A, B, C, DP, DQ, and DR. The study subjects were divided into three WNV infection outcome groups: asymptomatic (AS), symptomatic (S), and neuroinvasive disease (ND). Allele frequency distribution was compared pair-wise between the AS, S, and ND groups using χ2 and Fisher's exact tests and P values were corrected for multiple comparisons (Pc). Allele frequencies were compared between the groups and the North American population (NA) used as a control group. Logistic regression analysis was used to evaluate the potential synergistic effect of age and HLA allele phenotype on disease outcome.The alleles HLA-A*68, C*08 and DQB*05 were more frequently associated with severe outcomes (ND vs. AS, P(A*68) = 0.013/Pc = 0.26, P(C*08) = 0.0075/Pc = 0.064, and P(DQB1*05) = 0.029/Pc = 0.68), However the apparent DQB1*05 association was driven by age. The alleles HLA-B*40 and C*03 were more frequently associated with asymptomatic outcome (AS vs. S, P(B*40) = 0.021/Pc = 0.58 and AS vs. ND P(C*03) = 0.039/Pc = 0.64) and their frequencies were lower within WNV(+) subjects with neuroinvasive disease than within the North American population (NA vs. S, P(B*40) = 0.029 and NA vs. ND, P(C*03) = 0.032).Host HLA may be associated with the outcome of WNV disease; HLA-A*68 and C*08 might function as "susceptible" alleles, whereas HLA-B*40 and C*03 might function as "protective" alleles.

CD8+ T cell responses are often detected at large magnitudes in HIV-infected subjects, and eliciting these responses is the central aim of many HIV-1 vaccine strategies. Population differences in CD8+ T cell epitope specificity will need to be understood if vaccines are to be effective in multiple geographic regions.In a large Kenyan cohort, we compared responsive CD8+ T cell HIV-1 Env overlapping peptides (OLPs) to Best Defined Epitopes (BDEs), many of which have been defined in clade B infection. While the majority of BDEs (69%) were recognized in this population, nearly half of responsive OLPs (47%) did not contain described epitopes. Recognition frequencies of BDEs were inversely correlated to epitopic sequence differences between clade A1 and BDE (P = 0.019), and positively selected residues were more frequent in "new" OLPs (without BDEs). We assessed the impact of HLA and TAP binding on epitope recognition frequencies, focusing on predicted and actual epitopes in the HLA B7 supertype.Although many previously described CD8 epitopes were recognized, several novel CD8 epitopes were defined in this population, implying that epitope mapping efforts have not been completely exhausted. Expansion of these studies will be critical to understand population differences in CD8 epitope recognition.