The serological IgG and neutralizing antibody of SARS-CoV-2 omicron variant reinfection in Jiangsu Province, China.

Background: It is important to figure out the immunity of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) reinfection to understand the response of humans to viruses. A serological survey for previously infected populations in Jiangsu Province was conducted to compare the antibody level of SARS-CoV-2 in reinfection by Omicron or not. Methods: Reinfection with SARS-CoV-2 was defined as an individual being infected again after 90 days of the initial infection. Telephone surveys and face-to-face interviews were implemented to collect information. Experimental and control serum samples were collected from age-sex-matched reinfected and non-reinfected cases, respectively. IgG anti-S and neutralizing antibodies (Nab) concentrations were detected by the Magnetism Particulate Immunochemistry Luminescence Method (MCLIA). Antibody titers were log(2)-transformed and analyzed by a two-tailed Mann-Whitney U test. Subgroup analysis was conducted to explore the relationship between the strain type of primary infection, SARS-Cov-2 vaccination status, and antibody levels. Multivariate linear regression models were used to identify associations between reinfection with IgG and Nab levels. Results: Six hundred thirty-one individuals were enrolled in this study, including 327 reinfected cases and 304 non-reinfected cases. The reinfection group had higher IgG (5.65 AU/mL vs. 5.22 AU/mL) and Nab (8.02 AU/mL vs. 7.25 AU/mL) levels compared to the non-reinfection group (p < 0.001). Particularly, individuals who had received SARS-CoV-2 vaccination or were initially infected with the Wild type and Delta variant showed a significant increase in antibody levels after reinfection. After adjusting demographic variables, vaccination status and the type of primary infection together, IgG and Nab levels in the reinfected group increased by log(2)-transformed 0.71 and 0.64 units, respectively (p < 0.001). This revealed that reinfection is an important factor that affects IgG and Nab levels in the population. Conclusion: Reinfection with Omicron in individuals previously infected with SARS-CoV-2 enhances IgG and Nab immune responses.

Emergence of Rarely Reported Extensively Drug-Resistant Salmonella Enterica Serovar Paratyphi B among Patients in East China.

BACKGROUND: In recent years, global concern over increasing multidrug resistance (MDR) among various Salmonella serotypes has grown significantly. However, reports on MDR Salmonella Paratyphi B remain scarce, let alone the extensively drug-resistant (XDR) strains. METHODS: In this retrospective study, we investigated the isolates of Salmonella Paratyphi B in Jiangsu Province over the past decade and carried out antimicrobial susceptibility tests, then the strains were sequenced and bioinformatics analyses were performed. RESULTS: 27 Salmonella Paratyphi B strains were identified, of which the predominant STs were ST42 (11), ST86 (10), and ST2814 (5). Among these strains, we uncovered four concerning XDR Salmonella Paratyphi B ST2814 strains (4/5) which were previously unreported. These alarmingly resistant isolates showed resistance to all three major antibiotic classes for Salmonella treatment and even the last resort treatment tigecycline. Bioinformatics analysis revealed high similarity between the plasmids harbored by these XDR strains and diverse Salmonella serotypes and Escherichia coli from China and neighboring regions. Notably, these four plasmids carried the ramAp gene responsible for multiple antibiotic resistance by regulating the AcrAB-TolC pump, predominantly originating from China. Additionally, a distinct MDR ST42(1/11) strain with an ICE on chromosome was also identified. Furthermore, phylogenetic analysis of global ST42/ST2814 isolates highlighted the regional specificity of these strains, with Jiangsu isolates clustering together with domestic isolates and XDR ST2814 forming a distinct branch, suggesting adaptation to local antibiotic pressures. CONCLUSIONS: This research underscores the pressing need for closely monitoring the MDR/XDR Salmonella Paratyphi B, particularly the emerging ST2814 strains in Jiangsu Province, to effectively curb its spread and protect public health. Moreover, surveillance should be strengthened across different ecological niches and genera to track resistance genes and horizontal gene transfer elements under the concept of "ONE HEALTH".

The Influence of Maternal Condition on Fetal Cardiac Function during the Second Trimester.

OBJECTIVE: Maternal health has a direct, profound and lasting effect on the formation and development of the fetal cardiovascular system. The aim of this research was to find whether maternal age, BMI hypertension (GH) or gestational diabetic mellitus (GDM) would affect fetal cardiac function in the second trimester. METHOD: 329 mothers who had a fetal echocardiogram examination at the International Peace Maternity & Child Health Hospital of China Welfare Institute, Shanghai, China, from 1 January 2020 to 30 April 2020 were enrolled at the gestational age of 21 to 26 weeks (mean 22.78 ± 1.13 weeks). Single-factor analysis and multi-factor line regression analysis were used to find the contribution values of each factor to fetal cardiac function. RESULTS: at the second trimester, maternal age had a minor influence on the fetal left ventricle diastolic function. Higher maternal BMI could cause a decrease in the fetal diastolic function of both the left and right ventricle and the systolic function of the left ventricle. Maternal hypertension and gestational diabetic mellitus had a profound influence on both the left and right fetal heart ventricles of both systolic and diastolic function. CONCLUSION: maternal condition will have a profound influence on fetal cardiac function as early as the second trimester.

Unveiling a New Perspective on Distinguishing Omicron Breakthrough Cases and Postimmune COVID-19-Naive Individuals: Insights from Antibody Profiles.

In the situation of mass vaccination against COVID-19, few studies have reported on the early kinetics of specific antibodies (IgG/IgM/IgA) of vaccine breakthrough cases. There is still a lack of epidemiological evidence about the value of serological indicators in the auxiliary diagnosis of COVID-19 infection, especially when the nucleic acid results were undetectable. Omicron breakthrough cases post-inactivated vaccination (n = 456) and COVID-19-naive individuals with two doses of inactivated vaccination (n = 693) were enrolled. Blood samples were collected and tested for SARS-CoV-2 antibody levels based on the magnetic chemiluminescence enzyme immunoassay. Among Omicron breakthrough cases, the serum IgG antibody level was 36.34 Sample/CutOff (S/CO) (95% confidence interval [CI], 31.89 to 40.79) in the acute phase and 88.45 S/CO (95% CI, 82.79 to 94.12) in the recovery phase. Serum IgA can be detected in the first week post-symptom onset (PSO) and showed an almost linear increase within 5 weeks PSO. Compared with those of breakthrough cases, IgG and IgA titers of the postimmune group were much lower (4.70 S/CO and 0.46 S/CO, respectively). Multivariate regression showed that serum IgG and IgA levels in Omicron breakthrough cases were mainly affected by the weeks PSO (P < 0.001). Receiver operating characteristic ROC0 curve analysis showed that the area under the curve (AUC) was 0.744 and 0.806 when the cutoff values of IgA and IgG were 1 S/CO and 15 S/CO, respectively. Omicron breakthrough infection can lead to a further increase in IgG and IgA levels relative to those of the immunized population. When nucleic acid real-time PCR was negative, we would use the kinetics of IgG and IgA levels to distinguish the breakthrough cases from the immunized population. IMPORTANCE This study fills a gap in the epidemiological evidence by investigating the value of serological indicators, particularly IgG and IgA levels, in the auxiliary diagnosis of COVID-19 infections when nucleic acid results are undetectable. The findings reveal that among Omicron breakthrough cases, both IgG and IgA antibody levels exhibit significant changes. Serum IgG levels increase during the acute phase and rise further in the recovery phase. Serum IgA can be detected as early as the first week post-symptom onset (PSO), showing a consistent linear increase within 5 weeks PSO. Furthermore, receiver operating characteristic (ROC) curve analysis demonstrates the potential of IgG and IgA cutoff values as diagnostic markers. The study's conclusion underscores the importance of monitoring IgG and IgA kinetics in distinguishing Omicron breakthrough cases from vaccinated individuals. These findings contribute to the development of more accurate diagnostic approaches and help inform public health strategies during the ongoing COVID-19 pandemic.

Kinetics of SARS-CoV-2 neutralizing antibodies in Omicron breakthrough cases with inactivated vaccination: Role in inferring the history and duration of infection.

Background: The quantitative level and kinetics of neutralizing antibodies (NAbs) in individuals with Omicron breakthrough infections may differ from those of vaccinated individuals without infection. Therefore, we aimed to evaluate the difference in NAb levels to distinguish the breakthrough cases from the post-immunized population to identify early infected person in an outbreak epidemic when nasal and/or pharyngeal swab nucleic acid real-time PCR results were negative. Methods: We collected 1077 serum samples from 877 individuals, including 189 with Omicron BA.2 breakthrough infection and 688 post-immunized participants. NAb titers were detected using the surrogate virus neutralization test, and were log(2)-transformed to normalize prior to analysis using Student's unpaired t-tests. Geometric mean titers (GMT) were calculated with 95% confidence intervals (CI). Linear regression models were used to identify factors associated with NAb levels. We further conducted ROC curve analysis to evaluate the NAbs' ability to identify breakthrough infected individuals in the vaccinated population. Results: The breakthrough infection group had a consistently higher NAb levels than the post-immunized group according to time since the last vaccination. NAb titers in the breakthrough infection group were 6.4-fold higher than those in the post-immunized group (GMT: 40.72 AU/mL and 6.38 AU/mL, respectively; p<0.0001). In the breakthrough infection group, the NAbs in the convalescent phase were 10.9-fold higher than in the acute phase (GMT: 200.48 AU/mL and 18.46 AU/mL, respectively; p<0.0001). In addition, the time since infection, booster vaccination, and the time since last vaccination were associated with log(2)-transformed NAb levels in the breakthrough infection group. ROC curve analysis showed that ROC area was largest (0.728) when the cut-off value of log(2)-transformed NAb was 6, which indicated that NAb levels could identify breakthrough infected individuals in the vaccinated population. Conclusion: Our study demonstrates that the NAb titers of Omicron BA.2 variant breakthrough cases are higher than in the post-immunized group. The difference in NAb levels could be used to identify cases of breakthrough infection from the post-immunized population in an outbreak epidemic.

Long-Term Kinetics of SARS-CoV-2 Antibodies and Impact of Inactivated Vaccine on SARS-CoV-2 Antibodies Based on a COVID-19 Patients Cohort.

Background: Understanding the long-term kinetic characteristics of SARS-CoV-2 antibodies and the impact of inactivated vaccines on SARS-CoV-2 antibodies in convalescent patients can provide information for developing and improving vaccination strategies in such populations. Methods: In this cohort, 402 convalescent patients who tested positive for SARS-CoV-2 by RT-PCR from 1 January to 22 June 2020 in Jiangsu, China, were enrolled. The epidemiological data included demographics, symptom onset, and vaccination history. Blood samples were collected and tested for antibody levels of specific IgG, IgM, RBD-IgG, S-IgG, and neutralizing antibodies using a the commercial magnetic chemiluminescence enzyme immunoassay. Results: The median follow-up time after symptom onset was 15.6 months (IQR, 14.6 to 15.8). Of the 402 convalescent patients, 44 (13.84%) received an inactivated vaccine against COVID-19. A total of 255 (80.19%) patients were IgG-positive and 65 (20.44%) were IgM-positive. The neutralizing antibody was 83.02%. Compared with non-vaccinated individuals, the IgG antibody levels in vaccinated people were higher (P=0.007). Similarly, antibody levels for RBD-IgG, S-IgG, and neutralizing antibodies were all highly increased in vaccinated individuals (P<0.05). IgG levels were significantly higher after vaccination than before vaccination in the same population. IgG levels in those who received 'single dose and ≥14d' were similar to those with two doses (P>0.05). Similar conclusions were drawn for RBD-IgG and the neutralizing antibody. Conclusion: 15.6 months after symptom onset, the majority of participants remained positive for serum-specific IgG, RBD-IgG, S-IgG, and neutralizing antibodies. For convalescent patients, a single dose of inactivated vaccine against COVID-19 can further boost antibody titres.

Kinetics of SARS-CoV-2 Specific and Neutralizing Antibodies over Seven Months after Symptom Onset in COVID-19 Patients.

To assess the persistence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies produced by natural infection and describe the serological characteristics over 7 months after symptom onset among coronavirus disease 2019 (COVID-19) patients by age and severity group, we followed up COVID-19 convalescent patients confirmed from 1 January to 20 March 2020 in Jiangsu, China and collected serum samples for testing IgM/IgG and neutralizing antibodies against SARS-CoV-2 between 26 August and 28 October 2020. In total, 284 recovered participants with COVID-19 were enrolled in our study. Patients had a mean age of 46.72 years (standard deviation [SD], 17.09), and 138 (48.59%) were male. The median follow-up time after symptom onset was 225.5 (interquartile range [IQR], 219 to 232) days. During the follow-up period (162 to 282 days after symptom onset), the seropositive rate of IgM fluctuated around 25.70% (95% confidence interval [CI], 20.72% to 31.20%) and that of IgG fluctuated around 79.93% (95% CI, 74.79% to 84.43%). Of the 284 patients, 64 participants were tested when discharged from hospital. Compared with that at the acute phase, the IgM/IgG antibody levels and IgM seropositivity have decreased; however, the seropositivity of IgG was not significantly lower at this follow-up (78.13% versus 82.81%). Fifty percent inhibitory dilution (ID50) titers of neutralizing antibody for samples when discharged from hospital (geometric mean titer [GMT], 82; 95% CI, 56 to 121) were significantly higher than those at 6 to 7 months after discharge (GMT, 47; 95% CI, 35 to 63) (P < 0.001). After 7 months from symptom onset, the convalescent COVID-19 patients continued to have high IgG seropositive; however, many plasma samples decreased neutralizing activity. IMPORTANCE The long-term characteristics of anti-SARS-CoV-2 antibodies among COVID-19 patients remain largely unclear. Tracking the longevity of these antibodies can provide a forward-looking reference for monitoring COVID-19. We conducted a comprehensive assessment combining the kinetics of specific and neutralizing antibodies over 7 months with age and disease severity and revealed influencing factors of the protection period of convalescent patients. By observing the long-term antibody levels against SARS-CoV-2 and comparing antibody levels at two time points after symptom onset, we found that the convalescent COVID-19 patients continued to have a high IgG seropositive rate; however, their plasma samples decreased neutralizing activity. These findings provide evidence supporting that the neutralizing activity of SARS-CoV-2-infected persons should be monitored and the administration of vaccine may be needed.

Comprehensive Analysis of the Expression, Relationship to Immune Infiltration and Prognosis of TIM-1 in Cancer.

TIM-1 is a critical gene that regulates T-helper cell development. However, little research has revealed the distribution, prognosis, and immune infiltration of TIM-1 in cancers. TCGA, GEO, Oncomine, TIMER, Kaplan-Meier, PrognoScan, GEPIA, TISIDB, and HPA databases were used to analyze TIM-1 in cancers. High TIM-1 expression was observed in bladder, cholangio, head and neck, colorectal, gastric, kidney, liver, lung adenocarcinoma, skin, uterine corpus endometrial, and pancreatic cancers compared to the normal tissues, and immunofluorescence shows that TIM-1 is mainly localized in vesicles. Simultaneously, high TIM-1 expression was closely related with poorer overall survival in gastric, lung adenocarcinoma, and poorer disease-specific survival in gastric cancer in the TCGA cohort, and was validated in the GEO cohort. Moreover, high expression of TIM-1, correlated with clinical relevance of gastric cancer and lung adenocarcinoma, was associated with tumor-infiltrating lymphocytes in lung adenocarcinoma and gastric cancer. Finally, immunohistochemistry showed TIM-1 expression was higher in lung adenocarcinoma and gastric cancer compared to the normal tissues. In summary, we applied integrated bioinformatics approaches to suggest that TIM-1 can be used as a prognostic biomarker in gastric and lung adenocarcinoma, which might provide a novel direction to explore the pathogenesis of gastric and lung adenocarcinoma.

Existence of virulence genes in clinical Shigella sonnei isolates from Jiangsu Province of China: a multicenter study.

BACKGROUND: The ability of Shigella to invade, colonizes, and eventually kill host cells is influenced by many virulence factors. The aims of this study were to assess the presence of 11 virulence genes of S. sonnei strains isolated in this country. METHODS: A total of 166 S. sonnei was collected from 13 cities of Jiangsu province through the provincial Centers for Disease Control (CDC) from 2010 to 2015 and then the distribution of virulence genes was detected by polymerase chain reaction (PCR) technology. RESULTS: Invasive virulence genes included ipaH and ial, in which the positive rate of ipaH was 100% while the positive rate of ial was 15.1% in S. sonnei. The classic pathway of regulating expression of Shigella virulence gene involved virF and virB gene, which positive rates were 33.7% and 24.1% respectively. The most common serine protease autotransporters of Enterobacteriaceae among S. sonnei were sigA (100%), followed by sepA (3.0%), sat (3.0%), pic (1.2%). Shigella enterotoxin genes include sen, set1A, set1B were found in 16.3%, 6.0% and 1.8% of the isolates, respectively. CONCLUSIONS: This study provides baseline information on the distribution of virulence genes in clinical S. sonnei trains in Jiangsu province in China, which will be important for implementation of effective control strategies.

Increasing clinical resistance rate of Shigella sonnei to cefotaxime in Jiangsu Province, China, between 2012 and 2015.

BACKGROUND: The objective of this study is to evaluate the prevalence of Shigella sonnei (S. sonnei) and characterize the mechanism of its increasing resistance to cefotaxime, a third-generation cephalosporin agent between 2012 and 2015. METHODS: We investigated the drug resistance in 95 isolates of S. sonnei by K-B dilution method and isolates with the extended-spectrum beta-lactamases (ESBLs)-producing genes were detected by polymerase chain reaction (PCR) and sequencing. RESULTS: Over a 4-year period, the resistance rate of S. sonnei to cefotaxime increased from 31.6% to 64.3%, between 2012 and 2015. Molecular characterization of the ESBL genes, comprising 28 strains of CTX-M-1 group: blaCTX-M-55 (n=22), blaCTX-M-3 (n=3) and blaCTX-M-15 (n=3); 11 strains of CTX-M-9 group: blaCTX-M-14 (n=9) and blaCTX-M-65 (n=2), and 36 strains with blaTEM-1 gene. None of S. sonnei isolates carried blaCTX-M-2 group and SHV-type. CONCLUSIONS: The antimicrobial resistance rate of S. sonnei to cefotaxime significantly increased. Accordingly, regular surveillance of the cephalosporin-resistant S. sonnei should be emphasized. Moreover, exploration of the mechanism underlying the resistance of S. sonnei to cefotaxime contributes to the prophylaxis of further emergence of drug resistance.

Metacarpal Bone Plane Examination by Ultrasonography for the Diagnosis of Fetal Forearm and Hand Deformity.

We explored the value of the metacarpal bone plane in screening for serious fetal forearm and hand deformities, excluding simple polydactyly and dactylion deformity, by ultrasonographic examination. Observed the second to fifth metacarpal bone plane of fetuses in 20,139 pregnant women at a gestational age of 16 to 30 weeks in The International Peace Maternity &Child Health Hospital of China Welfare Institute (IPMCH). There was a total 138 cases of fetal forearm and/or hand deformity among the 20,139 pregnant women. Of these, 134 cases were diagnosed, 4 cases were not diagnosed, and 1 case was misdiagnosed. Among the 134 diagnosed cases, there were 19 cases of hand absence, 5 cases of cleft hand, 13 cases of ectrodactyly, 26 cases of radius absence, 9 cases of forearm and hand dysplasia, 55 cases of thanatophoric dysplasia, 6 cases of wrist joint dysplasia, and 1 case of forearm amputation deformity. The deformity rate was 0.76%, the diagnostic coincidence rate was 99.97%, the sensitivity was 97.10%, the specificity was 99.99%, and the false negative rate was 2.9%. As such, careful observation of the metacarpal bone plane can be used increase the diagnosis rate of fetal forearm and hand deformity.

Ecological effect and risk towards aquatic plants induced by perfluoroalkyl substances: Bridging natural to culturing flora.

In the present study, the concentrations and proportions of perfluoroalkyl substances (PFASs) in water and sediments (in different seasons) from the Qing River were investigated. The highest concentration of PFASs in water (207.59 ng L-1) was found in summer. The composition of PFASs in water changed with time, perfluorobutane sulfonate (PFBS) was the predominant compound in spring and summer, while long-chain PFASs, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), started to increase in autumn and winter. The PFASs concentration in sediments ranged from 0.96 to 4.05 ng g-1 dw. The proportion of long-chain PFASs was higher than that of short-chain PFASs in sediments, the dominant component in sediments was PFOA with a contribution of 24.6-75.4% to total PFASs in sediments, followed by PFOS. The concentrations of PFASs in roots of emergent plants were relatively higher than those in submerged plants. However, the translocation effect of PFASs was not remarkable. Bioaccumulation factors (BAFs) of the aquatic plants indicated the absorption of PFASs were effective. BAFs in submerged plants basically increased with increasing chain length accordingly. In general, aquatic plants had the absorption preference for long-chain PFASs, especially PFOS, which was the predominant compounds in both submerged and emergent plants. Based on the results above, hornworts were selected to be cultivated indoor in the nutrient solution spiked gradient concentrations of PFOS to assess the general ecological risk. The results revealed that hornworts were resistant to PFOS and might be used as remediation flora to eliminate PFOS contamination.

HBx-induced MiR-1269b in NF-κB dependent manner upregulates cell division cycle 40 homolog (CDC40) to promote proliferation and migration in hepatoma cells.

BACKGROUND: Occurrence and progression of hepatocellular carcinoma (HCC) are associated with hepatitis B virus (HBV) infection. miR-1269b is up-regulated in HCC cells and tissues. However, the regulation of miR-1269b expression by HBV and the mechanism underlying the oncogenic activity of miR-1269b in HCC are unclear. METHODS: Reverse transcription quantitative PCR (RT-qPCR) was used to measure the expression of miR-1269b and target genes in HCC tissues and cell lines. Western blot analysis was used to assess the expression of miR-1269b target genes and related proteins. Using luciferase reporter assays and EMSA, we identified the factors regulating the transcriptional level of miR-1269b. Colony formation, flow cytometry and cell migration assays were performed to evaluate the phenotypic changes caused by miR-1269b and its target in HCC cells. RESULTS: We demonstrated that the expression levels of pre-miR-1269b and miR-1269b in HBV-positive HepG2.2.15 cells were dramatically increased compared with HBV-negative HepG2 cells. HBx was shown to facilitate translocation of NF-κB from the cytoplasm to the nucleus, and NF-κB binds to the promoter of miR-1269b to enhance its transcription. miR-1269b targets and up-regulates CDC40, a cell division cycle 40 homolog. CDC40 increases cell cycle progression, cell proliferation and migration. Rescue experiment indicated that CDC40 promotes malignancy induced by miR-1269b in HCC cells. CONCLUSION: We found that HBx activates NF-κB to promote the expression of miR1269b, which augments CDC40 expression, contributing to malignancy in HCC. Our findings provide insights into the mechanisms underlying HBV-induced hepatocarcinogenesis.

Susceptibility to Bt proteins is not required for Agrotis ipsilon aversion to Bt maize.

BACKGROUND: Although Bacillus thuringiensis (Bt) maize has been widely adopted in diverse regions around the world, relatively little is known about the susceptibility and behavioral response of certain insect pests to Bt maize in countries where this maize is not currently cultivated. These are important factors to consider as management plans are developed. These factors were investigated for Agrotis ipsilon, a global pest of maize, with Cry1F and Cry34Ab1/Cry35Ab1 maize. RESULTS: Agrotis ipsilon demonstrated an initial, post-ingestive aversive response to Cry1F maize. Development and mortality were also affected - survival on Cry1F maize tissue was 40% and weight gain of survivors of Cry1F exposure was significantly reduced. A post-ingestive aversive response was also seen for Cry34Ab1/Cry35Ab1 maize; however, longer-term feeding, weight gain and survival were not affected. CONCLUSION: Agrotis ipsilon showed aversion to both Bt treatments. Aversion to Cry34Ab1/Cry35Ab1 maize was unexpected because these proteins have no known insecticidal effect against Lepidoptera; however, results confirm that this aversion was temporary and did not affect growth or development. The Cry1F results suggest that A. ipsilon will abandon Cry1F maize in the field before any selection for resistance. These data support the use of refuge to delay Cry1F resistance development in A. ipsilon populations.

Susceptibility and aversion of Spodoptera frugiperda (Lepidoptera: Noctuidae) to Cry1F Bt maize and considerations for insect resistance management.

Bacillus thuringiensis (Bt) maize was developed primarily for North American pests such as European corn borer (Ostrinia nubilalis (Hübner)). However, most Bt maize products are also cultivated outside of North America, where the primary pests may be different and may have lower susceptibility to Bt toxins. Fall armyworm (Spodoptera frugiperda JE Smith) is an important pest and primary target of Bt maize in Central and South America. S. frugiperda susceptibility to Cry1F (expressed in event TC1507) is an example of a pest-by-toxin interaction that does not meet the high-dose definition. In this study, the behavioral and toxic response of S. frugiperda to Cry1F maize was investigated by measuring the percentage of time naive third instars spent feeding during a 3-min exposure. S. frugiperda also were exposed as third instars to Cry1F maize for 14 d to measure weight gain and survival. S. frugiperda demonstrated an initial, postingestive aversive response to Cry1F maize, and few larvae survived the 14 d exposure. The role of susceptibility and avoidance are discussed in the context of global IRM refuge strategy development for Bt products.

A genome-wide association study for venous thromboembolism: the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium.

Venous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two-stage genome-wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community-based studies. Genotypes for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study-design appropriate regression methods. Meta-analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P ≤ 0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case-control studies. In the combined data from these two stages, additional genome-wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG; P < 5.0 × 10(-13) for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (P < 5.0 × 10(-6) ) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.

Environmental effects on allergen levels in commercially grown non-genetically modified soybeans: assessing variation across north america.

Soybean (Glycinemax) is a hugely valuable soft commodity that generates tens of billions of dollars annually. This value is due in part to the balanced composition of the seed which is roughly 1:2:2 oil, starch, and protein by weight. In turn, the seeds have many uses with various derivatives appearing broadly in processed food products. As is true with many edible seeds, soybeans contain proteins that are anti-nutritional factors and allergens. Soybean, along with milk, eggs, fish, crustacean shellfish, tree nuts, peanuts, and wheat, elicit a majority of food allergy reactions in the United States. Soybean seed composition can be affected by breeding, and environmental conditions (e.g., temperature, moisture, insect/pathogen load, and/or soil nutrient levels). The objective of this study was to evaluate the influence of genotype and environment on allergen and anti-nutritional proteins in soybean. To address genetic and environmental effects, four varieties of non-GM soybeans were grown in six geographically distinct regions of North America (Georgia, Iowa, Kansas, Nebraska, Ontario, and Pennsylvania). Absolute quantification of proteins by mass spectrometry can be achieved with a technique called multiple reaction monitoring (MRM), during which signals from an endogenous protein are compared to those from a synthetic heavy-labeled internal standard. Using MRM, eight allergens were absolutely quantified for each variety in each environment. Statistical analyses show that for most allergens, the effects of environment far outweigh the differences between varieties brought about by breeding.

Genome-wide association study identifies novel loci for plasma levels of protein C: the ARIC study.

Protein C is an important endogenous anticoagulant in hemostasis. Deficiencies of protein C due to genetic mutations or a low level of circulating protein C increase the risk of venous thromboembolism. We performed a genome-wide association scan for plasma protein C antigen concentration with approximately 2.5 million single-nucleotide polymorphisms in 8048 individuals of European ancestry and a replication analysis in a separate sample of 1376 individuals in the Atherosclerosis Risk in Communities Study. Four independent loci from 3 regions were identified with genome-wide significance: 2p23 (GCKR, best SNP rs1260326, P = 2.04 × 10(-17)), 2q13-q14 (PROC, rs1158867, P = 3.77 × 10(-36)), 20q11 (near and within PROCR, rs8119351, P = 2.68 × 10(-203)), and 20q11.22 (EDEM2, rs6120849, P = 7.19 × 10(-37) and 5.23 × 10(-17) before and after conditional analysis, respectively). All 4 loci replicated in the independent sample. Furthermore, pooling the discovery and replication sets yielded an additional locus at chromosome 7q11.23 (BAZ1B, rs17145713, P = 2.83 × 10(-8)). The regions marked by GCKR, EDEM2, and BAZ1B are novel loci that have not been previously reported for association with protein C concentration. In summary, this first genome-wide scan for circulating protein C concentration identified both new and known loci in the general population. These findings may improve the understanding of physiologic mechanisms in protein C regulation.

Partitioning degrees of freedom in hierarchical and other richly-parameterized models.

Hodges & Sargent (2001) developed a measure of a hierarchical model's complexity, degrees of freedom (DF), that is consistent with definitions for scatterplot smoothers, interpretable in terms of simple models, and that enables control of a fit's complexity by means of a prior distribution on complexity. DF describes complexity of the whole fitted model but in general it is unclear how to allocate DF to individual effects. We give a new definition of DF for arbitrary normal-error linear hierarchical models, consistent with Hodges & Sargent's, that naturally partitions the n observations into DF for individual effects and for error. The new conception of an effect's DF is the ratio of the effect's modeled variance matrix to the total variance matrix. This gives a way to describe the sizes of different parts of a model (e.g., spatial clustering vs. heterogeneity), to place DF-based priors on smoothing parameters, and to describe how a smoothed effect competes with other effects. It also avoids difficulties with the most common definition of DF for residuals. We conclude by comparing DF to the effective number of parameters p(D) of Spiegelhalter et al (2002). Technical appendices and a dataset are available online as supplemental materials.

Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium.

BACKGROUND: Plasma levels of coagulation factors VII (FVII), VIII (FVIII), and von Willebrand factor (vWF) influence risk of hemorrhage and thrombosis. We conducted genome-wide association studies to identify new loci associated with plasma levels. METHODS AND RESULTS: The setting of the study included 5 community-based studies for discovery comprising 23 608 European-ancestry participants: Atherosclerosis Risk In Communities Study, Cardiovascular Health Study, British 1958 Birth Cohort, Framingham Heart Study, and Rotterdam Study. All subjects had genome-wide single-nucleotide polymorphism (SNP) scans and at least 1 phenotype measured: FVII activity/antigen, FVIII activity, and vWF antigen. Each study used its genotype data to impute to HapMap SNPs and independently conducted association analyses of hemostasis measures using an additive genetic model. Study findings were combined by meta-analysis. Replication was conducted in 7604 participants not in the discovery cohort. For FVII, 305 SNPs exceeded the genome-wide significance threshold of 5.0x10(-8) and comprised 5 loci on 5 chromosomes: 2p23 (smallest P value 6.2x10(-24)), 4q25 (3.6x10(-12)), 11q12 (2.0x10(-10)), 13q34 (9.0x10(-259)), and 20q11.2 (5.7x10(-37)). Loci were within or near genes, including 4 new candidate genes and F7 (13q34). For vWF, 400 SNPs exceeded the threshold and marked 8 loci on 6 chromosomes: 6q24 (1.2x10(-22)), 8p21 (1.3x10(-16)), 9q34 (<5.0x10(-324)), 12p13 (1.7x10(-32)), 12q23 (7.3x10(-10)), 12q24.3 (3.8x10(-11)), 14q32 (2.3x10(-10)), and 19p13.2 (1.3x10(-9)). All loci were within genes, including 6 new candidate genes, as well as ABO (9q34) and VWF (12p13). For FVIII, 5 loci were identified and overlapped vWF findings. Nine of the 10 new findings were replicated. CONCLUSIONS: New genetic associations were discovered outside previously known biological pathways and may point to novel prevention and treatment targets of hemostasis disorders.