Fab glycosylation of immunoglobulin G does not associate with improvement of rheumatoid arthritis during pregnancy

Background: Changes in immunoglobulin G (IgG) constant domain (Fc) glycosylation are associated with changes in rheumatoid arthritis (RA) disease activity in response to pregnancy. Here, we sought to determine whether the same holds true for variable domain (Fab) glycosylation. Methods: IgGs were captured from RA and control sera obtained before (RA only), during and after pregnancy, followed by Fc and Fab separation, glycan release, and mass spectrometric detection. In parallel,

Acute ischaemic stroke associated with SARS-CoV-2 infection in North America

BACKGROUND: To analyse the clinical characteristics of COVID-19 with acute ischaemic stroke (AIS) and identify factors predicting functional outcome. METHODS: Multicentre retrospective cohort study of COVID-19 patients with AIS who presented to 30 stroke centres in the USA and Canada between 14 March and 30 August 2020. The primary endpoint was poor functional outcome, defined as a modified Rankin Scale (mRS) of 5 or 6 at discharge. Secondary endpoints include favourable outcome (mRS ≤2) and mortality at discharge, ordinal mRS (shift analysis), symptomatic intracranial haemorrhage (sICH) and occurrence of in-hospital complications. RESULTS: A total of 216 COVID-19 patients with AIS were included. 68.1% (147/216) were older than 60 years, while 31.9% (69/216) were younger. Median [IQR] National Institutes of Health Stroke Scale (NIHSS) at presentation was 12.5 (15.8), and 44.2% (87/197) presented with large vessel occlusion (LVO). Approximately 51.3% (98/191) of the patients had poor outcomes with an observed mortality rate of 39.1% (81/207). Age \u3e60 years (aOR: 5.11, 95% CI 2.08 to 12.56, p\u3c0.001), diabetes mellitus (aOR: 2.66, 95% CI 1.16 to 6.09, p=0.021), higher NIHSS at admission (aOR: 1.08, 95% CI 1.02 to 1.14, p=0.006), LVO (aOR: 2.45, 95% CI 1.04 to 5.78, p=0.042), and higher NLR level (aOR: 1.06, 95% CI 1.01 to 1.11, p=0.028) were significantly associated with poor functional outcome. CONCLUSION: There is relationship between COVID-19-associated AIS and severe disability or death. We identified several factors which predict worse outcomes, and these outcomes were more frequent compared to global averages. We found that elevated neutrophil-to-lymphocyte ratio, rather than D-Dimer, predicted both morbidity and mortality

Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors1,2, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies

Ordered and deterministic cancer genome evolution after p53 loss

Although p53 inactivation promotes genomic instability1 and presents a route to malignancy for more than half of all human cancers2,3, the patterns through which heterogenous TP53 (encoding human p53) mutant genomes emerge and influence tumorigenesis remain poorly understood. Here, in a mouse model of pancreatic ductal adenocarcinoma that reports sporadic p53 loss of heterozygosity before cancer onset, we find that malignant properties enabled by p53 inactivation are acquired through a predictable pattern of genome evolution. Single-cell sequencing and in situ genotyping of cells from the point of p53 inactivation through progression to frank cancer reveal that this deterministic behaviour involves four sequential phases-Trp53 (encoding mouse p53) loss of heterozygosity, accumulation of deletions, genome doubling, and the emergence of gains and amplifications-each associated with specific histological stages across the premalignant and malignant spectrum. Despite rampant heterogeneity, the deletion events that follow p53 inactivation target functionally relevant pathways that can shape genomic evolution and remain fixed as homogenous events in diverse malignant populations. Thus, loss of p53-the 'guardian of the genome'-is not merely a gateway to genetic chaos but, rather, can enable deterministic patterns of genome evolution that may point to new strategies for the treatment of TP53-mutant tumours

Estimation of earthquake damage probabilities for reinforced concrete buildings

Due to uncertainties involved both in the occurrence of earthquakes and in structural response, earthquake damage prediction has to be treated in a probabilistic manner. In this study two statistical methods are presented for the prediction of potential seismic damage to low and mid-rise reinforced concrete buildings in Turkey. These methods are based on the utilization of damage probability matrices and reliability theory. The damage data compiled during recent earthquakes that occurred in Turkey are used to compare the predictions of these two methods

Strong-Ground-Motion Simulation of the 6 April 2009 L’Aquila, Italy, Earthquake

On 6 April 2009, an earthquake of Mw 6:13 (Herrmann et al., 2011) occurred in central Italy, close to the town of L’Aquila. Although the earthquake is considered to be a moderate-size event, it caused extensive damage to the surrounding area. The earthquake is identified with significant directivity effects: highamplitude, short-duration motions are observed at the stations that are oriented along the rupture direction, whereas low-amplitude, long-duration motions are observed at the stations oriented in the direction opposite to the rupture. The complex nature of the earthquake combined with its damage potential brings the need for studies that assess the seismological characteristics of the 2009 L’Aquila mainshock. In this study, we present the strong-ground-motion simulation of this particular earthquake using a stochastic finite-fault model with a dynamic corner frequency approach. For modeling the resulting ground motions, we choose two finite-fault source models that take into account the source complexity of the L’Aquila mainshock. In order to test the sensitivity of ground-motion parameters to the seismic wave attenuation parameters, we use two different attenuation models obtained in the study region using weak-motion and strong-motion databases. Comparisons are made between the attenuation of synthetics and ground-motion prediction equations (GMPEs). Synthetic ground motions are further compared with the observed ones in terms of Fourier amplitude and response spectra at 21 strong-ground-motion stations that recorded the mainshock within an epicentral distance of 100 km. The spatial distribution of shaking intensity obtained from the “Did You Feel It?” project and site survey results are compared with the spatial distributions of simulated peak ground-motion intensity parameters. Our results show that despite the limitations of the method in simulating the directivity effects, the stochastic finite-fault model seems an effective and fast tool to simulate the high-frequency portion of ground motion

Rumen ciliated protozoa of the Turkish domestic goats (Capra hircus L.)

WOS: 000233664400004Rumen contents obtained from eight adult domesticated goats (Capra hircus L.) at slaughterhouses in the southeastern area of Turkey were surveyed for ciliate protozoa. As a result of our survey, 12 genera including 39 species were identified. Fifteen of the species were further divided into 35 formae. The average ciliate density in the rumen contents of Turkish goats (33.21 x 10(4)/ml) was less than that of other ruminants from Turkey and other domestic goats reported previously from different geographical areas. However, the number of genera, species and forms living in the rumen of Turkish goats were found to be higher than that of the goats in different countries around the world. The rich faunal content of the southeastern Turkish domestic goats shows the zoogeographical importance of SE Anatolia

An energy-based seismic response evaluation of simple structural systems with simulated ground motions

In recent years, there has been a strong interest on energy-based design and assessment methods for structural systems. The underlying research has been mostly performed using real ground motion records taken from existing earthquakes worldwide. Results may involve bias due to lack of homogeneity of the available ground motion dataset in terms of magnitudes, source to site distances or soil conditions. In this study a large set of ground motion records is simulated within a parametric exercise to investigate the effect of different intensity measures on the energy-based response of simple SDOF structures. To generate simulated records, the stochastic finite-fault methodology which is effective in simulating a wide range of frequencies including those that influence the built environment is used. The simulations are performed on active faults around Duzce city center located on the western segments of North Anatolian Fault zone in Turkey. The simulated records cover a wide range of moment magnitude, source-to-site distances and soil conditions. To assess the response statistics on SDOF models, time history analyses with simulated records are performed. Input energy, damping energy and hysteretic energy are considered as the main output parameters. The results of this study reveal that energy is a more stable parameter than the other response parameters such as displacement and force. However, it is important to dissipate the estimated input energy through damping and inelastic action. Finally, it is believed that conducting parametric seismic analysis based on simulated records yield realistic results since these records provide variability in seismic demand