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Background As SARS-CoV-2 continues to mutate into Variants of Concern (VOC), there is growing and urgent need to develop effective antivirals to combat COVID-19. Monoclonal antibodies developed earlier are no longer capable of effectively neutralizing currently active VOCs. This report describes the design of variant-agnostic chimeric molecules consisting of an Angiotensin-Converting Enzyme 2 (ACE-2) domain mutated to retain ultrahigh affinity binding to a wide variety of SARS-CoV-2 variants, coupled to an Fc-silent immunoglobulin domain that eliminates antibody-dependent enhancement and extends biological half-life. Methods Molecular modeling, Surrogate Viral Neutralization tests (sVNTs) and infection studies of human airway organoid cultures were performed with synthetic chimeras, SARS-CoV-2 spike protein mimics and SARS-CoV-2 Omicron variants B.1.1.214, BA.1, BA.2 and BA.5. Results ACE-2 mutations L27, V34 and E90 resulted in ultrahigh affinity binding of the LVE-ACE-2 domain to the widest variety of VOCs, with KDs of 93 pM and 73 pM for binding to the Alpha B1.1.7 and Omicron B.1.1.529 variants, and notably, 78fM, 133fM and 1.81pM affinities to the Omicron BA.2, BA2.75 and BQ.1.1 subvariants, respectively. sVNT assays revealed titers of ≥4.9 ng/ml, for neutralization of recombinant viral proteins corresponding to the Alpha, Delta and Omicron variants. The values above were obtained with LVE-ACE-2/mAB chimeras containing the FcRn-binding Y-T-E sequence which extends biological half-life 3–4-fold. Conclusions The ACE-2-mutant/Fc silent fusion proteins described have ultrahigh affinity to a wide variety of SARS-CoV-2 variants including Omicron. It is proposed that these chimeric ACE-2/mABs will constitute variant-agnostic and cost-effective prophylactics against SARS-CoV-2, particularly when administered nasally.

Norway’s Ringhorne Field is a faulted anticline, which produces oil from Triassic (Statfjord) and Paleocene (Hermod) sands. It is located on the Utsira High. Geochemical studies of the produced oil indicate that the oil is generated from mature Upper Jurassic marine shales in the adjacent Viking Graben. However, it is not clear how oil migrated into the Triassic reservoirs and charged the overlying Paleocene reservoirs. Lateral hydrocarbon migration is not detectable on seismic data. However, vertical hydrocarbon migration can be observed as a vertically aligned, low-amplitude, chaotic signature on normally processed seismic data. Gas-chimney detection is a proven neural network technique to detect these vertical hydrocarbon migration pathways. The processing results are then validated using a set of criteria to determine if they represented true hydrocarbon migration rather than seismic artifacts. The chimney processing results using this traditional (shallow) neural network are compared with convolutional neural network (deep learning) results and geomechanical modeling on key lines. Key reservoirs are delineated using a deterministic simultaneous seismic inversion approach. Reliable chimneys are then visualized in the vicinity of the producing reservoirs. The results indicate pathways by which the Triassic fluvial sands received the charge and how these reservoirs have flank leakage to provide the charge to shallower Paleocene reservoirs. This approach is currently being used over hundreds of fields and dry holes in the Norwegian North Sea and worldwide as analogs to assess the hydrocarbon charge and top seal risk predrill.

Anterior mitral valve leaflet (AMVL) elongation is a recognised feature of hypertrophic cardiomyopathy (HCM). However, whether AMVL elongation precedes left ventricular hypertrophy in cats is currently unknown. The aim of this study was to explore the risk of developing an HCM phenotype in cats with an elongated AMVL.FIFTY-FIVE APPARENTLY HEALTHY CATS WITH A NORMAL BASELINE ECHOCARDIOGRAM AND A FOLLOW-UP ECHOCARDIOGRAM ATONE YEAR.This was a retrospective longitudinal study. Cats at the baseline were grouped based on whether or not they developed an HCM phenotype at follow-up. AMVL length and left atrial and left ventricular dimensions were measured from two-dimensional images.The median follow-up period of the study population was 5.4 years (25th and 75th quartile, 2.7-6.7 years). During this time, 17 cats (30.9%) developed an HCM phenotype. At the baseline, cats that subsequently developed an HCM phenotype had greater AMVL length (9.4 mm [25th and 75th quartile, 9.0-10.6 mm] vs. 8.5 mm [25th and 75th quartile, 7.6-9.1 mm], P 0.0001) and maximal left ventricular wall thickness (4.5 mm [25th and 75th quartile, 4.1-4.7 mm] vs. 4.0 mm [25th and 75th quartile, 3.7-4.6 mm], P = 0.007) than those that did not. Multiple logistic regression analysis confirmed that both baseline variables were independent predictors for development of an HCM phenotype.The AMVL length was greater in cats that subsequently developed left ventricular hypertrophy. Further studies investigating the clinical application of AMVL in the natural history of feline HCM are warranted.

Background: GBM astrocytes may adopt fetal astrocyte transcriptomic signatures involved in brain development and migration programs to facilitate diffuse tumor infiltration. Our previous data show that ETS variant 6 (ETV6) is highly expressed in human GBM and fetal astrocytes compared to normal mature astrocytes. We hypothesized that ETV6 played a role in GBM tumor progression. Methods: Expression of ETV6 was first examined in two American and three Chinese tissue microarrays. The correlation between ETV6 staining intensity and patient survival was calculated, followed by validation using public databases—TCGA and REMBRANDT. The effect of ETV6 knockdown on glioma cell proliferation (EdU), viability (AnnexinV labeling), clonogenic growth (colony formation), and migration/invasion (transwell assays) in GBM cells was tested. RNA sequencing and Western blot were performed to elucidate the underlying molecular mechanisms. Results: ETV6 was highly expressed in GBM and associated with an unfavorable prognosis. ETV6 silencing in glioma cells led to increased apoptosis or decreased proliferation, clonogenicity, migration, and invasion. RNA-Seq-based gene expression and pathway analyses revealed that ETV6 knockdown in U251 cells led to the upregulation of genes involved in extracellular matrix organization, NF-κB signaling, TNF-mediated signaling, and the downregulation of genes in the regulation of cell motility, cell proliferation, PI3K-AKT signaling, and the Ras pathway. The downregulation of the PI3K-AKT and Ras-MAPK pathways were further validated by immunoblotting. Conclusion: Our findings suggested that ETV6 was highly expressed in GBM and its high expression correlated with poor survival. ETV6 silencing decreased an aggressive in vitro phenotype probably via the PI3K-AKT and Ras-MAPK pathways. The study encourages further investigation of ETV6 as a potential therapeutic target of GBM.

Introduction Both paroxysmal high-grade second-degree and persistent third-degree atrioventricular block (AVB) are recognised in cats. Our aim was to document the presentation, echocardiographic data, comorbidities and outcome in affected cats from a single referral hospital, including those that underwent epicardial pacemaker implantation (EPI). Animals, materials and methods This retrospective study included 64 cats diagnosed with persistent third-degree or paroxysmal high-grade AVB, for which detailed patient history was available. Non-parametric testing, Kaplan-Meier curves and Cox proportional hazard testing were performed. Results Atrioventricular block was persistent in 43 cats (67%) and paroxysmal in 21 (33%). Forty-seven cats (74%) were referred for cardiac complaints (e.g. collapse, arrhythmia, tachypnea), 6 (9%) had non-specific complaints and AVB was an incidental finding in 11 cats (17%). Median duration of clinical signs prior to presentation was 21 days (1–1138 days). Thirty-nine (63%) cats had echocardiographic abnormalities; 13 (20%) presented with congestive heart failure. Forty-five (70%) cats had one or more comorbidities. Fifteen cats underwent EPI with immediate resolution of signs in 12 cats. Following EPI, two and four cats experienced major and minor complications, respectively. Forty-seven cats died; median survival time was 799 days (all-cause mortality). Cardiac-related death occurred in 17 cats (36%); median survival in these cats was 132 days. Heart failure on presentation was the only independent risk factor for cardiac death (p=0.002). Conclusions Outcome in cats with AVB was variable, although most had good medium- to long-term survival. Cardiac death occurred in a minority of cats. Pacemaker implantation was effective in relieving clinical signs.

First of all, I would like to thank Freda Mishan (2021) for a fascinating and insightful article into English language teaching (ELT) coursebooks. She covers a wide range of perspectives and raises many important issues. Although I may have different views on some of these, I think she has done a great service in helping me look with fresh eyes at what many teachers take for granted: the humble yet ubiquitous ELT coursebook.

A method to calculate the elastic shakedown limit of transportation systems (e.g. pavements and railways) supported by geogrid reinforced soils is presented. For the first time, lower-bound shakedown theory is combined with a strength-based geogrid simulation approach, resulting in a rapid method to quantify the benefit of geogrids on the elastic shakedown limit. It allows decoupling of elastic stress generation and shakedown calculations, meaning it is straightforward to implement, and requires minimal computational effort. Therefore it presents a useful tool to optimise geogrid design for transportation structures such as highway pavements and railways. To show the capability of the method, shakedown limits are calculated for a variety of geogrid configurations using elastic stresses induced by a moving Hertz load. The effect of geogrid depth, soil cohesion, soil friction angle and loading type (normal versus tangential) are investigated for reinforced and non-reinforced soils. It is found that the optimum depth is sensitive to the soil strength properties. Regarding loading, it is shown that for highly tangential loads, shallower geogrids are effective, while for loads with a minimal tangential component, deeper geogrids are effective.

As the coronavirus SARS-CoV-2 continues to mutate into Variants of Concern (VOC), there is a growing and urgent need to develop effective antivirals to combat the newly emerged infectious disease COVID-19. Recent data indicate that monoclonal antibodies developed early in the pandemic are no longer capable of effectively neutralizing currently active VOCs. This report describes the design of a class of variant-agnostic chimeric molecules consisting of an Angiotensin Converting Enzyme-2 (ACE-2) domain mutated to retain ultrahigh affinity binding to a wide variety of SARS-CoV-2 variants, coupled to an Fc-silent immunoglobulin domain that eliminates antibody-dependent enhancement (ADE) and simultaneously extends biological half-life compared to existing mABs. Molecular modeling revealed that ACE-2 mutations L27, V34 and E90 resulted in ultrahigh affinity binding of the LVE-ACE-2 domain to the widest variety of VOCs, with KDs of 93 pM, 507 pM and 73 pM for binding to the Alpha B1.1.7, Delta B.1.617.2 and Omicron B.1.1.529 variants, and notably, 78fM affinity to the Omicron BA.2 variant, respectively. Surrogate viral neutralization assays (sVNT) revealed titers of ≥4.9ng/ml, for neutralization of recombinant viral proteins corresponding to the Alpha, Delta and Omicron variants. The values above were obtained with LVE-ACE-2/mAB chimeras containing the Y-T-E sequence that enhances binding to the FcRn receptor, which in turn is expected to extend biological half-life 3-4-fold. It is proposed that this new class of chimeric ACE-2/mABs will constitute variant-agnostic and cost-effective prophylactics against SARS-CoV-2, particularly when administered by nasal delivery systems.

Background Studies describing the clinical progression of animals with reverse patent ductus arteriosus (PDA) are lacking. Objectives To describe the signalment, presenting signs, echocardiographic features, and survival in a group of dogs and cats with bidirectional and continuous right-to-left PDA. Animals Forty-six client-owned animals included, comprising 43 dogs and 3 cats with bidirectional or continuous right-to-left PDA. Methods Retrospective multicenter study. Medical records and echocardiographic findings reviewed from animals diagnosed with bidirectional or continuous right-to-left PDA. Impact of ductal morphology, spectral Doppler flow profile, PCV, sildenafil treatment at presentation, sildenafil dose, severity of pulmonary hypertension, general anesthesia with or without surgery and the presence of right-sided congestive heart failure (R-CHF) on crude mortality rate were evaluated via Mantel-Cox log rank comparison of Kaplan-Meier survival curves. Univariable and multivariable Cox proportional hazards analysis was performed, and hazard ratio (HR) (95% confidence intervals [CI]) was presented. Results Hindlimb collapse was the most common presenting sign in dogs (n = 16). Clinical signs in cats were variable. Median survival time was 626 days in dogs (range 1-3628 days). Dogs with R-CHF had a shorter median survival time (58 days vs 1839 days, P = .03). Dogs treated with sildenafil at initial presentation survived longer (1839 days vs 302 days, P = .03), which was the only independent predictor of survival (HR 0.35, CI 0.15-0.86, P = 0.021). Conclusions and clinical importance Dogs and cats with reverse PDA have a variable clinical presentation and prognosis. Survival time was longer in animals prescribed sildenafil at diagnosis. Dogs with R-CHF at presentation have a worse overall outcome.

Background Quantitative methods for evaluating microstructure of arterial specimens typically rely on histologic techniques that involve random sampling, which cannot account for the unique spatial distribution of features in three dimensions. Methods To overcome this limitation, we demonstrate a nondestructive method for three-dimensional imaging of intact human blood vessels using microcomputed tomography (microCT). Human artery segments were dehydrated and stained in an iodine solution then imaged with a standard laboratory microCT scanner. Image visualization and segmentation was performed using commercially available and open source software. Results Staining of cadaveric vessels with iodine enabled clear visualization of the arterial wall with microCT, preserved tissue morphology, and generated high-resolution images with a voxel size of 5.4 μm. Various components of the arterial wall were segmented using a combination of manual and automatic thresholding algorithms. Conclusions Our approach allows for spatial mapping of human artery tissue samples that can guide targeted histologic analysis of smaller tissue segments, provide geometric data to inform finite element models, quantify degree of atherosclerosis, and help to evaluate the foreign body response to intravascular medical implants. (JVS–Vascular Science 2020;2:13-19.) Clinical Relevance In this article, we describe a powerful technique for whole artery analysis of pathologic human tissue specimens that provides high-resolution spatial detail regarding composition of the blood vessel wall. The protocol described here is a valuable adjunct that can be used as a research tool to inform finite element modeling of arteries, quantify pathologic response (ie, neointimal hyperplasia and vascular calcification), and evaluate the tissue/device interface of implanted medical devices.

OBJECTIVE To determine whether blood taurine concentrations in dogs with exocrine pancreatic insufficiency (EPI) were lower than the reference interval (200 to 350 nmol/mL) or the cutoff used to indicate taurine deficiency (< 150 nmol/mL). ANIMALS 18 dogs with clinical or presumptive subclinical EPI with residual blood samples available for taurine concentration analysis. PROCEDURES Dogs were classified as having clinical EPI if they had a serum trypsin-like immunoreactivity concentration of < 2.0 μg/L and presumptive subclinical EPI if they had a concentration of 2.0 to 5.0 μg/L. Archived, frozen blood samples stored in EDTA were submitted for measurement of taurine concentration with an automated high-performance liquid chromatography amino acid analyzer. Medical record data were examined for associations with blood taurine concentration. RESULTS None of the 18 dogs had a blood taurine concentration < 150 nmol/mL. Two dogs had a concentration < 200 nmol/mL. No clinical signs, physical examination findings, or serum biochemical abnormalities were associated with blood taurine concentration. Eleven of the 17 dogs for which diet histories were available were not receiving a diet that met recommendations of the World Small Animal Veterinary Association Global Nutrition Committee. CONCLUSIONS AND CLINICAL RELEVANCE A low blood taurine concentration was noted in a small subset of dogs with EPI. Additional research is needed to determine whether EPI was the primary cause of this low concentration. Findings suggested the importance of obtaining complete diet histories and ensuring dietary requirements are sufficiently met in dogs with EPI. (Am J Vet Res 2020;81:958–963)

Background N‐terminal pro B‐type natriuretic peptide (NT‐proBNP) and cardiac troponin‐I (cTnI) are biomarkers commonly evaluated in cats with suspected heart disease. Many cats with hypertrophic cardiomyopathy (HCM) have systolic anterior motion of the mitral valve (SAM), but its influence on circulating NT‐proBNP or cTnI concentrations is currently unknown. Hypothesis/Objectives Cats with HCM and SAM (HCMSAM+) have higher NT‐proBNP and cTnI concentrations than do cats with HCM but without SAM (HCMSAM−). Animals One hundred forty cats with HCM: 70 with SAM and 70 without SAM. Methods Retrospective case‐to‐case study. Cats were recruited if diagnosed with HCM by echocardiography and results were available for NT‐proBNP or cTnI concentrations or both. Cats with SAM were matched to those without SAM for clinical presentation, left atrial (LA) size and left ventricular (LV) fractional shortening. Results A total of 119 NT‐proBNP and 123 cTnI results were available. The HCMSAM+ cats had higher median concentrations than did HCMSAM− cats for NT‐proBNP (729 pmoL/L; interquartile range [IQR], 275‐1467 versus 65 pmoL/L; IQR, 25‐271; P

Compromised gut health and dysbiosis in people with heart failure has received a great deal of attention over the last decade. Whether dogs with heart failure have a similar dysbiosis pattern to what is described in people is currently unknown. We hypothesised that dogs with congestive heart failure have quantifiable dysbiosis compared to healthy dogs that are similar in sex and age. A total of 50 dogs (15 healthy dogs and 35 dogs with congestive heart failure) were prospectively recruited, and their faecal gut microbiome was assessed using 16S rRNA sequencing (Illumina MiSeq platform). There was no significant change in the microbial diversity and richness in dogs with congestive heart failure. However, there was an increase in abundance of Proteobacteria in the congestive heart failure group (p = 0.014), particularly due to an increase in the family Enterobacteriaceae (p = 0.002) and Escherichia coli (p = 0.033). We conclude that dogs with congestive heart failure have dysbiosis, and we show additional trends in our data suggesting that dogs may have a similar pattern to that described in people. The results of this study provide useful preliminary information and raise the possibility that dogs represent a clinically relevant animal model of dysbiosis in people with heart failure.

High speed railway track and earthwork structures experience varied levels of displacement amplification depending upon train speed. Protecting against amplified track deflections is challenging due to the complexity of deep wave propagation within both the track and supporting soil structures. Therefore it is challenging to derive design guidelines that encompass the full range of influential variables. As a solution, this paper uses a novel multi-model framework where 4 complimentary modelling strategies are combined, and thus able to generate new insights into railway ground dynamics and ‘critical velocity’. The four types of model are: 1) analytical, 2) hybrid analytical-numerical, 3) 2.5D numerical, 4) 3D numerical. They are used to explore subgrade layering, track type, train type, soil non-linearity, shakedown and ground improvement. The findings provide new insights into railway track-ground geodynamics and are useful when considering the design or upgrade of railroad lines.