The COVID-19 pandemic has had widespread effects across the globe, and its causative agent, SARS-CoV-2, continues to spread. Effective interventions need to be developed to end this pandemic. Single ...and combination therapies with monoclonal antibodies have received emergency use authorization
, and more treatments are under development
. Furthermore, multiple vaccine constructs have shown promise
, including two that have an approximately 95% protective efficacy against COVID-19
. However, these interventions were directed against the initial SARS-CoV-2 virus that emerged in 2019. The recent detection of SARS-CoV-2 variants B.1.1.7 in the UK
and B.1.351 in South Africa
is of concern because of their purported ease of transmission and extensive mutations in the spike protein. Here we show that B.1.1.7 is refractory to neutralization by most monoclonal antibodies against the N-terminal domain of the spike protein and is relatively resistant to a few monoclonal antibodies against the receptor-binding domain. It is not more resistant to plasma from individuals who have recovered from COVID-19 or sera from individuals who have been vaccinated against SARS-CoV-2. The B.1.351 variant is not only refractory to neutralization by most monoclonal antibodies against the N-terminal domain but also by multiple individual monoclonal antibodies against the receptor-binding motif of the receptor-binding domain, which is mostly due to a mutation causing an E484K substitution. Moreover, compared to wild-type SARS-CoV-2, B.1.351 is markedly more resistant to neutralization by convalescent plasma (9.4-fold) and sera from individuals who have been vaccinated (10.3-12.4-fold). B.1.351 and emergent variants
with similar mutations in the spike protein present new challenges for monoclonal antibody therapies and threaten the protective efficacy of current vaccines.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
The HIV-1-envelope (Env) trimer is covered by a glycan shield of ∼90 N-linked oligosaccharides, which comprises roughly half its mass and is a key component of HIV evasion from humoral immunity. To ...understand how antibodies can overcome the barriers imposed by the glycan shield, we crystallized fully glycosylated Env trimers from clades A, B, and G, visualizing the shield at 3.4–3.7 Å resolution. These structures reveal the HIV-1-glycan shield to comprise a network of interlocking oligosaccharides, substantially ordered by glycan crowding, that encase the protein component of Env and enable HIV-1 to avoid most antibody-mediated neutralization. The revealed features delineate a taxonomy of N-linked glycan-glycan interactions. Crowded and dispersed glycans are differently ordered, conserved, processed, and recognized by antibody. The structures, along with glycan-array binding and molecular dynamics, reveal a diversity in oligosaccharide affinity and a requirement for accommodating glycans among known broadly neutralizing antibodies that target the glycan-shielded trimer.
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•Crystallographic (3.4–3.7 Å) visualization of the HIV-1 glycan shield•Structures delineate a taxonomy of N-linked glycan-glycan interactions•Crowded and dispersed glycans are differently ordered, processed, and conserved•HIV-1-neutralizing antibodies recognizing the closed Env trimer accommodate glycan
Crystal structures of fully glycosylated Env trimers from clades A, B, and G reveal the HIV-1 glycan shield to comprise a network of interlocking oligosaccharides, substantially ordered by glycan crowding, that encase the protein component of Env and enable HIV-1 to avoid most antibody-mediated neutralization.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Thraustochytrids were first discovered in 1934, and since the 1960's they have been increasingly studied for their beneficial and deleterious effects. This review aims to provide an enhanced ...understanding of these protists with a particular emphasis on their taxonomy, ecology and biotechnology applications. Over the years, thraustochytrid taxonomy has improved with the development of modern molecular techniques and new biochemical markers, resulting in the isolation and description of new strains. In the present work, the taxonomic history of thraustochytrids is reviewed, while providing an up-to-date classification of these organisms. It also describes the various biomarkers that may be taken into consideration to support taxonomic characterization of the thraustochytrids, together with a review of traditional and modern techniques for their isolation and molecular identification. The originality of this review lies in linking taxonomy and ecology of the thraustochytrids and their biotechnological applications as producers of docosahexaenoic acid (DHA), carotenoids, exopolysaccharides and other compounds of interest. The paper provides a summary of these aspects while also highlighting some of the most important recent studies in this field, which include the diversity of polyunsaturated fatty acid metabolism in thraustochytrids, some novel strategies for biomass production and recovery of compounds of interest. Furthermore, a detailed overview is provided of the direct and current applications of thraustochytrid-derived compounds in the food, fuel, cosmetic, pharmaceutical, and aquaculture industries and of some of the commercial products available. This review is intended to be a source of information and references on the thraustochytrids for both experts and those who are new to this field.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Examining the Paradox of Occupational Stressors: Building Resilience or Creating Depletionrepresents insightful, intriguing, and timely research into the paradox of experienced stress in the ...workplace.
Deep learning for MRI detection of sports injuries poses unique challenges. To address these difficulties, this study examines the feasibility and incremental benefit of several customized network ...architectures in evaluation of complete anterior cruciate ligament (ACL) tears. Two hundred sixty patients, ages 18–40, were identified in a retrospective review of knee MRIs obtained from September 2013 to March 2016. Half of the cases demonstrated a complete ACL tear (624 slices), the other half a normal ACL (3520 slices). Two hundred cases were used for training and validation, and the remaining 60 cases as an independent test set. For each exam with an ACL tear, coronal proton density non-fat suppressed sequence was manually annotated to delineate: (1) a bounding-box around the cruciate ligaments; (2) slices containing the tear. Multiple convolutional neural network (CNN) architectures were implemented including variations in input field-of-view and dimensionality. For single-slice CNN architectures, validation accuracy of a dynamic patch-based sampling algorithm (0.765) outperformed both cropped slice (0.720) and full slice (0.680) strategies. Using the dynamic patch-based sampling algorithm as a baseline, a five-slice CNN input (0.915) outperformed both three-slice (0.865) and single-slice (0.765) inputs. The final highest performing five-slice dynamic patch-based sampling algorithm resulted in independent test set AUC, sensitivity, specificity, PPV, and NPV of 0.971, 0.967, 1.00, 0.938, and 1.00. A customized 3D deep learning architecture based on dynamic patch-based sampling demonstrates high performance in detection of complete ACL tears with over 96% test set accuracy. A cropped field-of-view and 3D inputs are critical for high algorithm performance.
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NUK, OBVAL, SBMB, SBNM, UL, UM, UPUK, VSZLJ
Radiographic assessment with magnetic resonance imaging (MRI) is widely used to characterize gliomas, which represent 80% of all primary malignant brain tumors. Unfortunately, glioma biology is ...marked by heterogeneous angiogenesis, cellular proliferation, cellular invasion, and apoptosis. This translates into varying degrees of enhancement, edema, and necrosis, making reliable imaging assessment challenging. Deep learning, a subset of machine learning artificial intelligence, has gained traction as a method, which has seen effective employment in solving image-based problems, including those in medical imaging. This review seeks to summarize current deep learning applications used in the field of glioma detection and outcome prediction and will focus on (1) pre- and post-operative tumor segmentation, (2) genetic characterization of tissue, and (3) prognostication. We demonstrate that deep learning methods of segmenting, characterizing, grading, and predicting survival in gliomas are promising opportunities that may enhance both research and clinical activities.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The HIV-1 fusion peptide, comprising 15 to 20 hydrophobic residues at the N terminus of the Env-gp41 subunit, is a critical component of the virus-cell entry machinery. Here, we report the ...identification of a neutralizing antibody, N123-VRC34.01, which targets the fusion peptide and blocks viral entry by inhibiting conformational changes in gp120 and gp41 subunits of Env required for entry. Crystal structures of N123-VRC34.01 liganded to the fusion peptide, and to the full Env trimer, revealed an epitope consisting of the N-terminal eight residues of the gp41 fusion peptide and glycan N88 of gp120, and molecular dynamics showed that the N-terminal portion of the fusion peptide can be solvent-exposed. These results reveal the fusion peptide to be a neutralizing antibody epitope and thus a target for vaccine design.
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BFBNIB, NMLJ, NUK, ODKLJ, PNG, SAZU, UL, UM, UPUK
OBJECTIVE
The association between high glycemic variability and all-cause mortality has been widely investigated in epidemiological studies but rarely validated in glucose-lowering clinical trials. ...We aimed to identify the prognostic significance of visit-to-visit HbA1c variability in treated patients in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial population.
RESEARCH DESIGN AND METHODS
We studied the risk of all-cause mortality in relation to long-term visit-to-visit HbA1c variability, expressed as coefficient of variation (CV), variability independent of the mean (VIM), and average real variability (ARV), from the 8th month to the transition from intensive to standard glycemic therapy. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratio (HR) and 95% CI.
RESULTS
Compared with the standard therapy group (n = 4,728), the intensive therapy group (n = 4,755) had significantly lower mean HbA1c (6.6% 49 mmol/mol vs. 7.7% 61 mmol/mol, P < 0.0001) and lower CV, VIM, and ARV (P < 0.0001). In multivariate adjusted analysis, all three HbA1c variability indices were significantly associated with total mortality in all patients as well as in the standard- and intensive-therapy groups analyzed separately. The hazard ratios for a 1-SD increase in HbA1c variability indices for all-cause mortality were 1.19 and 1.23 in intensive and standard therapy, respectively. Cross-tabulation analysis showed the third tertile of HbA1c mean and VIM had significantly higher all-cause mortality (HR 2.05; 95% CI 1.17–3.61; P < 0.01) only in the intensive-therapy group.
CONCLUSIONS
Long-term visit-to-visit HbA1c variability was a strong predictor of all-cause mortality. HbA1c VIM combined with HbA1c mean conferred an increased risk for all-cause mortality in the intensive-therapy group.
We investigate the applicability of an incompressible diffuse interface model for two-phase incompressible fluid flows with large viscosity and density contrasts. Diffuse-interface models have been ...used previously primarily for density-matched fluids, and it remains unclear to what extent such models can be used for fluids of different density, thereby potentially limiting the application of these models. In this paper, the convective Cahn–Hilliard equation and the condition that the velocity field is divergence-free are derived from the conservation law of mass of binary mixtures in a straightforward way, for fluids with large density and viscosity ratios. Differences in the equations of motion with a previously derived quasi-incompressible model are shown to result from the respective assumptions made regarding the relationship between the diffuse fluxes of two species. The convergence properties of the model are investigated for cases with large density ratio. Quantitative comparisons are made with results from previous studies to validate the model and its numerical implementation. Tests show that the variation in volume during the computation is of the order of machine accuracy, which is consistent with our use of a conservative discretization scheme (finite volume methods) for the Cahn–Hilliard equation. Results of the method are compared with previous work for the change in topology of rising bubbles and Rayleigh–Taylor instability. Additional results are presented for head-on droplet collision and the onset of droplet entrainment in stratified flows.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Molecular understanding of serological immunity to influenza has been confounded by the complexity of the polyclonal antibody response in humans. Here we used high-resolution proteomics analysis of ...immunoglobulin (referred to as Ig-seq) coupled with high-throughput sequencing of transcripts encoding B cell receptors (BCR-seq) to quantitatively determine the antibody repertoire at the individual clonotype level in the sera of young adults before and after vaccination with trivalent seasonal influenza vaccine. The serum repertoire comprised between 40 and 147 clonotypes that were specific to each of the three monovalent components of the trivalent influenza vaccine, with boosted pre-existing clonotypes accounting for ∼60% of the response. An unexpectedly high fraction of serum antibodies recognized both the H1 and H3 monovalent vaccines. Recombinant versions of these H1 + H3 cross-reactive antibodies showed broad binding to hemagglutinins (HAs) from previously circulating virus strains; several of these antibodies, which were prevalent in the serum of multiple donors, recognized the same conserved epitope in the HA head domain. Although the HA-head-specific H1 + H3 antibodies did not show neutralization activity in vitro, they protected mice against infection with the H1N1 and H3N2 virus strains when administered before or after challenge. Collectively, our data reveal unanticipated insights regarding the serological response to influenza vaccination and raise questions about the added benefits of using a quadrivalent vaccine instead of a trivalent vaccine.
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IJS, NUK, SBMB, UL, UM, UPUK
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