Most antibodies isolated from individuals with coronavirus disease 2019 (COVID-19) are specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, COVA1-16 is a relatively rare ...antibody that also cross-neutralizes SARS-CoV. Here, we determined a crystal structure of the COVA1-16 antibody fragment (Fab) with the SARS-CoV-2 receptor-binding domain (RBD) and negative-stain electron microscopy reconstructions with the spike glycoprotein trimer to elucidate the structural basis of its cross-reactivity. COVA1-16 binds a highly conserved epitope on the SARS-CoV-2 RBD, mainly through a long complementarity-determining region (CDR) H3, and competes with the angiotensin-converting enzyme 2 (ACE2) receptor because of steric hindrance rather than epitope overlap. COVA1-16 binds to a flexible up conformation of the RBD on the spike and relies on antibody avidity for neutralization. These findings, along with the structural and functional rationale for epitope conservation, provide insights for development of more universal SARS-like coronavirus vaccines and therapies.
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•X-ray and EM structures of cross-neutralizing antibody COVA1-16 with SARS-CoV-2 RBD•COVA1-16 binding to SARS-CoV-2 RBD is dominated by CDR H3•COVA1-16 binds to a highly conserved non-RBS epitope but still competes with ACE2•IgG avidity is the key for the cross-neutralization activity of COVA1-16
COVA1-16 is a SARS-CoV-2 antibody from an individual with COVID-19 that cross-neutralizes SARS-CoV. Liu et al. reveal that COVA1-16 binds to a highly conserved epitope using a long CDR H3, where its approach angle sterically blocks ACE2 from engaging the RBS. Virus neutralization by COVA1-16 is driven by IgG avidity.
Augmented reality (AR) devices, as smart glasses, enable users to see both the real world and virtual images simultaneously, contributing to an immersive experience in interactions and visualization. ...Recently, to reduce the size and weight of smart glasses, waveguides incorporating holographic optical elements in the form of advanced grating structures have been utilized to provide light-weight solutions instead of bulky helmet-type headsets. However current waveguide displays often have limited display resolution, efficiency and field-of-view, with complex multi-step fabrication processes of lower yield. In addition, current AR displays often have vergence-accommodation conflict in the augmented and virtual images, resulting in focusing-visual fatigue and eye strain. Here we report metasurface optical elements designed and experimentally implemented as a platform solution to overcome these limitations. Through careful dispersion control in the excited propagation and diffraction modes, we design and implement our high-resolution full-color prototype, via the combination of analytical-numerical simulations, nanofabrication and device measurements. With the metasurface control of the light propagation, our prototype device achieves a 1080-pixel resolution, a field-of-view more than 40°, an overall input-output efficiency more than 1%, and addresses the vergence-accommodation conflict through our focal-free implementation. Furthermore, our AR waveguide is achieved in a single metasurface-waveguide layer, aiding the scalability and process yield control.
IGHV3-53-encoded neutralizing antibodies are commonly elicited during SARS-CoV-2 infection and target the receptor-binding domain (RBD) of the spike (S) protein. Such IGHV3-53 antibodies generally ...have a short CDR H3 because of structural constraints in binding the RBD (mode A). However, a small subset of IGHV3-53 antibodies to the RBD contain a longer CDR H3. Crystal structures of two IGHV3-53 neutralizing antibodies here demonstrate that a longer CDR H3 can be accommodated in a different binding mode (mode B). These two classes of IGHV3-53 antibodies both target the ACE2 receptor binding site, but with very different angles of approach and molecular interactions. Overall, these findings emphasize the versatility of IGHV3-53 in this common antibody response to SARS-CoV-2, where conserved IGHV3-53 germline-encoded features can be combined with very different CDR H3 lengths and light chains for SARS-CoV-2 RBD recognition and virus neutralization.
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•Crystal structures of IGHV3-53 antibodies that frequently bind SARS-CoV-2 RBD•Binding modes (A and B) of these IGHV3-53 antibodies depend on CDR H3 length•Germline-encoded CDR H1 and H2 motifs dominate the two binding poses•CDR H3 length of IGHV3-53 antibodies is associated with light chain preference
Antibodies to the SARS-CoV-2 receptor-binding domain are commonly encoded by IGHV3-53, and most have a short CDR H3. Wu et al. show that IGHV3-53 antibodies with a long CDR H3 adopt an alternative binding mode, demonstrating that IGHV3-53 is even more versatile than previously thought in targeting SARS-CoV-2.
This study tested whether aerobic exercise delivered during the consolidation window following fear extinction learning reduces the return of fear among women with posttraumatic stress disorder ...(PTSD). Participants (n=35) completed an initial clinical assessment followed by a 3-day fear acquisition, extinction, and recall protocol. On day 1, participants completed a fear acquisition training task in which one geometric shape (conditioning stimulus; CS+) was paired (with 50% probability) with a mild electric shock (unconditioned stimulus; US), while a different shape (CS-) was never paired with the US. On day 2 (24 h later), participants completed a fear extinction training task in which the CS+ no longer predicted administration of the US. Shortly following extinction, participants were randomly assigned to complete either moderate-intensity aerobic exercise (EX) or a light-intensity exercise control (CON) condition. On day 3 (24 h later), participants completed fear recall tests assessing the return of fear (spontaneous recovery, renewal, and reinstatement). Fear responding was assessed via threat expectancy ratings and skin conductance responses (SCR). In the threat expectancy ratings, there were no significant differences between groups in spontaneous recovery; however, EX significantly (p=.02) reduced threat expectancy ratings following reinstatement relative to CON. In SCR measures, there were no significant differences between groups in spontaneous recovery, renewal, or reinstatement. These results support a role for moderate-intensity aerobic exercise during the consolidation window in reducing threat expectations following reinstatement in women with PTSD. Research should continue to examine exercise as a potential method for improving the efficacy of exposure-based therapies.
ClinicalTrials.gov Identifier: NCT04113798.
•Fear extinction paradigms are widely used as a model of exposure therapy in PTSD.•Women with PTSD completed exercise (or control) following fear extinction training.•24 h later, participants completed fear recall tests assessing return of fear.•Exercise during the consolidation window decreased threat expectancy ratings following reinstatement compared to control.•Exercise may be a promising candidate for improving exposure-based therapies in PTSD.
Outcome of TGFβ1 signaling is context dependent and differs between individuals due to germ-line genetic variation. To explore innate genetic variants that determine differential outcome of reduced ...TGFβ1 signaling, we dissected the modifier locus Tgfbm3 , on mouse chromosome 12. On a NIH/OlaHsd genetic background, the Tgfbm3b C⁵⁷ haplotype suppresses prenatal lethality of Tgfb1 ⁻/⁻ embryos and enhances nuclear accumulation of mothers against decapentaplegic homolog 2 (Smad2) in embryonic cells. Amino acid polymorphisms within a disintegrin and metalloprotease 17 (Adam17) can account, at least in part, for this Tgfbm3b effect. ADAM17 is known to down-regulate Smad2 signaling by shedding the extracellular domain of TGFβRI, and we show that the C57 variant is hypomorphic for down-regulation of Smad2/3-driven transcription. Genetic variation at Tgfbm3 or pharmacological inhibition of ADAM17, modulates postnatal circulating endothelial progenitor cell (CEPC) numbers via effects on TGFβRI activity. Because CEPC numbers correlate with angiogenic potential, this suggests that variant Adam17 is an innate modifier of adult angiogenesis, acting through TGFβR1. To determine whether human ADAM17 is also polymorphic and interacts with TGFβ signaling in human vascular disease, we investigated hereditary hemorrhagic telangiectasia (HHT), which is caused by mutations in TGFβ/bone morphogenetic protein receptor genes, ENG , encoding endoglin (HHT1), or ACVRL1 encoding ALK1 (HHT2), and considered a disease of excessive abnormal angiogenesis. HHT manifests highly variable incidence and severity of clinical features, ranging from small mucocutaneous telangiectases to life-threatening visceral and cerebral arteriovenous malformations (AVMs). We show that ADAM17 SNPs associate with the presence of pulmonary AVM in HHT1 but not HHT2, indicating genetic variation in ADAM17 can potentiate a TGFβ-regulated vascular disease.
We recently demonstrated that moderate-intensity aerobic exercise delivered during the consolidation of fear extinction learning reduced threat expectancy during a test of extinction recall among ...women with posttraumatic stress disorder (PTSD). These findings suggest that exercise may be a potential candidate for improving the efficacy of exposure-based therapies, which are hypothesized to work via the mechanisms of fear extinction learning. The purpose of this secondary analysis was to examine whether exercise-induced increases in circulating concentrations of candidate biomarkers: endocannabinoids (anandamide AEA; 2-arachidonoylglycerol 2-AG, brain-derived neurotrophic factor (BDNF), and homovanillic acid (HVA), mediate the effects of exercise on extinction recall.
Participants (N = 35) completed a 3-day fear acquisition (day 1), extinction (day 2), and extinction recall (day 3) protocol, in which participants were randomly assigned to complete either moderate-intensity aerobic exercise (EX) or a light-intensity control (CON) condition following extinction training (day 2). Blood was obtained prior to and following EX or CON. Threat expectancy ratings during tests of extinction recall (i.e., initial fear recall and fear recall following reinstatement) were obtained 24 h following EX or CON. Mediation was tested using linear-mixed effects models and bootstrapping of the indirect effect.
Circulating concentrations of AEA and BDNF (but not 2-AG and HVA) were found to mediate the relationship between moderate-intensity aerobic exercise and reduced threat expectancy ratings following reinstatement (AEA 95% CI: −0.623 to −0.005; BDNF 95% CI: −0.941 to −0.005).
Exercise-induced increases in peripheral AEA and BDNF appear to play a role in enhancing consolidation of fear extinction learning, thereby leading to reduced threat expectancies following reinstatement among women with PTSD. Future mechanistic research examining these and other biomarkers (e.g., brain-based biomarkers) is warranted.
•Exposure-based therapies are hypothesized to work via the mechanisms of fear extinction learning.•Aerobic exercise delivered after extinction learning enhanced consolidation of fear extinction learning.•Exercise-induced increases in AEA and BDNF were found to mediate this relationship.•Aerobic exercise may be a promising candidate for improving exposure-based therapies.
The exchange bias phenomenon, inherent in exchange-coupled ferromagnetic and antiferromagnetic systems, has intrigued researchers for decades. Van der Waals materials, with their layered structures, ...offer an ideal platform for exploring exchange bias. However, effectively manipulating exchange bias in van der Waals heterostructures remains challenging. This study investigates the origin of exchange bias in MnPS3/Fe3GeTe2 van der Waals heterostructures, demonstrating a method to modulate nearly 1000% variation in magnitude through simple thermal cycling. Despite the compensated interfacial spin configuration of MnPS3, a substantial 170 mT exchange bias is observed at 5 K, one of the largest observed in van der Waals heterostructures. This significant exchange bias is linked to anomalous weak ferromagnetic ordering in MnPS3 below 40 K. The tunability of exchange bias during thermal cycling is attributed to the amorphization and changes in the van der Waals gap during field cooling. The findings highlight a robust and adjustable exchange bias in van der Waals heterostructures, presenting a straightforward method to enhance other interface-related spintronic phenomena for practical applications. Detailed interface analysis reveals atom migration between layers, forming amorphous regions on either side of the van der Waals gap, emphasizing the importance of precise interface characterization in these heterostructures.The exchange bias phenomenon, inherent in exchange-coupled ferromagnetic and antiferromagnetic systems, has intrigued researchers for decades. Van der Waals materials, with their layered structures, offer an ideal platform for exploring exchange bias. However, effectively manipulating exchange bias in van der Waals heterostructures remains challenging. This study investigates the origin of exchange bias in MnPS3/Fe3GeTe2 van der Waals heterostructures, demonstrating a method to modulate nearly 1000% variation in magnitude through simple thermal cycling. Despite the compensated interfacial spin configuration of MnPS3, a substantial 170 mT exchange bias is observed at 5 K, one of the largest observed in van der Waals heterostructures. This significant exchange bias is linked to anomalous weak ferromagnetic ordering in MnPS3 below 40 K. The tunability of exchange bias during thermal cycling is attributed to the amorphization and changes in the van der Waals gap during field cooling. The findings highlight a robust and adjustable exchange bias in van der Waals heterostructures, presenting a straightforward method to enhance other interface-related spintronic phenomena for practical applications. Detailed interface analysis reveals atom migration between layers, forming amorphous regions on either side of the van der Waals gap, emphasizing the importance of precise interface characterization in these heterostructures.
Abstract Aims To examine temporal trends in lower extremity amputations in people with type 1 diabetes, type 2 diabetes and cardiovascular disease (CVD) without diabetes in Western Australia (WA) ...from 2000 to 2010. Methods We used linked health data to identify all non-traumatic lower extremity amputations in adults aged ≥20years with diabetes and/or CVD from 2000 to 2010 in WA. Annual age- and sex-standardised rates of total, initial and recurrent amputations, stratified by major and minor status, were calculated for type 1 and type 2 diabetes, and CVD without diabetes, from the at-risk population for each group. Age- and sex-adjusted trends were estimated from Poisson regression models. Results 5891 lower extremity amputations were identified. Peripheral vascular disease (71%), hypertension (70%) and chronic kidney disease (60%) were highly prevalent. Average annual rates of total amputations were 724, 564 and 66 per 100,000 person-years in type 1, type 2 diabetes and CVD without diabetes respectively. Rates of initial amputations fell significantly by 2.4%/year (95% CI −3.5, −1.4) in type 2 diabetes, with similar declines for type 1 diabetes and CVD without diabetes (interaction p = 0.96), driven by large falls in major amputations. There was limited improvement in recurrence rates overall, with recurrent minor amputations increasing significantly in type 2 diabetes (+3.5%/year, 95% CI +1.3%, +5.7%). Conclusion Lower extremity amputation rates have declined at a population level in people with diabetes and CVD without diabetes, suggesting improvements in prevention and management for this high-risk patient group, however limited declines in recurrent amputations requires further investigation.
Long-term mortality following myocardial infarction is higher in diabetic than non-diabetic individuals. Early case-fatality after myocardial infarction has improved but it is unclear whether trends ...extend to long-term mortality. We aimed to determine whether the disparity in long-term all-cause and cardiovascular disease mortality by diabetes status has decreased.
All incident myocardial infarction cases were identified from Western Australian whole-population linked data for 1998-2009. Mortality follow-up was available until 30 June 2011. Unadjusted survival was estimated using Kaplan-Meier survival curves. Hazard ratios comparing five-year mortality in diabetic versus non-diabetic people across three periods (1998-2001, 2002-2005, 2006-2009) were estimated from multivariable Cox regression models, and adjusted trends calculated from interaction (diabetes status × period) models.
There were 22,594 30-day survivors of incident MI. There was little change across the three periods in all-cause mortality in diabetic men (27.1%, 28.2%, 25.5%) and women (34.9%, 36.8%, 36.1%), but small declines from first to last periods in non-diabetic men (14.5% to 12.1%, p = 0.03) and women (21.0% to 19.4%, p = 0.08). There was no temporal change in the increased all-cause mortality hazard ratios in diabetic versus non-diabetic men and women. Multivariable-adjusted relative risk for cardiovascular disease mortality remained elevated in diabetic women (2006-2009 hazard ratio 1.73, 95% confidence interval 1.29, 2.32) but not in men (2006-2009 hazard ratio 1.08, 95% confidence interval 0.85, 1.37).
The excess long-term mortality associated with diabetes and excess cardiovascular disease mortality in diabetic women indicates a need for improved secondary prevention in diabetic patients, especially women.
Non-invasive focused ultrasound stimulation (FUS) is a non-ionising neuromodulatory technique that employs acoustic energy to acutely and reversibly modulate brain activity of deep-brain structures. ...It is currently being investigated as a potential novel treatment for Parkinson's disease (PD). This scoping review was carried out to map available evidence pertaining to the provision of FUS as a PD neuromodulatory tool. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Reviews, a search was applied to Ovid MEDLINE, Embase, Web of Science and Cochrane Central Register of Controlled Trials on 13 January 2022, with no limits applied. In total, 11 studies were included: 8 were from China and 1 each from Belgium, South Korea and Taiwan. All 11 studies were preclinical (6
, 2
, 2 mix of
and
and 1
). The preclinical evidence indicates that FUS is safe and has beneficial neuromodulatory effects on motor behaviour in PD. FUS appears to have a therapeutic role in influencing the disease processes of PD, and therefore holds great promise as an attractive and powerful neuromodulatory tool for PD. Though these initial studies are encouraging, further study to understand the underlying cellular and molecular mechanisms is required before FUS can be routinely used in PD.
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