Emerging clinical evidence suggests that thrombosis in the microvasculature of patients with Coronavirus disease 2019 (COVID-19) plays an essential role in dictating the disease progression. Because ...of the infectious nature of SARS-CoV-2, patients' fresh blood samples are limited to access for in vitro experimental investigations. Herein, we employ a novel multiscale and multiphysics computational framework to perform predictive modeling of the pathological thrombus formation in the microvasculature using data from patients with COVID-19. This framework seamlessly integrates the key components in the process of blood clotting, including hemodynamics, transport of coagulation factors and coagulation kinetics, blood cell mechanics and adhesive dynamics, and thus allows us to quantify the contributions of many prothrombotic factors reported in the literature, such as stasis, the derangement in blood coagulation factor levels and activities, inflammatory responses of endothelial cells and leukocytes to the microthrombus formation in COVID-19. Our simulation results show that among the coagulation factors considered, antithrombin and factor V play more prominent roles in promoting thrombosis. Our simulations also suggest that recruitment of WBCs to the endothelial cells exacerbates thrombogenesis and contributes to the blockage of the blood flow. Additionally, we show that the recent identification of flowing blood cell clusters could be a result of detachment of WBCs from thrombogenic sites, which may serve as a nidus for new clot formation. These findings point to potential targets that should be further evaluated, and prioritized in the anti-thrombotic treatment of patients with COVID-19. Altogether, our computational framework provides a powerful tool for quantitative understanding of the mechanism of pathological thrombus formation and offers insights into new therapeutic approaches for treating COVID-19 associated thrombosis.
Microaneurysms (MAs) are one of the earliest clinically visible signs of diabetic retinopathy (DR). MA leakage or rupture may precipitate local pathology in the surrounding neural retina that impacts ...visual function. Thrombosis in MAs may affect their turnover time, an indicator associated with visual and anatomic outcomes in the diabetic eyes. In this work, we perform computational modeling of blood flow in microchannels containing various MAs to investigate the pathologies of MAs in DR. The particle-based model employed in this study can explicitly represent red blood cells (RBCs) and platelets as well as their interaction in the blood flow, a process that is very difficult to observe in vivo. Our simulations illustrate that while the main blood flow from the parent vessels can perfuse the entire lumen of MAs with small body-to-neck ratio (BNR), it can only perfuse part of the lumen in MAs with large BNR, particularly at a low hematocrit level, leading to possible hypoxic conditions inside MAs. We also quantify the impacts of the size of MAs, blood flow velocity, hematocrit and RBC stiffness and adhesion on the likelihood of platelets entering MAs as well as their residence time inside, two factors that are thought to be associated with thrombus formation in MAs. Our results show that enlarged MA size, increased blood velocity and hematocrit in the parent vessel of MAs as well as the RBC-RBC adhesion promote the migration of platelets into MAs and also prolong their residence time, thereby increasing the propensity of thrombosis within MAs. Overall, our work suggests that computational simulations using particle-based models can help to understand the microvascular pathology pertaining to MAs in DR and provide insights to stimulate and steer new experimental and computational studies in this area.
Accurate prediction of blood glucose variations in type 2 diabetes (T2D) will facilitate better glycemic control and decrease the occurrence of hypoglycemic episodes as well as the morbidity and ...mortality associated with T2D, hence increasing the quality of life of patients. Owing to the complexity of the blood glucose dynamics, it is difficult to design accurate predictive models in every circumstance, i.e., hypo/normo/hyperglycemic events. We developed deep-learning methods to predict patient-specific blood glucose during various time horizons in the immediate future using patient-specific every 30-min long glucose measurements by the continuous glucose monitoring (CGM) to predict future glucose levels in 5 min to 1 h. In general, the major challenges to address are (1) the dataset of each patient is often too small to train a patient-specific deep-learning model, and (2) the dataset is usually highly imbalanced given that hypo- and hyperglycemic episodes are usually much less common than normoglycemia. We tackle these two challenges using transfer learning and data augmentation, respectively. We systematically examined three neural network architectures, different loss functions, four transfer-learning strategies, and four data augmentation techniques, including mixup and generative models. Taken together, utilizing these methodologies we achieved over 95% prediction accuracy and 90% sensitivity for a time period within the clinically useful 1 h prediction horizon that would allow a patient to react and correct either hypoglycemia and/or hyperglycemia. We have also demonstrated that the same network architecture and transfer-learning methods perform well for the type 1 diabetes OhioT1DM public dataset.
The major ion chemistry in the Taihu watershed has dramatically changed due to human disturbances; however, little is known about the similarities and differences in the responses of the inflow ...rivers and Taihu lake to the disturbances. Using historical (1950s–1970s) and recent (2018–2021) water chemistry data of inflow rivers and the lake, as well as socioeconomic and land use data, we explored the drivers for the major ion chemistry change and different responses of the inflow rivers and the receiving lake. The results indicated that, compared with 1950s–1970s, all the major ions and TDS in rivers and Taihu lake significantly increased (by 91% for Mg
2+
and by 395% for Cl
−
in rivers; by 68% for HCO
3
−
and 134% for Na
+
in the lake); however, their increases in major ion composition presented a clear difference, i.e., although current dominant cation remained Ca in inflow rivers, the second dominant cation has shifted from Mg
2+
(1950s–1970s) to Na
+
(2018–2021) for rivers, while for the lake, the second dominant cation has become frequently Na
+
(2018–2021), followed by Ca
2+
, indicating a clear salinization tendency. Furthermore, the change of some indicative ratio indices of inflow rivers and the lake in the past decades presented an apparent difference, i.e., the river systems had a higher increase rate in Ca
2+
/Mg
2+
and SO
4
2−
/Cl
−
than the lake, while the lake had a higher increase in (Ca
2+
+ Mg
2+
)/HCO
3
−
, TH/TA, and Cl
−
/Na
+
than the river systems. Analyses indicated that increased human disturbances were the major driver for the similar increase in the TDS and major ions for both river systems and the lake, while the different algal biomass in the rivers and lake, the land use change, and declined hydrological connectivity in this watershed played important roles in the different alterations of the water chemistry indices. Comparison of major ion correlation change between the running and stagnant waters indicated a clear “lacunification” trend of inflow rivers in terms of water chemistry characteristics in this dense river-network region. Our work revealed the cause and effect of the fundamental water chemistry change in a rapid development region and will provide scientific basis for the integrated management and recovery in the watershed.
Although Taihu watershed is an “acid-insensitive” region, anthropogenic acidification has greatly changed the water chemistry in Taihu Lake. However, how soil carbonates responded to the long-term ...human-induced acidification received less attention. In this work, we investigated soil carbonate concentrations from different land uses in the upstream of the lake and sediment carbonate profiles in the lake, to explore the linkage of carbonates dissolution in the land and sedimentation in the lake. The result showed that the wheat-rice surface soil, the most acidification-impacted by fertilization and acid deposition, had significantly lower pH than vegetable and wetland soils (
p
< 0.05). Meanwhile, the carbonate concentration in wetland soils, only impacted by acid deposition, was significantly higher than that in wheat-rice and vegetable soils (
p
< 0.05). The pH profile of fertilized soils, with an increasing trend from the surface to bottom, further indicated the acidifying effect of fertilization. Although the average soil pH across all land uses was 6.6 in the upstream of the lake, remaining carbonate buffering system, the significant carbonate decrease especially in surface soils evidenced the definite carbonate dissolution by acidification, which is cumulative and irreversible. Contrary to the topsoils, the sediment carbonate concentration presented an increasing trend from the depth of 15 cm (denoting around the early 1980s) to the surface, indicating that lake sediment is a major sink of carbonate Ca and Mg from the watershed, particular under an alkaline lake environment caused by frequent algae blooms in the past decades. In addition, Ca/Mg ratio in the sediment, having higher values in a higher pH environment, was quite different from the watershed soil pattern, suggesting different biogeochemical processes Ca and Mg underwent during their transportation and sedimentation. The effects of acidification-altered re-distribution of carbonate Ca and Mg and Ca/Mg ratio in the terrestrial and aquatic environments deserve wider considerations of ecosystem consequence.
Vaso-occlusive crisis, a common painful complication of sickle cell disease, is a complex process triggered by intercellular adhesive interactions among blood cells and the endothelium in all human ...organs (e.g., the oxygen-rich lung as well as hypoxic systems such as liver and kidneys). We present a combined experimental-computational study to quantify the adhesive characteristics of sickle mature erythrocytes (SMEs) and irreversibly sickled cells (ISCs) under flow conditions mimicking those in postcapillary venules. We employed an in vitro microfluidic cell adherence assay, which is coated uniformly with fibronectin. We investigated the adhesion dynamics of SMEs and ISCs in pulsatile flow under well-controlled hypoxic conditions, inferring the cell adhesion strength by increasing the flow rate (or wall shear stress (WSS)) until the onset of cell detachment. In parallel, we performed simulations of individual SMEs and ISCs under shear. We introduced two metrics to quantify the adhesion process, the cell aspect ratio (AR) as a function of WSS and its rate of change (the dynamic deformability index). We found that the AR of SMEs decreases significantly with the increase of WSS, consistent between the experiments and simulations. In contrast, the AR of ISCs remains constant in time and independent of the flow rate. The critical WSS value for detaching a single SME in oxygenated state is in the range of 3.9–5.5 Pa depending on the number of adhesion sites; the critical WSS value for ISCs is lower than that of SMEs. Our simulations show that the critical WSS value for SMEs in deoxygenated state is above 6.2 Pa (multiple adhesion sites), which is greater than their oxygenated counterparts. We investigated the effect of cell shear modulus on the detachment process; we found that for the same cell adhesion spring constant, the higher shear modulus leads to an earlier cell detachment from the functionalized surface. These findings may aid in the understanding of individual roles of sickle cell types in sickle cell disease vaso-occlusion.
Accumulation and aggregation of amyloid are associated with the pathogenesis of many human diseases, such as Alzheimer’s disease and Type 2 diabetes mellitus. Therefore, a quantitative understanding ...of the molecular mechanisms causing different aggregated structures and biomechanical properties of amyloid fibrils could shed some light into the progression of these diseases. In this work, we develop coarse-grained molecular dynamics (CGMD) models to simulate the dynamic self-assembly of two types of amyloids (amylin and amyloid β (Aβ)). We investigate the structural and mechanical properties of different types of aggregated amyloid fibrils. Our simulations demonstrate that amyloid fibrils could result from longitudinal growth of protofilament bundles, confirming one of the hypotheses on the fibril formation. In addition, we find that the persistence length of amylin fibrils increases concurrently with their pitch length, suggesting that the bending stiffness of amylin fibrils becomes larger when the amylin fibrils are less twisted. Similar results are observed for Aβ fibrils. These findings quantify the connection between the structural and the biomechanical properties of the fibrils. The CGMD models developed in this work can be potentially used to examine efficacy of anti-aggregation drugs, which could help in developing new treatments.
Acid deposition and algae blooms have resulted in great changes in the water chemistry of Taihu Lake; however, there have been few calculated results to describe these processes. Here we used a mass ...balance model to estimate base cation losses and evaluate the model applicability in this intensively human-impacted watershed based on a long-term database (1985–2015). The results showed that carbonate weathering induced Ca2+ and Mg2+ losses in the watershed were responsible for the increased ion net reaction (INR) of Ca2+and Mg2+ in the lake. While the increase of K+ and Na+ were not appropriate to provide independents check on the mass balance model because they generally entered the lake as human discharges, not reflecting change of the geochemical process in the watershed as the watershed dominant bedrock is carbonate but not silicate. Acid deposition in Taihu region caused decrease in pH, lime potential, and different Ca, Mg species of surface soils. Our field measurements of sediments in the two lake parts showed that the sediment lime potential was significantly higher in the algae dominated lake area than in the hydrophyte-dominated area due to the in-lake alkalinization by algae blooms, indicating that algae blooms played a significant role in the acidification resistance. Meanwhile, the measured lime potential of the watershed soils was lower than that of the sediment, implying a potential risk of acidification in the watershed. This research helps understand the accelerated interactions between human activities and natural geochemical processes and accelerated water chemistry change at the watershed level.
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•Mass balance model reveals increased base cation losses from watershed to Taihu Lake in the past decades.•Human-induced carbonate weathering has accelerated and altered the natural geochemical balance.•Concentrations of Ca and Mg species are differentiated in soils and sediments due to impacts of acid deposition.•Watershed soils have become more sensitive to acid deposition than lake sediments.
Although young children generally experience mild symptoms following infection with SARS-CoV-2, severe acute and long-term complications can occur. SARS-CoV-2 mRNA vaccines elicit robust ...immunoglobulin profiles in children ages 5 years and older, and in adults, corresponding with substantial protection against hospitalizations and severe disease. Whether similar immune responses and humoral protection can be observed in vaccinated infants and young children, who have a developing and vulnerable immune system, remains poorly understood. To study the impact of mRNA vaccination on the humoral immunity of infant, we use a system serology approach to comprehensively profile antibody responses in a cohort of children ages 6 months to 5 years who were vaccinated with the mRNA-1273 COVID-19 vaccine (25 μg). Responses are compared with vaccinated adults (100 μg), in addition to naturally infected toddlers and young children. Despite their lower vaccine dose, vaccinated toddlers elicit a functional antibody response as strong as adults, with higher antibody-dependent phagocytosis compared to adults, without report of side effects. Moreover, mRNA vaccination is associated with a higher IgG3-dependent humoral profile against SARS-CoV-2 compared to natural infection, supporting that mRNA vaccination is effective at eliciting a robust antibody response in toddlers and young children.
The reduced effectiveness of COVID-19 vaccines due to the emergence of variants of concern (VOCs) necessitated the use of vaccine boosters to bolster protection against disease. However, it remains ...unclear how boosting expands protective breadth when primary vaccine platforms are distinct and how boosters containing VOC spike(s) broaden humoral responses. Here, we report that boosters composed of recombinant spike antigens of ancestral (prototype) and Beta VOCs elicit a robust, pan-VOC, and multi-functional humoral response in non-human primates largely independent of the primary vaccine series platform. Interestingly, Beta-spike-containing boosters stimulate immunoglobulin A (IgA) with a greater breadth of recognition in protein-primed recipients when administered with adjuvant system 03 (AS03). Our results highlight the utility of a component-based booster strategy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for broad humoral recognition, independent of primary vaccine series. This is of high global health importance given the heterogeneity of primary vaccination platforms distributed.
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•Subunit-based boosters with AS03 restore waned humoral responses to VOC spikes•Expansion of antibody binding breadth is independent of the primary series platform•Beta-containing boosters stimulate high IgA to VOC spikes including XBB lineages
Cost-effective vaccine-boosting strategies to restore waned antibody responses and expand humoral breadth are of paramount global health interest as SARS-CoV-2 continues to evolve. Deng et al. demonstrate that subunit-based boosters can be used independent of primary series immunizations and that Beta-spike-containing formulations enhance IgA breadth, even to XBB lineages.
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