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Abstract Background Human Papillomavirus (HPV) is implicated in the pathogenesis of cancer in the cervix, vagina, throat and anogenital region. Although HPV vaccination rates in the Hispanic community have increased owing to public health efforts, the COVID-19 pandemic has brought unique public health challenges and contributed to health inequity in this population. Methods To evaluate the impact of the COVID-19 pandemic on HPV vaccine uptake in a program designed to improve HPV vaccination rate in a predominantly Hispanic community in the border region of Texas (Tiempo de Vacunarte [time to get vaccinated]), we performed a retrospective cross-sectional analysis to evaluate the uptake of the first dose of HPV vaccine series among eligible adolescents and adults before (2016–2019), during (2020–2021), and after the COVID-19 pandemic (2022–2023). Results We observed a decrease in HPV vaccine uptake during the pandemic (69.59% vs. 89.92%) and post-pandemic (76% vs. 89.92%) compared to the pre-pandemic period. After adjusting for confounding factors, the reduction in the odds ratio was more pronounced in the pandemic (OR = 0.091, p

To delve into the intricacies of sustainable agricultural practices, our study investigates both the behavioral and non-behavioral factors influencing farmers' decision-making processes. Employing the New Ecological Model (NEP) to capture social factors, our research framework integrates insights from the sustainable livelihood framework, which delineates five crucial types of livelihood capital: (1) human capital, (2) natural capital, (3) financial capital, (4) physical capital, and (5) social capital. This comprehensive approach enables us to incorporate additional non-behavioral factors and their impacts on farmers' decisions. We underscore the pivotal role of farmers' decisions in fostering sustainable agriculture, aligning with seven of the Sustainable Development Goals (SDGs). Leveraging survey data collected from 303 Vietnamese farmers, we validate our research framework using two analytical models: Structural Equation Model (SEM) and binary logit analysis. Our findings underscore the significant influence of farmers' risk propensity and concerns regarding food safety and environmental conservation on the adoption of organic farming practices. Notably, farmers' level of knowledge emerges as a critical determinant shaping their inclination towards sustainable agriculture. The study underscores the importance of targeted educational initiatives and awareness campaigns, identifying key determinants such as proximity to green spaces and farm size in shaping farmers' choices towards sustainable practices.

Droughts have a substantial impact on water supplies, agriculture, and ecosystems worldwide. Agricultural sustainability and production in the Mekong Delta of Vietnam are being jeopardized by droughts caused by climate change. Conventional forecasting methods frequently struggle to comprehend the intricate dynamics of meteorological occurrences connected to drought, necessitating the use of sophisticated prediction techniques. This study assesses the effectiveness of various statistical models (ARIMA), machine learning, and deep learning models (Gradient Boosting, XGBoost, RNN, and LSTM) in forecasting the SPEI over different time periods (1, 3, 6, and 12 months) across six prediction intervals. The models were developed and evaluated using data from 11 meteorological stations spanning from 1985 to 2022. These models incorporated various climatic variables, including precipitation, temperature, humidity, potential evapotranspiration (PET), Southern Oscillation Index (SOI) Anomaly, and sea surface temperature in the NINO4 region (SST_NINO4). The results demonstrate that XGBoost and LSTM models exhibit outstanding performance, showcasing lower error metrics and higher R² values compared to Gradient Boosting and RNN. The performance of the model fluctuated depending on the forecast step, with error metrics often increasing with longer prediction horizons. The use of climatic indices improved the accuracy of the model. These findings are consistent with earlier research on drought episodes in the Mekong Delta and support studies from other areas that show the effectiveness of advanced modeling tools for predicting droughts. The work emphasizes the capacity of machine learning and deep learning models to enhance the precision of drought forecasting, which is vital for efficient water resource management and agricultural planning in places prone to drought.

Abstract Background Dengue virus serotypes (DENV-1 to -4) can be transmitted vertically in Aedes aegpti mosquitoes. Whether infection with the wMel strain of the endosymbiont Wolbachia can reduce the incidence of vertical transmission of DENV from infected females to their offspring is not well understood. Methods A laboratory colony of Vietnamese Ae. aegypti, both with and without wMel infection, were infected with DENV-1 by intrathoracic injection (IT) to estimate the rate of vertical transmission (VT) of the virus. VT in the DENV-infected mosquitoes was calculated via the infection rate estimation from mosquito pool data using maximum likelihood estimation (MLE). Results In 6047 F1 Vietnamese wild-type Ae. aegypti, the MLE of DENV-1 infection was 1.49 per 1000 mosquitoes (95% confidence interval [CI] 0.73–2.74). In 5500 wMel-infected Ae. aegypti, the MLE infection rate was 0 (95% CI 0–0.69). The VT rates between mosquito lines showed a statistically significant difference. Conclusions The results reinforce the view that VT is a rare event in wild-type mosquitoes and that infection with wMel is effective in reducing VT. Graphical Abstract

Landslide susceptibility mapping (LSM) is essential for land-use planning, as it helps to identify areas at risk of landslides and enables effective prevention measures to be taken. Various statistical and machine learning (ML) models are used in LSM, including SVM and ANFIS, which have shown promising results. However, determining which model performs better remains a key challenge. To address this issue, this paper aims to compare six hybrid models constructed with two well-known and powerful ML models, namely SVM and ANFIS, and three meta-heuristic algorithms, namely Genetic Algorithm (GA), Differential Evolution (DE), and Cultural Algorithm (CA), for LSM in a case study in western Serbia. In the process of building the models, 359 landslide sites and 14 determinants were used. The accuracy of the models was evaluated using several indexes, including Root Mean-Squared Error (RMSE), coefficient of determination (R2), and Area under the Receiver Operating Characteristic Curve (AUROC). The modeling results showed that the SVM-GA model has the highest accuracy (AUROC = 0.78) in predicting landslide incidence, followed by the ANFIS-GA (AUROC = 0.775), SVM-CA (AUROC = 0.773), ANFIS-DE (AUROC = 0.771), SVM-DE (AUROC = 0.76), and ANFIS-CA (AUROC = 0.65) models in validation phase. Therefore, the study suggested that SVM-based hybrid models are more accurate than ANFIS-based models for LSM, and thus, modelers may use SVM-based hybrid models for such applications. This study provides valuable insights into identifying the most appropriate and effective models for LSM, which can help to mitigate the risks associated with landslides and ensure sustainable land-use practices.

Abstract Cost-efficient library generation by early barcoding has been central in propelling single-cell RNA sequencing. Here, we optimize and validate prime-seq, an early barcoding bulk RNA-seq method. We show that it performs equivalently to TruSeq, a standard bulk RNA-seq method, but is fourfold more cost-efficient due to almost 50-fold cheaper library costs. We also validate a direct RNA isolation step, show that intronic reads are derived from RNA, and compare cost-efficiencies of available protocols. We conclude that prime-seq is currently one of the best options to set up an early barcoding bulk RNA-seq protocol from which many labs would profit.

The severe heatwaves and hot spells in Vietnam were observed more frequently in intensity and duration due to global warming and climate change impacts. The hot days and extreme summer events make the weather harsh and significantly affect human health and the environment. This study presents the spatiotemporal distribution of the number of hot days (NHDs) in Vietnam. The variability of NHD in seven climate subregions is also examined in association with the large-scale drivers. The European Center for Medium-Range Weather Forecasts (ECMWF) reanalysis version 5 (ERA5) data for the period 1981–2020 are used. Principal component analysis is also applied to the observed monthly NHD to obtain spatial patterns and time series. The results show that the NHD in the Highland and South subregions from March to May is linked with the subtropical high associated with decreased 500hPa-level vertical velocity (VV500). From May to June, the North and Central subregions seem related to deepening the Asiatic low and enhancement of southwest flows across the Indochina Peninsula. Finally, both increased southwest flows and decreased VV500 can partly contribute to the intensification of NHD in the North and Central subregions during July and August. The long trends of NHD are also examined. The results reveal that the increasing trends in NHD occur in most subregions, except for the Central Highland, and changing trends of NHD in June greatly contribute to the annual trend of NHD. Finally, the examinations with the El Niño-Southern Oscillation events show that NHD is significantly higher in El Niño events than in La Niña events in March and April for the Northwest, South Central, Central Highlands, and South, in May and June for all subregions, and in July and August for only the Red River Delta subregion. This suggests that ENSO can provide the potential for improving seasonal climate forecasts and mitigating natural disaster risks for the community.

Abstract Prenatal stress through glucocorticoid (GC) exposure leads to an increased risk of developing diseases such as cardiovascular disease, metabolic syndrome and hypertension in adulthood. We have previously shown that administration of the synthetic glucocorticoid, dexamethasone (Dex), to pregnant Wistar–Kyoto dams produces offspring with elevated blood pressures and disrupted circadian rhythm signaling. Given the link between stress, circadian rhythms and metabolism, we performed an untargeted metabolomic screen on the livers of offspring to assess potential changes induced by prenatal Dex exposure. This metabolomic analysis highlighted 18 significantly dysregulated metabolites in females and 12 in males. Pathway analysis using MetaboAnalyst 4.0 highlighted key pathway-level metabolic differences: glycerophospholipid metabolism, purine metabolism and glutathione metabolism. Gene expression analysis revealed significant upregulation of several lipid metabolism genes in females while males showed no dysregulation. Triglyceride concentrations were also found to be significantly elevated in female offspring exposed to Dex in utero, which may contribute to lipid metabolism activation. This study is the first to conduct an untargeted metabolic profile of liver from GC exposed offspring. Corroborating metabolic, gene expression and lipid profiling results demonstrates significant sex-specific lipid metabolic differences underlying the programming of hepatic metabolism.

Abstract How to make the learning of complex subjects engaging, motivating, and effective? The use of immersive virtual reality offers exciting, yet largely unexplored solutions to this problem. Taking neuroanatomy as an example of a visually and spatially complex subject, the present study investigated whether academic learning using a state-of-the-art Cave Automatic Virtual Environment (CAVE) yielded higher learning gains compared to conventional textbooks. The present study leveraged a combination of CAVE benefits including collaborative learning, rich spatial information, embodied interaction and gamification. Results indicated significantly higher learning gains after collaborative learning in the CAVE with large effect sizes compared to a textbook condition. Furthermore, low spatial ability learners benefitted most from the strong spatial cues provided by immersive virtual reality, effectively raising their performance to that of high spatial ability learners. The present study serves as a concrete example of the effective design and implementation of virtual reality in CAVE settings, demonstrating learning gains and thus opening opportunities to more pervasive use of immersive technologies for education. In addition, the study illustrates how immersive learning may provide novel scaffolds to increase performance in those who need it most.

Abstract Background Dengue viruses (DENV) can be transmitted from an adult female Aedes aegypti mosquito through the germ line to the progeny; however, there is uncertainty if this occurs at a frequency that is epidemiologically significant. We measured vertical transmission of DENV from field-reared Ae. aegypti to their F1 progeny after feeding upon blood from dengue patients. We also examined the transmission potential of F1 females. Methods We examined the frequency of vertical transmission in field-reared mosquitoes, who fed upon blood from acutely viremic dengue patients, and the capacity for vertically infected females to subsequently transmit virus horizontally, in two sets of experiments: (i) compared vertical transmission frequency of field-reared Ae. aegypti and Ae. albopictus, in individual progeny; and (ii) in pooled progeny derived from field- and laboratory-reared Ae. aegypti. Results Of 41 DENV-infected and isofemaled females who laid eggs, only a single female (2.43%) transmitted virus to one of the F1 progeny, but this F1 female did not have detectable virus in the saliva when 14 days-old. We complemented this initial study by testing for vertical transmission in another 460 field-reared females and > 900 laboratory-reared counterparts but failed to provide any further evidence of vertical virus transmission. Conclusions In summary, these results using field-reared mosquitoes and viremic blood from dengue cases suggest that vertical transmission is uncommon. Field-based studies that build on these observations are needed to better define the contribution of vertical DENV transmission to dengue epidemiology.

Health workers around the world have taken on massive frontline roles in the fight against COVID-19, often under intense pressure and in the face of uncertainty. In this study, we determined the rates of depression, anxiety, stress and related factors among health workers in COVID-19 designated hospitals in southern Vietnam during the second wave of COVID-19. From July-September 2020, we collected self-administered surveys from 499 health workers in 14 hospitals that were designated for the care and treatment of patients with COVID-19. The survey included sections on demographics, co-morbid health conditions, symptoms experienced during patient care, a depression, anxiety and stress assessment (DASS-21), and other related factors. We used logistic regression models to identify factors associated with depression, anxiety and stress, and adjusted for confounding factors. 18%, 11.5%, 7.7% of participants had symptoms of depression, anxiety, and stress, respectively with the majority at mild and moderate levels. The risk factors for increased mental health impact included long working hours, experiencing physical symptoms, fear of transmission to family, COVID-19 related stigma, and worry when watching media about COVID-19. Psychological counseling and training in infection prevention were protective factors that reduced the risk of mental health problems. Further exploration of the association between physical symptoms experienced by health workers and mental health may guide interventions to improve health outcomes. More routine COVID-19 testing among health workers could reduce anxieties about physical symptoms and alleviate the fear of transmitting COVID-19 to family and friends. Medical institutions need to ensure that health workers have access to basic trainings prior to initiation of work, and mental health support during the pandemic and into the future.

This work proposed a novel procedure of Water Quality Index (WQI) development that could be used for practical applications on a local or regional scale, based on available monitoring data. Principal component analysis (PCA) was applied to the monthly data of 11 water quality parameters (pH, conductivity (EC), total suspended solid (TSS), dissolved oxygen (DO), five -day biological oxygen demand (BOD), chemical oxygen demand (COD), ammonia (N-NH4), nitrate (N-NO3), phosphate (P-PO4), total coliform, and total dissolved iron monitored at 11 sites at Huong river in the years 2014–2016. From the PCA, the three extracted principal components explained 67% of the total variance of original variables. From the set of communality values, the weight (wi) for each parameter was determined. Linear sub-index functions were established based on the permissible limits from the National Technical Regulations on Surface Water Quality set up by the Vietnam Environment Agency (VEA) to derive the sub-index (qi) for each parameter. The multiplicative formula that is the product of the sub-indices (qi) raised to the respective weights (wi), was used for calculation of the final WQI values. The proposed index (WQI) was then applied to the river with quarterly data of the 11 parameters monitored at ten sites in the years 2017–2020. The WQI representatively reflected the actual status of the river overall water quality, of which 97.8% of the WQI values belonged to grades of EXCELLENT and GOOD, and 2.2% of grade MODERATE. Comparison between the river water quality evaluations resulting from the developed WQI with the WQI adopted by National Sanitation Foundation (NSF-WQI) and the index issued by Vietnam Environment Agency (VN-WQI) indicated that the proposed WQI was more suitable for river quality assessment.

Introduction: Electromagnetic imaging is an emerging technology which promises to provide a mobile, and rapid neuroimaging modality for pre-hospital and bedside evaluation of stroke patients based on the dielectric properties of the tissue. It is now possible due to technological advancements in materials, antennae design and manufacture, rapid portable computing power and network analyses and development of processing algorithms for image reconstruction. The purpose of this report is to introduce images from a novel, portable electromagnetic scanner being trialed for bedside and mobile imaging of ischaemic and haemorrhagic stroke.Methods: A prospective convenience study enrolled patients (January 2020 to August 2020) with known stroke to have brain electromagnetic imaging, in addition to usual imaging and medical care. The images are obtained by processing signals from encircling transceiver antennae which emit and detect low energy signals in the microwave frequency spectrum between 0.5 and 2.0 GHz. The purpose of the study was to refine the imaging algorithms.Results: Examples are presented of haemorrhagic and ischaemic stroke and comparison is made with CT, perfusion and MRI T2 FAIR sequence images.Conclusion: Due to speed of imaging, size and mobility of the device and negligible environmental risks, development of electromagnetic scanning scanner provides a promising additional modality for mobile and bedside neuroimaging.

The coastline of the Ca Mau and Kien Giang provinces in the Vietnamese Mekong Delta has been severely eroded in recent decades. Pile–Rock Breakwaters (PRBWs) are among the most widely adopted structures for controlling shoreline erosion in this region. These structures are effective for wave energy dissipation, stimulating sediment accumulation, and facilitating the restoration of mangrove forests. These breakwaters are generally considered to be the best-engineering practice; however, there is currently insufficient scientific evidence with regard to specific structural design aspects. This can lead to PRBW structures being compromised when deployed in the field. This study used a physical model of a PRBW in a laboratory to investigate several design parameters, including crest width and working states (i.e., submerged, transition, and emerged), and investigated their relationship with the wave transmission coefficient, wave reflection coefficient, and wave energy dissipation. To investigate these relationships further, empirical formulas were derived for PRBWs under different sea states and crest widths to aid the design process. The results showed that the PRBW width had a significant influence on the wave energy coefficients. The findings revealed that the crest width of the breakwater was inversely proportional to the wave transmission coefficient (Kt) under the emerged state. The crest width was also proportional to the wave reduction efficiency and wave energy dissipation in both working states (i.e., the submerged and emerged states). The front wave disturbance coefficient (Kf) was found to be proportional to the wave reflection coefficient, and the wave height in front of the structure was found to increase by up to 1.4 times in the emerged state. The wave reflection coefficient requires special consideration to reduce the toe erosion in the structure. Lastly, empirical equations including linear and non-linear formulas were compared with previous studies for different classes of breakwaters. These empirical equations will be useful for understanding the wave transmission efficiency of PRBWs. The findings of this study provide important guidance for PRBW design in the coastal area of the Mekong Delta.

Abstract This paper uses multimedia to showcase the narratives and lived experiences of those who live and work in tropical Asian mega‐deltas, and as such is the first journal article of its kind in the field of Regional Geography. Using videos, photography and audio this paper describes the characteristics of ponds and their place in the intrinsically connected human‐environmental fabric of these delta regions. The aim is to bring to life descriptive inventories and provide greater weight in support of our conclusion that tropical Asian mega‐delta ponds are important and threatened systems. River deltas comprise just 1% of land cover worldwide but support the livelihoods of more than 500 million people. Delta research has historically focused on the major river channels and the socio‐ecological role of ponds has been overlooked despite their large number and surface area. Ponds are intrinsically linked to daily life (potable water, sanitation, bathing, washing), industry (aquaculture, agriculture) and the natural‐cultural heritage (religion, folklore) of deltas. In contrast to the larger river channels, ponds are likely to be significant stores and processors of nutrients, including carbon, and pollutants at annual to decadal scales, on account of their heavy anthropogenic use and smaller individual sizes. Consequently, they are severely polluted water sources and pose significant public health risks. In this review, we use case studies from three Asian mega‐deltas (the Red River Delta and the Mekong River Delta, Vietnam, and the Ganges‐Brahmaputra‐Meghna Delta, India and Bangladesh) to highlight the importance of Asian mega‐delta ponds as important socio‐ecological systems in their own right. We discuss future environmental challenges, knowledge gaps on the ecological function and biodiversity of these habitats, management and policy practices, and the capacity of ponds to achieve the UN Sustainable Development Goals.

Circadian clocks control many vital aspects of physiology from the sleep-wake cycle to metabolism. The circadian clock operates through transcriptional-translational feedback loops. The normal circadian signaling relies on a ‘master clock’, located in the suprachiasmatic nucleus (SCN), which synchronizes peripheral oscillators. Glucocorticoid receptor (GR) signaling has the ability to reset the phase of peripheral clocks. It has been shown that maternal exposure to glucocorticoids (GCs) can lead to modification of hypothalamic-pituitary-adrenal (HPA) function, impact stress-related behaviors, and result in a hypertensive state via GR activation. We previously demonstrated altered circadian rhythm signaling in the adrenal glands of offspring exposed to the synthetic GC, dexamethasone (Dex). Results from the current study show that prenatal exposure to Dex affects circadian rhythm gene expression in a brain region-specific and a sex-specific manner within molecular oscillators of the amygdala, hippocampus, paraventricular nucleus, and prefrontal cortex, as well as the main oscillator in the SCN. Results also show that spontaneously hypertensive rats (SHR) exhibited dysregulated circadian rhythm gene expression in these same brain regions compared with normotensive Wistar-Kyoto rats (WKY), although the pattern of dysregulation was markedly different from that seen in adult offspring prenatally exposed to GCs.

The most common treatment for patients with sickle cell disease (SCD) is the chemotherapeutic hydroxyurea, a therapy with pleiotropic effects, including increasing fetal hemoglobin (HbF) in red blood cells and reducing adhesion of white blood cells to the vascular endothelium. Hydroxyurea has been proposed to mediate these effects through a mechanism of increasing cellular cGMP levels. An alternative path to increasing cGMP levels in these cells is through the use of phosphodiesterase-9 inhibitors that selectively inhibit cGMP hydrolysis and increase cellular cGMP levels. We have developed a novel, potent and selective phosphodiesterase-9 inhibitor (IMR-687) specifically for the treatment of SCD. IMR-687 increased cGMP and HbF in erythroid K562 and UT-7 cells and increased the percentage of HbF positive erythroid cells generated in vitro using a two-phase liquid culture of CD34+ progenitors from sickle cell blood or bone marrow. Oral daily dosing of IMR-687 in the Townes transgenic mouse SCD model, increased HbF and reduced red blood cell sickling, immune cell activation and microvascular stasis. The IMR-687 reduction in red blood cell sickling and immune cell activation was greater than that seen with physiological doses of hydroxyurea. In contrast to other described phosphodiesterase-9 inhibitors, IMR-687 did not accumulate in the central nervous system, where it would inhibit phosphodiesterase-9 in neurons, or alter rodent behavior. IMR-687 was not genotoxic or myelotoxic and did not impact fertility or fetal development in rodents. These data suggest that IMR-687 may offer a safe and effective oral alternative for hydroxyurea in the treatment of SCD.

There are many studies on the effectiveness by employing management systems and this paper tries to point out the critical components that embodied the obstacles on system deployment on the context of the emerging markets in Viet Nam. The study is conducted as an exploratory research project which uses a quantitative approach to gain insight and information of the businesses in question. The data was collected via a survey questionnaire derived from experts and focus groups. The findings of this study indicated the significant role of organizational factors such as employee participation and communication, demonstrating they were critical mediators in the given context. Upon completion of the research, we advanced the study of these factors that directly and indirectly affect the success of PMS implementation throughout the empirical approach on Vietnamese firms.

Biochemical changes in utero may alter normal fetal development, resulting in disease later in life, a phenomenon known as fetal programming. Recent epidemiological studies link fetal programming to negative health outcomes, such as low birth weight and hypertension in adulthood. Here, we used a WKY rat model and studied the molecular changes triggered by prenatal glucocorticoid (GC) exposure on the development of hypertension, and on the regulation of phenylethanolamine N-methyl transferase (PNMT), the enzyme responsible for biosynthesis of epinephrine, and a candidate gene linked to hypertension. Clinically, high doses of the synthetic GC dexamethasone (DEX) are used to treat infant respiratory distress syndrome. Elevated maternal GCs have been correlated with fetal programming of hypertension. The aim of this study was to determine if lower doses of DEX would not lead to detrimental fetal programming effects such as hypertension. Our data suggests that prenatal stress programs for increased expression of PNMT and altered regulation of PNMT in males and females. Importantly, we identified that DEX mediated programming was more apparent in the male rats, and the lower dose 10μg/kg/day of DEX did not lead to changes in blood pressure (BP) in female rats suggesting that this dose is below the threshold for programming of hypertension. Furthermore, sex-specific differences were observed in regards to programming mechanisms that may account for hypertension in males.

Abstract Sickle cell disease (SCD) patients have low serum hemopexin (Hpx) levels due to chronic hemolysis. We hypothesized that in SCD mice, hepatic overexpression of hemopexin would scavenge the proximal mediator of vascular activation, heme, and inhibit inflammation and microvascular stasis. To examine the protective role of Hpx in SCD, we transplanted bone marrow from NY1DD SCD mice into Hpx−/− or Hpx+/+ C57BL/6 mice. Dorsal skin fold chambers were implanted 13 wks post-transplant, and microvascular stasis (% nonflowing venules) was evaluated in response to heme infusion. Hpx−/− sickle mice had significantly greater microvascular stasis in response to heme infusion than Hpx+/+ sickle mice (p < 0.05), demonstrating the protective effect of Hpx in SCD. We utilized Sleeping Beauty (SB) transposon-mediated gene transfer to overexpress wild-type rat Hpx (wt-Hpx) in NY1DD and Townes-SS SCD mice. Control SCD mice were treated with lactated Ringer’s solution (LRS) or a luciferase (Luc) plasmid. Plasma and hepatic Hpx were significantly increased compared with LRS and Luc controls. Microvascular stasis in response to heme infusion in NY1DD and Townes-SS mice overexpressing wt-Hpx had significantly less stasis than controls (p < 0.05). Wt-Hpx overexpression markedly increased hepatic nuclear Nrf2 expression, HO-1 activity and protein, and the heme-Hpx binding protein and scavenger receptor CD91/LRP1, and decreased NF-κB activation. Two missense (ms)-Hpx SB constructs that bound neither heme nor the Hpx receptor CD91/LRP1 did not prevent heme-induced stasis. In conclusion, increasing Hpx levels in transgenic sickle mice via gene transfer activates the Nrf2/HO-1 antioxidant axis and ameliorates inflammation and vasoocclusion.

During hemolysis, hemoglobin and heme released from red blood cells promote oxidative stress, inflammation and thrombosis. Plasma haptoglobin and hemopexin scavenge free hemoglobin and heme, respectively, but can be depleted in hemolytic states. Haptoglobin and hemopexin supplementation protect tissues, including the vasculature, liver and kidneys. It is widely assumed that these protective effects are due primarily to hemoglobin and heme clearance from the vasculature. However, this simple assumption does not account for the consequent cytoprotective adaptation seen in cells and organs. To further address the mechanism, we used a hyperhemolytic murine model (Townes-SS) of sickle cell disease to examine cellular responses to haptoglobin and hemopexin supplementation. A single infusion of haptoglobin or hemopexin (± equimolar hemoglobin) in SS-mice increased heme oxygenase-1 (HO-1) in the liver, kidney and skin several fold within 1 hour and decreased nuclear NF-ĸB phospho-p65, and vaso-occlusion for 48 hours after infusion. Plasma hemoglobin and heme levels were not significantly changed 1 hour after infusion of haptoglobin or hemopexin. Haptoglobin and hemopexin also inhibited hypoxia/reoxygenation and lipopolysaccharide-induced vaso-occlusion in SS-mice. Inhibition of HO-1 activity with tin protoporphyrin blocked the protections afforded by haptoglobin and hemopexin in SS-mice. The HO-1 reaction product carbon monoxide, fully restored the protection, in part by inhibiting Weibel-Palade body mobilization of P-selectin and von Willebrand factor to endothelial cell surfaces. Thus, the mechanism by which haptoglobin and hemopexin supplementation in hyperhemolytic SS-mice induces cytoprotective cellular responses is linked to increased HO-1 activity.

2-Fluorofucose (2FF) blocks the fucosylation and the tethering of sialyl-Lewisx tetrasaccharide and structural variants on leukocytes and red blood cells to P- and E-selectins on activated endothelial cell surfaces. Because P- and E-selectin are required for vaso-occlusion in murine sickle cell disease (SCD), we investigated whether 2FF would inhibit vaso-occlusion in SCD mice. Microvascular stasis was measured in subcutaneous venules in NY1DD and HbSS-Townes SCD mice with dorsal skin-fold chambers after infusion of hemoglobin or exposure to hypoxia/reoxygenation. 2FF in drinking water or administered by gavage inhibited stasis in sickle mice in a dose-responsive manner. Significant inhibitory effects on stasis were seen 1 day post-treatment. 2FF treatment of SCD mice also significantly reduced leukocyte rolling and adhesion along the vessel walls of SCD mice and the static adhesion of neutrophils and sickle red blood cells isolated from 2FF-treated SCD mice to resting and activated endothelial cells. Total white blood cell counts increased in response to 2FF. NF-ĸB activation and VCAM-1 and E-selectin expression were inhibited in the livers of SCD mice consistent with an overall decrease in vascular inflammation and ischemia-reperfusion physiology. Pretreatment with 2FF completely eliminated heme-induced lethality in HbSS-Townes mice, consistent with the observed anti-inflammatory and anti-adhesive properties of 2FF in SCD mice. These data suggest that 2FF may be beneficial for preventing or treating vaso-occlusive crises in SCD patients.