Disruption of Phosphodiesterase 3A Binding to SERCA2 Increases SERCA2 Activity and Reduces Mortality in Mice With Chronic Heart Failure.

BACKGROUND: Increasing SERCA2 (sarco[endo]-plasmic reticulum Ca2+ ATPase 2) activity is suggested to be beneficial in chronic heart failure, but no selective SERCA2-activating drugs are available. PDE3A (phosphodiesterase 3A) is proposed to be present in the SERCA2 interactome and limit SERCA2 activity. Disruption of PDE3A from SERCA2 might thus be a strategy to develop SERCA2 activators. METHODS: Confocal microscopy, 2-color direct stochastic optical reconstruction microscopy, proximity ligation assays, immunoprecipitations, peptide arrays, and surface plasmon resonance were used to investigate colocalization between SERCA2 and PDE3A in cardiomyocytes, map the SERCA2/PDE3A interaction sites, and optimize disruptor peptides that release PDE3A from SERCA2. Functional experiments assessing the effect of PDE3A-binding to SERCA2 were performed in cardiomyocytes and HEK293 vesicles. The effect of SERCA2/PDE3A disruption by the disruptor peptide OptF (optimized peptide F) on cardiac mortality and function was evaluated during 20 weeks in 2 consecutive randomized, blinded, and controlled preclinical trials in a total of 148 mice injected with recombinant adeno-associated virus 9 (rAAV9)-OptF, rAAV9-control (Ctrl), or PBS, before undergoing aortic banding (AB) or sham surgery and subsequent phenotyping with serial echocardiography, cardiac magnetic resonance imaging, histology, and functional and molecular assays. RESULTS: PDE3A colocalized with SERCA2 in human nonfailing, human failing, and rodent myocardium. Amino acids 277-402 of PDE3A bound directly to amino acids 169-216 within the actuator domain of SERCA2. Disruption of PDE3A from SERCA2 increased SERCA2 activity in normal and failing cardiomyocytes. SERCA2/PDE3A disruptor peptides increased SERCA2 activity also in the presence of protein kinase A inhibitors and in phospholamban-deficient mice, and had no effect in mice with cardiomyocyte-specific inactivation of SERCA2. Cotransfection of PDE3A reduced SERCA2 activity in HEK293 vesicles. Treatment with rAAV9-OptF reduced cardiac mortality compared with rAAV9-Ctrl (hazard ratio, 0.26 [95% CI, 0.11 to 0.63]) and PBS (hazard ratio, 0.28 [95% CI, 0.09 to 0.90]) 20 weeks after AB. Mice injected with rAAV9-OptF had improved contractility and no difference in cardiac remodeling compared with rAAV9-Ctrl after aortic banding. CONCLUSIONS: Our results suggest that PDE3A regulates SERCA2 activity through direct binding, independently of the catalytic activity of PDE3A. Targeting the SERCA2/PDE3A interaction prevented cardiac mortality after AB, most likely by improving cardiac contractility.

Wearing masks as a protective measure for children against traffic-related air pollution: A comparison of perceptions between school children and their caregivers in Ho Chi Minh City, Vietnam.

BACKGROUND: Traffic-related air pollution (TRAP) problems are unlikely to be solved in the short term, making it imperative to educate children on protective measures to mitigate the negative impact on their health. Children and their caregivers may hold differing views on wearing a face mask as a safeguard against air pollution. While many studies have focused on predicting children's health-protective behaviours against air pollution, few have explored the differences in perceptions between children and their caregivers. OBJECTIVES: To examine this, we conducted a study that compared the health beliefs of two generations and evaluated the factors that influence the use of masks by children to reduce air pollution exposure. METHODS: The study was conducted in 24 secondary schools and involved 8420 children aged 13-14 and their caregivers. We used a Health Belief Model (HBM)-based instrument containing 17-item self-administered health beliefs questionnaires to gather data. The results were analysed using hierarchical logistic regression to determine the probability of children frequently wearing masks to protect against TRAP. RESULTS: Our study showed both children and caregivers recognised that several factors could influence mask-wearing among children: discomfort or difficulty breathing while wearing a mask and forgetting to bring a mask when going outside; perceived threats of the poor quality of air and children's respiratory health problems; and cues to mask use (i.e., seeing most of their friends wearing facemasks and ease of finding masks in local stores). However, only children were significantly concerned with public perception of their appearance while wearing a mask. Females were more likely to wear masks, and caregivers with higher levels of education were more likely to encourage their children to wear masks. Children who commuted to schools by walking, biking, or motorbiking were also more accepting of mask-wearing than those who travelled by car or bus. CONCLUSIONS: Children and their caregivers hold different perceptions of wearing masks to protect against air pollution. Children are more susceptible to social judgements regarding their appearance when wearing a mask.

Validation of a new simple scoring system to predict spontaneous bacterial peritonitis in patients with cirrhosis and ascites.

BACKGROUND: Recently, a simple scoring system named the Mansoura scoring system was developed to predict spontaneous bacterial peritonitis (SBP) in patients with cirrhosis and ascites. However, the efficacy of this newly developed system has not been extensively investigated. We aimed to validate a new simple scoring system for the rapid diagnosis or exclusion of SBP without paracentesis. METHODS: Adult patients with cirrhosis and ascites admitted to Cho Ray Hospital between November 2021 and May 2022 were included. The area under the receiver operating characteristic (AUROC) curve of the Mansoura simple scoring system for predicting SBP was calculated using the Stata software. Other independent laboratory tests for predicting SBP (C-reactive protein [CRP], neutrophil-to-lymphocyte ratio [NLR], and mean platelet volume [MPV]) were assessed and compared using the Mansoura scoring system. RESULTS: A total of 121 patients were included in this study. The Mansoura scoring system showed good performance in predicting SBP in patients with cirrhosis and ascites (AUROC:0.89). At the cut-off ≥ 4 points, the scoring system achieved a specificity of 97.7% with a positive predictive value for the diagnosis of SBP of 93.5%. Multivariate analysis was performed using our data and showed that NLR, CRP level, and MPV were independent factors related to SBP. CONCLUSION: The Mansoura scoring system demonstrated good performance in predicting SBP in patients with cirrhosis and ascites and may help guide management decisions.

Arteriovenous fistula creation by nephrologist and its outcomes: a prospective cohort study from Vietnam.

BACKGROUND: Arteriovenous fistula (AVF) is the gold standard vascular access for effective hemodialysis. There is a growing interest in AVF creations performed by nephrologists to help reduce vascular surgeons' workload and enhance the timely treatment of patients with end-stage renal disease (ESRD). However, little is known about the feasibility and effectiveness of this approach in the low-resource settings. We examined the AVF surgical success and failure rates and associated predictors as well as early complications of AVF creations by a trained nephrologist with supports from vascular surgeons in Vietnam. METHODS: A prospective cohort study was conducted on all adult ESRD patients at the Hemodialysis Department of Thong Nhat Hospital between April 2018 and October 2020. Information on demographic characteristics, comorbidities, and AVF creations was collected using a standardized questionnaire. All patients were followed up until 18 weeks post-surgery. RESULTS: Among 100 patients with a mean age of 61.22 ± 17.11 years old, male accounted for 54%. Common causes of ESRD included hypertension (57%) and diabetes (32%). Just more than half (52%) of them reported having an AVF creation prior to ESRD. The successful first-time AVF creation rate was 98% (13/99, 95%CI: 8.74-21.18%). The primary and secondary AVF failure rates were 13.13% (13/99, 95%CI: 8.74-21.18%) and 16.87% (14/83, 95%CI: 10.32-26.25%), respectively. Early complications included bleeding (1%) and early thrombosis of the anastomosis (2%). There was a statistically significant association between age and primary AVF failure (P = 0.005) and between operation time and secondary AVF failure (P = 0.038). CONCLUSIONS: AVF creations performed by well-trained and skilled interventional nephrologists with supports from vascular surgeons can result in favorable short- and long-term outcomes. It is important to follow up older patients and those with a long operation time to detect AVF failures. A standardized AVF creation training program and practice for nephrologists is needed to increase successful rates.

Novel Clinical Monitoring Approaches for Reemergence of Diphtheria Myocarditis, Vietnam.

Diphtheria is a life-threatening, vaccine-preventable disease caused by toxigenic Corynebacterium bacterial species that continues to cause substantial disease and death worldwide, particularly in vulnerable populations. Further outbreaks of vaccine-preventable diseases are forecast because of health service disruptions caused by the coronavirus disease pandemic. Diphtheria causes a spectrum of clinical disease, ranging from cutaneous forms to severe respiratory infections with systemic complications, including cardiac and neurologic. In this synopsis, we describe a case of oropharyngeal diphtheria in a 7-year-old boy in Vietnam who experienced severe myocarditis complications. We also review the cardiac complications of diphtheria and discuss how noninvasive bedside imaging technologies to monitor myocardial function and hemodynamic parameters can help improve the management of this neglected infectious disease.

Molecular subtype classification of low-grade gliomas using magnetic resonance imaging-based radiomics and machine learning.

In 2016, the World Health Organization (WHO) updated the glioma classification by incorporating molecular biology parameters, including low-grade glioma (LGG). In the new scheme, LGGs have three molecular subtypes: isocitrate dehydrogenase (IDH)-mutated 1p/19q-codeleted, IDH-mutated 1p/19q-noncodeleted, and IDH-wild type 1p/19q-noncodeleted entities. This work proposes a model prediction of LGG molecular subtypes using magnetic resonance imaging (MRI). MR images were segmented and converted into radiomics features, thereby providing predictive information about the brain tumor classification. With 726 raw features obtained from the feature extraction procedure, we developed a hybrid machine learning-based radiomics by incorporating a genetic algorithm and eXtreme Gradient Boosting (XGBoost) classifier, to ascertain 12 optimal features for tumor classification. To resolve imbalanced data, the synthetic minority oversampling technique (SMOTE) was applied in our study. The XGBoost algorithm outperformed the other algorithms on the training dataset by an accuracy value of 0.885. We continued evaluating the XGBoost model, then achieved an overall accuracy of 0.6905 for the three-subtype classification of LGGs on an external validation dataset. Our model is among just a few to have resolved the three-subtype LGG classification challenge with high accuracy compared with previous studies performing similar work.

Microalgae Chlorella vulgaris and kraft lignin stabilized cellulosic wet foams for camouflage.

Plants, animals, and humans use camouflage to blend in with their surroundings. The camouflage is achieved with different combinations of colors, patterns, and morphologies. In stealth applications, the simplest camouflage uses textiles colored similarly to the environment to create an illusion. However, often, visible light range camouflage is not enough since the multispectral detection technologies of today are readily utilized for identification. Foams can be created with a straightforward fabricating process, and lightweight material exhibits good thermal insulation properties, providing stealth in the infrared light region. Herein, we produce cellulosic wet foams from surfactant and bleached pulp or cellulose nanofibrils. The visible light camouflage is created with green microalgae, Chlorella vulgaris, and brown kraft lignin, which also stabilized the foams. The thermal and spectral camouflage performance of foams was influenced by the cellulose content as well as the stability and water content of foams. Overall, these results give insight into how stability impacts the thermal and spectral properties of wet foams and provide a solid base for further material development to improve camouflage performance. While there is plenty of data on dry foams, the functional behavior of wet foams is currently not well known. Our method, using plant-based components can be exploited in a variety of other applications where simplicity and scalability are important.

It's not one size fits all: a case for how equity-based knowledge translation can support rural and remote communities to optimize virtual health care.

CONTEXT: People living in rural and remote British Columbia (BC) in Canada experience complex barriers to care, resulting in poorer health outcomes compared to their urban counterparts. Virtual healthcare (VH) can act as a tool to address some of the care barriers, including reducing travel time, cost, and disruptions to people's lives. Conversely, VH can exacerbate inequities through unique difficulties in rural implementation, such as a lack of access to necessary infrastructure (eg internet), social supports, and technological capacity (eg devices and literacy). ISSUE: The impacts of the COVID-19 pandemic induced a rapid shift to VH, providing new opportunities for health care while simultaneously highlighting and exacerbating inequities for people living in rural and remote settings. Equity-informed knowledge translation processes can help address these concerns. This commentary reports on an equity-informed knowledge translation process engaged by a diverse group of health researchers, community members, and practitioners in BC. LESSONS LEARNED: Informed by equity principles from the Canadian Coalition for Global Health Research, this knowledge exchange and translation process led to the co-creation of two practical tools: a set of VH appointment tip sheets and an open access report. Through stakeholder engagement and literature consultation, VH appointments were found to have many benefits for those in rural and remote communities, including expanding access to basic and specialized health services. However, some hesitation was noted when relying solely on these modes of care, as they can lack relationality, clarity, and time to process medical information. The tip sheets resulting from this process are an interactional-level tool developed to address this concern and optimize VH appointments, for rural patients and care providers. They offer the respective stakeholder group insights on how to actively prepare for and participate in inclusive virtual care. On a systems level, there is a continually echoed need for equity-based processes to ensure that VH is striking the balance of meeting rural health needs without exacerbating inequities. Additionally, incorporating the voices of rural and remote community members is essential. To help address this gap, an open-access report was compiled to serve as a small-scale example of integrating rural voices with existing literature to recommend systems-level adjustments. Overall, VH holds promise as an effective tool for addressing inequities experienced by those living in rural areas. To maximize this potential, rural and remote stakeholders must be proactively engaged and listened to throughout the processes of considering, planning, and implementing shifts in the utilization of VH options.

Structure guided development of potent piperazine-derived hydroxamic acid inhibitors targeting falcilysin.

The protozoan parasite Plasmodium falciparum causes the most severe form of human malaria and is estimated to kill 400,000 people a year. The parasite infects and replicates in host red blood cells (RBCs), where it expresses an array of proteases to carry out multiple essential processes. We are investigating the function of falcilysin (FLN), a protease known to be required for parasite development in the RBC. We previously developed a piperazine-based hydroxamic acid scaffold to generate the first inhibitors of FLN, and the current study reports the optimization of the lead compound from that series. A range of substituents were tested at the N1 and N4 positions of the piperazine core, and inhibitors with significantly improved potency against purified FLN and cultured P. falciparum were identified. Computational studies were also performed to understand the mode of binding for these compounds, and predicted a binding model consistent with the biochemical data and the distinctive SAR observed at both the N1 and N4 positions.

Where is critical analysis of power and positionality in knowledge translation?

In Canada, the Eurocentric epistemological foundations of knowledge translation (KT) approaches and practices have been significantly influenced by the Canadian Institutes of Health Research (CIHR) KT definition. More recently, integrated knowledge translation (IKT) has emerged in part as epistemic resistance to Eurocentric discourse to critically analyse power relations between researcher and participants. Yet, despite the proliferation of IKT literature, issues of power in research relationships and strategies to equalize relationships remain largely unaddressed. In this paper, we analyse the gaps in current IKT theorizing against the backdrop of the CIHR KT definition by drawing on critical scholars, specifically those writing about standpoint theory and critical reflexivity, to advance IKT practice that worked to surface and change research-based power dynamics within the context of health research systems and policy.

Pipercyclobutanamide D, a new member of the cyclobutanamide-type alkaloid, from the roots of Piper nigrum.

From the EtOH-soluble extract of the roots of Piper nigrum, one new dimeric alkamide, pipercyclobutanamide D (1) was isolated. Its structure was elucidated on the basis of NMR spectroscopic interpretation. The relative configuration of 1 was determined based on the NOESY analysis. Compound 1 showed α-glucosidase inhibitory activity with an IC50 value of 158.5 µM. In addition, compound 1 exhibited cytotoxicity against the MCF-7 and HepG2 cell lines with the IC50 values of 45.6 and 63.9 µM, respectively. Plausible biosynthetic pathway for the formation of 1 was proposed based on regioselective [2 + 2] cycloaddition reaction.

Is the cross-correlation of EU carbon market price with policy uncertainty really being? A multiscale multifractal perspective.

This paper aims to examine the cross-correlation relationship between EU carbon market price and the economic policy uncertainty. The United Kingdom and the United State of America are chosen as the representative countries. We first conduct the linear analysis to explore the correlation of EU carbon market futures return with the economic policy uncertainty of the two countries. Our findings show that there is no linear correlation between EU carbon market return and economic policy uncertainty. Then, we apply the multifractal detrended cross-correlation analysis to examine the cross-correlation between the return of EU carbon market futures and economic policy uncertainty. The empirical results indicate that the cross-correlations really exist, and the cross-correlation behavior structure over different carbon trading phases are not the same. Moreover, the empirical results show that the anti-persistence between the EU carbon futures return and economic policy uncertainty changes from the UK and the USA are both relatively strong. The findings provide deeper insights and management implications for the carbon market from a new perspective.

Synthesis, α-glucosidase inhibition, and molecular docking studies of novel N-substituted hydrazide derivatives of atranorin as antidiabetic agents.

A series of novel N-substituted hydrazide derivatives were synthesized by reacting atranorin, a compound with a natural depside structure (1), with a range of hydrazines. The natural product and 12 new analogues (2-13) were investigated for inhibition of α-glucosidase. The N-substituted hydrazide derivatives showed more potent inhibition than the original. The experimental results were confirmed by docking analysis. This study suggests that these compounds are promising molecules for diabetes therapy. Molecular dynamics simulations were carried out with compound 2 demonstrating the best docking model using Gromac during simulation up to 20 ns to explore the stability of the complex ligand-protein. Furthermore, the activity of all synthetic compounds 2-13 against a normal cell line HEK293, used for assessing their cytotoxicity, was evaluated.

Antimicrobial residues, non-typhoidal Salmonella, Vibrio spp. and associated microbiological hazards in retail shrimps purchased in Ho Chi Minh city (Vietnam).

We investigated antimicrobial residues, non-typhoidal Salmonella (NTS), Vibrio spp. and their associated antimicrobial resistance (AMR), in shrimps locally purchased in Ho Chi Minh City (Vietnam). In addition, we investigated the relationship between AMR in NTS, Vibrio spp. and antimicrobial residue in the same sample. A total of 40 samples of shrimp heads/shells from different retail sources was cultured using ISO 6579-1:2017 (NTS) and ISO/TS 21872-1:2007 (Vibrio spp.). Phenotypic antimicrobial susceptibility was investigated using Vitek (NTS, 34 antimicrobials) and disk diffusion (Vibrio spp., 12 antimicrobials). A total of 9 (22.5%) samples contained antimicrobial residue, including tetracyclines, fluoroquinolones, sulfonamides and macrolides (in 7.5%, 7.5%, 2.5% and 2.5% of samples, respectively). Shrimp samples from supermarkets had a higher prevalence of antimicrobial residue than those purchased in street markets (50% vs. 13.3%) (p = 0.049). A total of 30 (75%) samples were contaminated with NTS. All samples contained Vibrio spp., with V. parahaemolyticus being most common (87.5% samples). A total of 58.9% NTS isolates were multidrug resistant. With regards to the highest priority, critically important antimicrobials, the highest resistance corresponded to quinolones (14.4-47.8%), followed by 3rd and 4th generation cephalosporins (3.3-7.8%). Vibrio spp. isolates were characterised by their high resistance against ampicillin (82.7%) and 3rd generation cephalosporins (8.3-16.5%). Extended Spectrum Beta-Lactamase (ESBL) activity was detected in 28.1% V. parahaemolyticus isolates. Half of ESBL-positive V. parahaemolyticus strains harboured bla CTX-M1. We found an association between the presence of residues and the number of resistances for NTS (p = 0.075) and Vibrio spp. isolates (p = 0.093) from the same sample. These findings suggest that the presence of residues may contribute to the selection of AMR in foodborne pathogens in shrimps. Authorities should strengthen policies aiming at restricting inappropriate antimicrobial usage in shrimp farming, and step up monitoring of antimicrobial residues and food-borne pathogens at retail in Vietnam.

Long-term outcome in survivors of neonatal tetanus following specialist intensive care in Vietnam.

BACKGROUND: Neonatal tetanus continues to occur in many resource-limited settings but there are few data regarding long-term neurological outcome from the disease, especially in settings with critical care facilities. METHODS: We assessed long-term outcome following neonatal tetanus in infants treated in a pediatric intensive care unit in southern Vietnam. Neurological and neurodevelopmental testing was performed in 17 survivors of neonatal tetanus and 18 control children from the same communities using tools previously validated in Vietnamese children. RESULTS: The median age of children assessed was 36 months. Eight neonatal tetanus survivors and 9 community control cases aged < 42 months were tested using the Bayley III Scales of Infant and Toddler Development (Bayley III-VN) and 8 neonatal tetanus survivors and 9 community controls aged ≥42 months were tested using the Movement Assessment Battery for Children. No significant reductions in growth indices or neurodevelopmental scores were shown in survivors of neonatal tetanus compared to controls although there was a trend towards lower scores in neonatal tetanus survivors. Neurological examination was normal in all children except for two neonatal tetanus survivors with perceptive deafness and one child with mild gross motor abnormality. Neonatal tetanus survivors who had expienced severe disease (Ablett grade ≥ 3) had lower total Bayley III-VN scores than those with mild disease (15 (IQR 14-18) vs 24 (IQR 19-27), p = 0.05) with a significantly lower cognitive domain score (3 (IQR 2-6) severe disease vs 7 (IQR 7-8) mild disease, p = 0.02). CONCLUSIONS: Neonatal tetanus is associated with long-term sequelae in those with severe disease. In view of these findings, prevention of neonatal tetanus should remain a priority.

Exploring the structure of household social capital in rural Vietnam: Applying Bayesian network approach.

This study aims to explore the structure of the households' social capital of rural Vietnam households with secondary data from 2008 to 2018. This paper applied the fundamental theories (resource and network theories) and the Bayesian network to estimate the interaction of proxies to explore the structure of social capital. Results showed that the triangle structure in household social capital with the core point is organization participation. The connections show the tendency from organization participation, linking to household networks. Alongside that, linking social capital and Organization participation are determinants of social capital indicators (social events, social cost). Therefore, this paper suggests employing proxies such as structured indicators for integrating social capital into the livelihood papers.

Correction: The role of social capital in shaping livelihood for rural Vietnamese households.

[This corrects the article DOI: 10.1371/journal.pone.0295292.].

Understanding glioblastoma stromal barriers against NK cell attack using tri-culture 3D spheroid model.

Glioblastoma multiforme (GBM), a highly aggressive tumor type with a dismal survival rate, has a poor outcome which is at least partly attributed to the crosstalk between cancer cells and cells from the tumor microenvironment such as astrocytes and microglia. We aimed to decipher the effect of these cells on GBM progression and on cell-based therapies using 3D co-cultures. Co-culturing of glioblastoma cells with patient-derived astrocytes or microglia or both formed dense and heterogeneous spheroids. Both, astrocytes and microglia, enhanced the spheroid growth rate and formed a physical barrier for macromolecules penetration, while only astrocytes enhanced the migration. Interestingly bi-/tri-cultured spheroids showed significant resistance against NK-92 cells, likely attributed to dense stroma and induced expression of immunosuppressive genes such as IDO1 or PTGES2. Altogether, our novel 3D GBM spheroid model recapitulates the cell-to-cell interactions of human glioblastoma and can serve as a suitable platform for evaluating cancer therapeutics.

Insights into spheroids formation in cellulose nanofibrils and Matrigel hydrogels using AFM-based techniques.

The recent FDA decision to eliminate animal testing requirements emphasises the role of cell models, such as spheroids, as regulatory test alternatives for investigations of cellular behaviour, drug responses, and disease modelling. The influence of environment on spheroid formation are incompletely understood, leading to uncertainty in matrix selection for scaffold-based 3D culture. This study uses atomic force microscopy-based techniques to quantify cell adhesion to Matrigel and cellulose nanofibrils (CNF), and cell-cell adhesion forces, and their role in spheroid formation of hepatocellular carcinoma (HepG2) and induced pluripotent stem cells (iPS(IMR90)-4). Results showed different cell behaviour in CNF and Matrigel cultures. Both cell lines formed compact spheroids in CNF but loose cell aggregates in Matrigel. Interestingly, the type of cell adhesion protein, and not the bond strength, appeared to be a key factor in the formation of compact spheroids. The gene expression of E- and N-cadherins, proteins on cell membrane responsible for cell-cell interactions, was increased in CNF culture, leading to formation of compact spheroids while Matrigel culture induced integrin-laminin binding and downregulated E-cadherin expression, resulting in looser cell aggregates. These findings enhance our understanding of cell-biomaterial interactions in 3D cultures and offer insights for improved 3D cell models, culture biomaterials, and applications in drug research.