Human Circulation Research Articles

A new imputation method for population mean in the presence of missing data based on a transformed variable with applications to air pollution data in Chiang Mai, Thailand

Introduction: Chiang Mai’s air pollution has risen to number one in the world for the highest level of fine particulate matter which further exacerbates the damage to human health. Fine particulate matter can enter the human body and blood circulation, destroying organ systems, increasing the risk for chronic disease and cancer, despite not having smoking habits or other morbidities. The Thai government must sort out this issue before it is too late as the whole nation’s health is at risk due to excessive dust levels higher than standard guidelines. Collection of pollution data can help us to come up with solutions and prevent it from turning into a hazardous situation. Unfortunately, pollution data are missing and need to be dealt with before analysis to obtain accurate results. Materials and methods: A new method of imputation for estimating population mean based on a transformed variable has been suggested under simple random sampling without replacement and the uniform nonresponse mechanism. The bias and mean square error of the proposed estimator are investigated up to the first order of approximation. The performance of the proposed estimator is studied via applications to air pollution data in Chiang Mai, Thailand. Results: The proposed estimator shows the best performance, giving the least bias and mean square error for all levels of sampling fractions. For the results from application the estimated value of sulfur dioxide from Particulate Matter 2.5 (PM2.5), the Percentage Relative Efficiency (PRE) is higher than all existing estimators by at least 16%. For the estimated PM2.5 from PM10 the PRE is higher than all existing estimators by at least 1600%, an extremely significant difference exhibiting similarity to real values. Conclusion: The proposed imputation technique based on the transformed auxiliary variable can be helpful for imputing missing values and improving the efficiency of the estimators.

New results of obsidian artifact analysis from the middle and lower basin of the Salado stream, Río Negro province, Argentina

AbstractThe Salado and Verde streams constitute the two main seasonally available freshwater courses that flow into the Atlantic coast of the Río Negro province (continental Patagonia, Argentina, 42° South). This would have favored their use in the past as corridors for human circulation between the coast and the interior. This paper presents the results of the technomorphological and geochemical analyses of the obsidian artifacts recovered in the area to constrain mobility. The results allow us to propose the existence of toolkit reconditioning or replacement activities, and the identification of different sources of provenance of the obsidians (Sacanana, Telsen, and Portada Covunco, distant up to 800 km from the study area), reinforcing the hypothesis of a coast–inland circulation, with the possible existence of circuits of exchange of this raw material.

Kinetics of Trisulfide-to-Disulfide Conversion of Therapeutic IgG1 Monoclonal Antibodies Under Physiological Conditions: A Case Study of Casirivimab And Imdevimab

The percentage of trisulfide variants is a product quality metric that is monitored during the manufacture of monoclonal antibody (mAb)-based therapeutics. Results from earlier preclinical studies revealed that trisulfide linkages in mAbs are rapidly converted to disulfides in circulation. In this study, casirivimab and imdevimab, which are both IgG1 subclass mAbs that target the non-overlapping epitopes in SARS-CoV2 Spike protein, are used as models to study the kinetics of trisulfide-to-disulfide conversion in vivo in human circulation. To determine the percentage of trisulfide variants in systemic circulation immediately after intravenous injection, both mAbs were immunoprecipitated from serum samples collected from COVID-19 patients that received this cocktail antibody treatment as part of a first-in-human study. The immunoprecipitated mAbs were then digested under non-reducing conditions and evaluated by liquid-chromatography–mass spectrometry (LC-MS). Significant reductions in the percentages of trisulfide variants were observed in serum samples as early as 1 hr after completion of the intravenous infusion. A flow-through dialysis model designed to mimic the redox potential of blood revealed a plausible chemical mechanism for the rapid trisulfide-to-disulfide conversion of IgG1 subclass mAbs under physiological conditions.

KAJIAN POLA SIRKULASI MANUSIA TERHADAP KENYAMANAN PENUMPANG KERETA REL LISTRIK PADA STASIUN TANAH TINGGI KOTA TANGERANG

Technological progress develops rapidly from time to time. Railways as a mode of transportation, especially mass transportation, cannot be separated from other modes of transportation used in the national transportation system which have their own characteristics and advantages of mass transportation. Train stations also need to further develop their potential and improve good human circulation patterns so that passengers feel comfortable. As a transit point, Tanah Tinggi Station is a class III/small train station which only has 2 railroad tracks located in Tanah Tinggi, Tangerang City. However, circulation at stations can be very ironic when public facilities at stations do not pay much attention to the use of circulation for users of rail services. The author sees many problems that arise related to human circulation for the comfort of Electric Rail Train passengers at Tanah Tinggi Station, Tangerang City. This study aims to provide an overview of human circulation patterns and spatial planning, especially at the Tanah Tinggi station, so as to obtain the concept of circulation patterns and good spatial planning to increase passenger comfort. On This research uses descriptive analysis methods carried out in 3 ways, namely, literature studies, conducting surveys of research objects, and conducting interviews with users and managers of the highland station. The research was conducted in 5 sections, (1) the main entrance of the building, (2) supporting building corridors, (3) counters, (4) ticketing areas, and (5) platforms. It can be said that the results of the analysis carried out were not good enough for passengers because they have not been able to meet the standards and eligibility according to the regulations so that the ease of circulation for pedestrians to move can be disrupted and uncomfortable.

The Influence of the Discovery Learning Model on the Learning Outcomes of Human Blood Circulation Material for Class V Elementary School Students

Penelitian ini dilatarbelakangi oleh rendahnya hasil belajar siswa pada materi peredaran darah manusia, sebagaimana berdasarkan hasil penilaian harian siswa kelas V UPT SDN 163 Gresik yang menunjukkan masih terdapat banyak siswa tidak mencapai target KKM. Adapun tujuan dari penelitian ini adalah untuk mengetahui pengaruh model Discovery Learning terhadap hasil belajar materi peredaran darah manusia siswa kelas V SD. Model Discovery Learning dipilih karena mampu membuat pembelajaran menjadi aktif dengan membuat siswa mencari tahu dan menggali pengetahuannya sendiri. Pendekatan yang digunakan adalah kuantitatif eksperimen. Adapun Jenis penelitian ini adalah Quasi Experimental memakai bentuk Nonequivalent Posttest Only Control Design. Populasinya merupakan siswa kelas V UPT SDN 163 Gresik. Melalui teknik purposive sampling didapat sampel siswa kelas VA dan VB. Metode yang dipakai untuk menghimpun data yaitu tes hasil belajar sebanyak 15 soal mengenai materi peredaran darah manusia. Untuk menganalisis data dibantu SPSS 25, diketahui nilai rata-rata posttest dari kelas eksperimen unggul dibanding kelas kontrol. Berlandaskan perolehan uji-t pada independent sample T test , didapat nilai Sig. (2-tailed) 0,000<0,05, artinya H0 ditolak sedangkan H1 diterima, sehingga didapat simpulan bahwa ada pengaruh model Discovery Learning terhadap hasil belajar materi peredaran darah manusia siswa kelas V SD di UPT SDN 163 Gresik.

Human Blood Circular System Educational Digital Comics for Improving Learning Outcomes

The learning outcomes of class V at SDN Bendungan Semarang in science subjects on the human circulatory system are low. The average learning outcome of fifth-grade students at SDN Bendungan is 63, where the score is less than the standard of minimum value for science subjects, namely 75. This study aims to develop the learning media "Digital Comics for Education on the Human Circulatory System" as well as to test the design of media development, test the feasibility of media, as well as to find out the effectiveness of the learning media "Digital Comic Education for the Human Blood Circulation System." The method used in this study is the Research and Development method with the Borg and Gall development model. The subjects in this research and development were: (1) Grade V students at SDN Bendungan Semarang in the 2022/2023 school year with 28 students; (2) Class V teachers at SDN Bendungan; (3) experts, expert lecturers, or experts as testers of learning media and provide input to the learning media. Data collection techniques are questionnaires, interviews, documentation, observation, and tests. Data analysis used validity, reliability, normality, t-tests, and N-gain tests. Based on the study's results, suitable for use with a percentage of material experts' assessment of 86% and a percentage of media experts' assessment of 95%. The percentage of teacher responses is 91%, and the percentage of student responses is 89%. The t-test result is 0.000, so there is a significant difference between the pretest and the post-test results. The result of the N-gain test is 0.60957 in the medium criteria category. So that the results obtained are: (1) the design of learning media that is developed according to the needs of students and teachers in teaching and learning activities; (2) the assessment of media experts and material experts with very feasible criteria; (3) the use of effective learning media in increasing student effectiveness and motivation. Based on the responses of teachers and students, the results of the study show that learning media is appropriate for use in teaching and learning activities

Transmission Dynamics of Crimean-Congo Haemorrhagic Fever Virus (CCHFV): Evidence of Circulation in Humans, Livestock, and Rodents in Diverse Ecologies in Kenya.

Crimean-Congo haemorrhagic fever virus (CCHFV) is the causative agent of CCHF, a fatal viral haemorrhagic fever disease in humans. The maintenance of CCHFV in the ecosystem remains poorly understood. Certain tick species are considered as vectors and reservoirs of the virus. Diverse animals are suspected as amplifiers, with only scarce knowledge regarding rodents in virus epidemiology. In this study, serum samples from febrile patients, asymptomatic livestock (cattle, donkeys, sheep, and goats), and peridomestic rodents from Baringo (Marigat) and Kajiado (Nguruman) counties within the Kenyan Rift Valley were screened for acute CCHFV infection by RT-PCR and for CCHFV exposure by ELISA. RT-PCR was performed on all livestock samples in pools (5-7/pool by species and site) and in humans and rodents individually. CCHFV seropositivity was significantly higher in livestock (11.9%, 113/951) compared to rodents (6.5%, 6/93) and humans (5.9%, 29/493) (p = 0.001). Among the livestock, seropositivity was the highest in donkeys (31.4%, 16/51), followed by cattle (14.1%, 44/310), sheep (9.8%, 29/295) and goats (8.1%, 24/295). The presence of IgM antibodies against CCHFV was found in febrile patients suggesting acute or recent infection. CCHFV RNA was detected in four pooled sera samples from sheep (1.4%, 4/280) and four rodent tissues (0.83%, 4/480) showing up to 99% pairwise nucleotide identities among each other. Phylogenetic analyses of partial S segment sequences generated from these samples revealed a close relationship of 96-98% nucleotide identity to strains in the CCHFV Africa 3 lineage. The findings of this study suggest active unnoticed circulation of CCHFV in the study area and the involvement of livestock, rodents, and humans in the circulation of CCHFV in Kenya. The detection of CCHF viral RNA and antibodies against CCHFV in rodents suggests that they may participate in the viral transmission cycle.

A quadruplet 3-D laser scribed graphene/MoS2, functionalised N2-doped graphene quantum dots and lignin-based Ag-nanoparticles for biosensing

Troponin I is a protein released into the human blood circulation and a commonly used biomarker due to its sensitivity and specificity in diagnosing myocardial injury. When heart injury occurs, elevated troponin Troponin I levels are released into the bloodstream. The biomarker is a strong and reliable indicator of myocardial injury in a person, with immediate treatment required. For electrochemical sensing of Troponin I, a quadruplet 3D laser-scribed graphene/molybdenum disulphide functionalised N2-doped graphene quantum dots hybrid with lignin-based Ag-nanoparticles (3D LSG/MoS2/N-GQDs/L-Ag NPs) was fabricated using a hydrothermal process as an enhanced quadruplet substrate. Hybrid MoS2 nanoflower (H3 NF) and nanosphere (H3 NS) were formed independently by varying MoS2 precursors and were grown on 3D LSG uniformly without severe stacking and restacking issues, and characterized by morphological, physical, and structural analyses with the N-GQDs and Ag NPs evenly distributed on 3D LSG/MoS2 surface by covalent bonding. The selective capture of and specific interaction with Troponin I by the biotinylated aptamer probe on the bio-electrode, resulted in an increment in the charge transfer resistance. The limit of detection, based on impedance spectroscopy, is 100 aM for both H3 NF and H3 NS hybrids, with the H3 NF hybrid biosensor having better analytical performance in terms of linearity, selectivity, repeatability, and stability.

Decreased serum soluble programmed cell death ligand-1 level as a potential biomarker for missed miscarriage.

Can maternal serum levels of soluble programmed cell death-1 (sPD-1) and its ligand (sPD-L1) serve as biomarkers for missed miscarriage (MM)? Serum sPD-L1 levels are significantly decreased in MM patients and may serve as a potential predictive biomarker for miscarriage. Programmed cell death-1 (PD-1) and its ligand (PD-L1) comprise important immune inhibitory checkpoint signaling to maintain pregnancy. Their soluble forms are detectable in human circulation and are associated with immunosuppression. Three independent cohorts attending tertiary referral hospitals were studied. The first (discovery) cohort was cross-sectional and included MM patients and healthy pregnant (HP) women matched on BMI. The second validation cohort contained MM patients and women with legally induced abortion (IA). The third prospective observational study recruited subjects requiring IVF treatment. In the discovery cohort, we enrolled 108 MM patients and 115 HP women who had a full-term pregnancy at 6-14 weeks of gestation. In the validation cohort, we recruited 25 MM patients and 25 women with IA. Blood samples were collected at the first prenatal visit for HP women or on the day of dilatation and curettage surgery (D&C) for MM and IA subjects to determine serum sPD-1 and sPD-L1 levels. Placenta samples were harvested during the D&C within the validation cohort to measure gene and protein expression. The prospective cohort collected serial blood samples weekly from 75 volunteers with embryo transfer (ET) after IVF. Circulating sPD-L1 levels were reduced by 50% in patients with MM (55.7 ± 16.04 pg/ml) compared to HP controls (106.7 ± 58.46 pg/ml, P < 0.001) and the difference remained significant after adjusting for maternal age and gestational age, whereas no significant differences in sPD-1 level were observed. Likewise, serum sPD-L1 was lower in MM patients than in IA subjects and accompanied by downregulated PD-L1-related gene expression levels in the placenta. In the IVF cohort, applying the changing rate of sPD-L1 level after ET achieved a predictive performance for miscarriage with receiver operating characteristics = 0.73 (95% CI: 0.57-0.88, P < 0.01). The study was mainly confined to East Asian pregnant women. Further large prospective pregnancy cohorts are required to validate the predictive performance of sPD-L1 on miscarriage. Reduced circulating sPD-L1 level and downregulated placental PD-L1 expression in miscarriage indicate that dysfunction in PD-L1 signals is a potential underlying mechanism for pregnancy loss. Our findings further extend the importance of the PD-L1 axis in pregnancy maintenance in early pregnancy. This study was financially supported by grants from the Subject Innovation Team of Shaanxi University of Chinese Medicine (2019-Y502), General Research Fund (14122021), and Key Laboratory of Model Animal Phenotyping and Basic Research in Metabolic Diseases (2018KSYS003). The authors declare that they have no competing interests to be disclosed. N/A.

Continued adaptation of A/H2N2 viruses during pandemic circulation in humans.

Influenza A viruses of the H2N2 subtype sparked a pandemic in 1957 and circulated in humans until 1968. Because A/H2N2 viruses still circulate in wild birds worldwide and human population immunity is low, the transmissibility of six avian A/H2N2 viruses was investigated in the ferret model. None of the avian A/H2N2 viruses was transmitted between ferrets, suggesting that their pandemic risk may be low. The transmissibility, receptor binding preference and haemagglutinin (HA) stability of human A/H2N2 viruses were also investigated. Human A/H2N2 viruses from 1957 and 1958 bound to human-type α2,6-linked sialic acid receptors, but the 1958 virus had a more stable HA, indicating adaptation to replication and spread in the new host. This increased stability was caused by a previously unknown stability substitution G205S in the 1958 H2N2 HA, which became fixed in A/H2N2 viruses after 1958. Although individual substitutions were identified that affected the HA receptor binding and stability properties, they were not found to have a substantial effect on transmissibility of A/H2N2 viruses via the air in the ferret model. Our data demonstrate that A/H2N2 viruses continued to adapt during the first year of pandemic circulation in humans, similar to what was previously shown for the A/H1N1pdm09 virus.

REDESAIN TERMINAL TIPE B KM. 6 KOTA BANJARMASIN DENGAN MENGOPTIMALKAN SIRKULASI

The background for the redesign of Terminal Type B km.6 in the city of Banjarmasin is thedevelopment plan and the current condition of the terminal. The current condition of the terminal hasproblems with facilities and circulation, where facilities at the terminal are difficult to identify, and arenot functioning properly. Circulation at the terminal often experiences crossing, this is due to unclearvehicle paths and leakage of human circulation in buildings. The purpose of redesign is to obtain anew design of the terminal, which meets the criteria, facilities and circulation with minimal crossings.The method used in this redesign is the behavioral architectural approach, which addresses theinteraction between humans and public spaces. The concept raised is interaction, where this conceptpays attention to spatial planning and circulation. The elaboration of the concept uses thesuperimpose method, which creates layers related to the concept on the layering which will becombined to create a new design. The result of this redesign is a terminal design that meets thecriteria as a type B terminal, and has regular circulation without crossing.

Design and validation of a laboratory-developed diagnostic assay for monkeypox virus

Mpox is a viral zoonosis with endemic circulation in animals and humans in some West and Central African countries. The disease was imported a few times in the past to countries outside the African continent through infected animals or travelers, one of which resulted in an unprecedented global outbreak sustained by human-to-human transmission in 2022. Although timely and reliable diagnosis is a cornerstone of any disease control, availability of accurate diagnostic assays and comparative performance studies of diagnostic assays remains limited despite of the long-known identification of monkeypox virus (MPXV) as a human pathogen since 1970. We laboratory-developed a real-time PCR test (LDT) and evaluated its performance against the commercial TaqMan™ Monkeypox Virus Microbe Detection Assay (Applied Biosystems, Cat A50137). The limit of detection of the LDT was established at 1.2 genome copies/ml. The sensitivity and specificity of both assays were 99.14% and 100%, respectively, and both are capable of detecting both clade I and clade II of MPXV. Our results demonstrate the validity and accuracy of the LDT for confirmation of MPXV infection from lesion swabs samples.

Interactive Learning Multimedia in Supporting Personalized Learning Grade V Primary School

The absence of interactive media and media development in an area shows that adaptation to technology has yet to be maximized. The research aimed to produce interactive multimedia material on human blood circulation for grade V SD and determine its quality and feasibility by conducting validation trials on experts, teachers, and students. This research method is R&amp;D (Research and Development) with the ADDIE model. The subjects in this study were fifth-grade elementary school students. Data collection methods are assessment sheets and documentation. Data collection instrument using a questionnaire. Data analysis techniques are quantitative data analysis and qualitative descriptive data analysis. The results of the research are in the form of interactive multimedia based on storylines of articulation of human blood circulation in science subjects for class V SD which can be used by students with a score of 92.5% from material experts; media experts 86.66%; learning experts 88.88%; linguists 74.26%; teacher assessment 98.88%; Penialain students 93.40%. The scores of each expert, teacher, and student assessment were then searched for the average value and obtained a percentage value of 89.096% with the "Very Good" criterion. It was concluded that the developed multimedia is very good quality, is suitable for use in learning activities, and has personalized learning characteristics that support student-centered learning activities.

Contemporary epidemiological data of Rift Valley fever virus in humans, mosquitoes and other animal species in Africa: A systematic review and meta-analysis.

Rift Valley fever (RVF) is a severe zoonotic mosquito-borne disease that represents an important threat to human and animal health, with major public health and socioeconomic impacts. This disease is endemic throughout many African countries and the Arabian Peninsula. This systematic review with meta-analysis was conducted to determine the RVF prevalence in humans, mosquitoes and other animal species in Africa. The review also provides contemporary data on RVF case fatality rate (CFR) in humans. In this systematic review with meta-analysis, a comprehensive literature search was conducted on the PubMed, Embase, Web of Science and Global Index Medicus databases from January 2000 to June 2022 to identify relevant studies. Pooled CFR and prevalence estimates were calculated using the random-effects model. Subgroup analysis and sensitivity analysis were performed, and the I2 -statistic was used to investigate a potential source of heterogeneity. A total of 205 articles were included in the final analysis. The overall RVF CFR in humans was found to be 27.5% [95% CI=8.0-52.5]. The overall pooled prevalence was 7.8% [95% CI=6.2-9.6] in humans and 9.3% [95% CI=8.1-10.6] in animals, respectively. The RVF prevalence in individual mosquitoes ranged from 0.0% to 25%. Subgroup analysis showed substantial heterogeneity with respect to geographical regions and human categories. The study shows that there is a correspondingly similar prevalence of RVF in human and animals; however, human CFR is much higher than the observed prevalence. The lack of a surveillance programme and the fact that this virus has subclinical circulation in animals and humans could explain these observations. The implementation of a One Health approach for RVF surveillance and control would be of great interest for human and animal health.

Reverse-zoonoses of 2009 H1N1 pandemic influenza A viruses and evolution in United States swine results in viruses with zoonotic potential.

The 2009 H1N1 pandemic (pdm09) lineage of influenza A virus (IAV) crosses interspecies barriers with frequent human-to-swine spillovers each year. These spillovers reassort and drift within swine populations, leading to genetically and antigenically novel IAV that represent a zoonotic threat. We quantified interspecies transmission of the pdm09 lineage, persistence in swine, and identified how evolution in swine impacted zoonotic risk. Human and swine pdm09 case counts between 2010 and 2020 were correlated and human pdm09 burden and circulation directly impacted the detection of pdm09 in pigs. However, there was a relative absence of pdm09 circulation in humans during the 2020-21 season that was not reflected in swine. During the 2020-21 season, most swine pdm09 detections originated from human-to-swine spillovers from the 2018-19 and 2019-20 seasons that persisted in swine. We identified contemporary swine pdm09 representatives of each persistent spillover and quantified cross-reactivity between human seasonal H1 vaccine strains and the swine strains using a panel of monovalent ferret antisera in hemagglutination inhibition (HI) assays. The swine pdm09s had variable antigenic reactivity to vaccine antisera, but each swine pdm09 clade exhibited significant reduction in cross-reactivity to one or more of the human seasonal vaccine strains. Further supporting zoonotic risk, we showed phylogenetic evidence for 17 swine-to-human transmission events of pdm09 from 2010 to 2021, 11 of which were not previously classified as variants, with each of the zoonotic cases associated with persistent circulation of pdm09 in pigs. These data demonstrate that reverse-zoonoses and evolution of pdm09 in swine results in viruses that are capable of zoonotic transmission and represent a potential pandemic threat.

Development of an E-module Based on STEAM on the Topic of Human Blood Circulation

The purpose of this research is to develop a STEAM-based e-module for mastering the topic of human blood circulation. The developed e-module is named "Radar.” "Radar" e-module from the content validity analysis test obtained a content validity value of 0.9167, construct validity of 0.9208, and language validity of 0.8819. The final validity value of the e-module was 0.9065 with valid criteria. The practicality test results get a percentage of 86.67% and are included in the convenience category. Based on the validity and practicality of test results, the "Radar" e-module is feasible and practical to use to improve students' concepts of human blood circulation

Comprehensive views toward the biomolecular recognition of an anticancer drug, leflunomide with human serum albumin

Biomolecular association of an anticancer drug, leflunomide (LEF) with human serum albumin (HSA), the leading ligands carrier in human circulation was characterized using biophysical (i.e., fluorescence, absorption and voltammetric) methods and computational (i.e., molecular docking and molecular dynamics simulation) techniques. Evaluations of fluorescence, absorption and voltammetric findings endorsed the complex formation between LEF and HSA. An inverse relationship of Stern-Volmer constant–temperature and hyperchromic shift of the protein’s absorption signal with addition of LEF confirmed the LEF quenched the HSA fluorescence through static process. Moderate nature of binding strength (binding constant = 2.76–4.77 × 104 M−1) was detected towards the LEF–HSA complexation, while the association process was naturally driven via hydrophobic interactions, van der Waals interactions and hydrogen bonds, as evident from changes in entropy (ΔS= + 19.91 J mol−1 K−1) and enthalpy (ΔH = − 20.09 kJ mol−1), and molecular docking assessments. Spectral analyses of synchronous and three-dimensional fluorescence validated microenvironmental fluctuations near Trp and Tyr residues upon LEF binding to the protein. LEF association with HSA significantly defended temperature-induced destabilization of the protein. Although LEF was found to attach to HSA at Sudlow’s sites I and II, but exhibited greater preference toward its site I, as detected by the investigations of competitive site-marker displacement. Molecular dynamics simulation assessment revealed that the complex attained equilibrium throughout simulations, showing the LEF–HSA complex constancy. Communicated by Ramaswamy H. Sarma

Numerical coupling of 0D and 1D models in networks of vessels including transonic flow conditions. Application to short-term transient and stationary hemodynamic simulation of postural changes.

When modeling complex fluid networks using one-dimensional (1D) approaches, boundary conditions can be imposed using zero-dimensional (0D) models. An application case is the modeling of the entire human circulation using closed-loop models. These models can be considered as a tool to investigate short-term transient and stationary hemodynamic responses to postural changes. The first shortcoming of existing 1D modeling methods in simulating these sudden maneuvers is their inability to deal with rapid variations in flow conditions, as they are limited to the subsonic case. On the other hand, numerical modeling of 0D models representing microvascular beds, venous valves or heart chambers is also currently modeled assuming subsonic flow conditions in 1D connecting vessels, failing when transonic and supersonic flow conditions appear. Therefore, if numerical simulation of sudden maneuvers is a goal in closed-loop models, it is necessary to reformulate the current methodologies used when coupling 0D and 1D models, allowing the correct handling of flow evolution for both subsonic and transonic conditions. This work focuses on the extension of the general methodology for the Junction Riemann Problem (JRP) when coupling 0D and 1D models. As an example of application, the short-term transient response to head-up tilt (HUT) from supine to upright position of a closed-loop model is shown, demonstrating the potential, capability and necessity of the presented numerical models when dealing with sudden maneuvers.

Modeling essential hypertension with a closed-loop mathematical model for the entire human circulation.

Arterial hypertension, defined as an increase in systemic arterial pressure, is a major risk factor for the development of diseases affecting the cardiovascular system. Every year, 9.4 million deaths worldwide are caused by complications arising from hypertension. Despite well-established approaches to diagnosis and treatment, fewer than half of all hypertensive patients have adequately controlled blood pressure. In this scenario, computational models of hypertension can be a practical approach for better quantifying the role played by different components of the cardiovascular system in the determination of this condition. In the present work we adopt a global closed-loop multi-scale mathematical model for the entire human circulation to reproduce a hypertensive scenario. In particular, we modify the model to reproduce alterations in the cardiovascular system that are cause and/or consequence of the hypertensive state. The adaptation does not only affect large systemic arteries and the heart but also the microcirculation, the pulmonary circulation and the venous system. Model outputs for the hypertensive scenario are validated through assessment of computational results against current knowledge on the impact of hypertension on the cardiovascular system.

Acrolein produced by glioma cells under hypoxia inhibits neutrophil AKT activity and suppresses anti-tumoral activities

Acrolein, which is the most reactive aldehyde, is a byproduct of lipid peroxidation in a hypoxic environment. Acrolein has been shown to form acrolein-cysteine bonds, resulting in functional changes in proteins and immune effector cell suppression. Neutrophils are the most abundant immune effector cells in circulation in humans. In the tumor microenvironment, proinflammatory tumor-associated neutrophils (TANs), which are termed N1 neutrophils, exert antitumor effects via the secretion of cytokines, while anti-inflammatory neutrophils (N2 neutrophils) support tumor growth. Glioma is characterized by significant tissue hypoxia, immune cell infiltration, and a highly immunosuppressive microenvironment. In glioma, neutrophils exert antitumor effects early in tumor development but gradually shift to a tumor-supporting role as the tumor develops. However, the mechanism of this anti-to protumoral switch in TANs remains unclear. In this study, we found that the production of acrolein in glioma cells under hypoxic conditions inhibited neutrophil activation and induced an anti-inflammatory phenotype by directly reacting with Cys310 of AKT and inhibiting AKT activity. A higher percentage of cells expressing acrolein adducts in tumor tissue are associated with poorer prognosis in glioblastoma patients. Furthermore, high-grade glioma patients have increased serum acrolein levels and impaired neutrophil functions. These results suggest that acrolein suppresses neutrophil function and contributes to the switch in the neutrophil phenotype in glioma.