How ATP suppresses the fibrillation of amyloid peptides: analysis of the free-energy contributions.

Recent experiments have revealed that adenosine triphosphate (ATP) suppresses the fibrillation of amyloid peptides - a process closely linked to neurodegenerative diseases such as Alzheimer's and Parkinson's. Apart from the adsorption of ATP onto amyloid peptides, the molecular understanding is still limited, leaving the underlying mechanism for the fibrillation suppression by ATP largely unclear, especially in regards to the molecular energetics. Here we provide an explanation at the molecular scale by quantifying the free energies using all-atom molecular dynamics simulations. We found that the changes of the free energies due to the addition of ATP lead to a significant equilibrium shift towards monomeric peptides in agreement with experiments. Despite ATP being a highly charged species, the decomposition of the free energies reveals that the van der Waals interactions with the peptide are decisive in determining the relative stabilization of the monomeric state. While the phosphate moiety exhibits strong electrostatic interactions, the compensation by the water solvent results in a minor, overall Coulomb contribution. Our quantitative analysis of the free energies identifies which intermolecular interactions are responsible for the suppression of the amyloid fibril formation by ATP and offers a promising method to analyze the roles of similarly complex cosolvents in aggregation processes.

Knowledge, Attitudes and Practices on Reproductive Health Among Abortion Adolescents in Vietnam.

Background: Adolescent pregnancy is a global issue. The majority of these adolescents experience unintended pregnancy ending in abortion. Knowledge gaps and misconceptions about reproductive health are the main reasons for unintended pregnancy among adolescents. Objective: This study aims to identify knowledge, attitudes, practices, and related factors of reproductive health among adolescent post-abortion or those seeking abortion at Hanoi Obstetrics and Gynecology Hospital (HOGH), a tertiary hospital in Vietnam. Methods: Ours was a descriptive cross-sectional study of 103 adolescents who sought induced abortions between January 1, 2022 and June 30, 2023. Participants were interviewed directly via questionnaires to collect information. Results: The mean age of participants was 16.3 years. 64.1% of the population did not have general knowledge regarding reproductive health, 42.7% of subjects displayed incorrect attitudes regarding reproductive health. As a result, lack of knowledge and incorrect attitudes led to unsafe sex. The percentage of adolescents practicing unsafe sex is incredibly high (90.3%) thus causing unintended pregnancies. Education levels and family economic status were the main factors linked to knowledge, attitudes, and practices (KAP) regarding reproductive health. Conclusion: Most adolescents seeking abortion had poor KAP regarding reproductive health. Their KAP of reproductive health were linked to levels of education and family economic status. The findings emphasize the need to provide reproductive health care information and services for adolescents, and the need for appropriate attention from both family and society to the target group. We believe this will result in the improvement of their health and the avoidance of unfortunate consequences.

IOTA simple rules: An efficient tool for evaluation of ovarian tumors by non-experienced but trained examiners - A prospective study.

Objectives: A simple and efficient tool for evaluating ovarian tumors in general hospitals where radiologists without experience in gynecological ultrasound is necessary. This study aims to evaluate the diagnostic performance of IOTA simple rules in initial classification of ovarian tumors by non-experienced examiners who have received simple training. Materials and method: A prospective single-center study was conducted at Hanoi Obstetrics and Gynecology Hospital. Three resident gynecologists trained themselves for two weeks and then received hands-on practice under the supervision of experts for another two weeks. The examiners performed ultrasound on 424 eligible women scheduled for surgery for ovarian tumors and classified the tumors based on IOTA simple rules. The postoperative pathology of ovarian tumors was used as the gold standard. Results: 90.8 % (385/424) of the tumors were benign. Simple rules were applicable in 399/424 (94.1 %) tumors, with a sensitivity of 84.8 % (95 % CI, 70.2-94.3), specificity of 98.9 % (95 % CI, 97.5-99.7), positive predictive value of 87.5 % (95 % CI, 73.3-95.9), and negative predictive value of 98.6 % (95 % CI, 97.1-99.5). The sensitivity of IOTA simple rules was higher in postmenopausal women (91.7 % vs. 81.0 %), while the specificity was higher in premenopausal women (99.4 % vs. 95.8 %). Accuracy was 100 % in all ten pregnant women were assessed using these rules. Conclusion: In conclusion, in the hands of non-expert examiners who were trained thoroughly, IOTA simple rules are a simple and efficient tool for clinical practice in centers where expert radiologists in gynecology are not always available. The training program is simple and could be applied widely in other clinical centers. Further studies are necessary to evaluate the effectiveness of the IOTA simple rules in assessing ovarian tumors among pregnant women.

An innovative strategy to identify new targets for delivering antibodies to the brain has led to the exploration of the integrin family.

BACKGROUND: Increasing brain exposure of biotherapeutics is key to success in central nervous system disease drug discovery. Accessing the brain parenchyma is especially difficult for large polar molecules such as biotherapeutics and antibodies because of the blood-brain barrier. We investigated a new immunization strategy to identify novel receptors mediating transcytosis across the blood-brain barrier. METHOD: We immunized mice with primary non-human primate brain microvascular endothelial cells to obtain antibodies. These antibodies were screened for their capacity to bind and to be internalized by primary non-human primate brain microvascular endothelial cells and Human Cerebral Microvascular Endothelial Cell clone D3. They were further evaluated for their transcytosis capabilities in three in vitro blood-brain barrier models. In parallel, their targets were identified by two different methods and their pattern of binding to human tissue was investigated using immunohistochemistry. RESULTS: 12 antibodies with unique sequence and internalization capacities were selected amongst more than six hundred. Aside from one antibody targeting Activated Leukocyte Cell Adhesion Molecule and one targeting Striatin3, most of the other antibodies recognized ß1 integrin and its heterodimers. The antibody with the best transcytosis capabilities in all blood-brain barrier in vitro models and with the best binding capacity was an anti-αnß1 integrin. In comparison, commercial anti-integrin antibodies performed poorly in transcytosis assays, emphasizing the originality of the antibodies derived here. Immunohistochemistry studies showed specific vascular staining on human and non-human primate tissues. CONCLUSIONS: This transcytotic behavior has not previously been reported for anti-integrin antibodies. Further studies should be undertaken to validate this new mechanism in vivo and to evaluate its potential in brain delivery.

Long-Term Follow-Up Of Anti-Mullerian Hormone Levels After Laparoscopic Endometrioma Cystectomy.

Objective: The study aims to evaluate long-term ovarian reserve change by serum anti-Mullerian hormone (AMH) level and determine the factors that affect the changes after laparoscopic endometrioma cystectomy. Methods: In a prospective longitudinal study, 104 patients with unilateral (n=77) and bilateral (n=27) endometrioma underwent laparoscopic endometrioma cystectomy. AMH levels were measured preoperatively and at 1, 3, 6, and 12 months postoperatively. Multivariate linear regression analysis was performed to determine factors related to AMH level changes. Results: Median preoperative AMH levels significantly declined from 3.77 ng/mL to 1.60 ng/mL (P<0.001), 1.66 ng/mL (P<0.001), 1.67 ng/mL (P<0.001), and 1.72 ng/mL (P<0.001) at 1, 3, 6, and 12 months postoperatively, respectively. The rate of decrease in AMH was unchanged six months after surgery, 52.2%, 53.7%, 54.8% at 1, 3, 6 months, respectively, and declined to 43.2% at 12 months. Although most factors were associated with AMH level changes in monovariant linear regression, multivariant linear regression analysis showed only three factors that reached the statistical significance, including bilateral endometriomas, mean size of the endometrioma, and preoperative AMH levels. Conclusions: Serum AMH levels decline significantly after laparoscopic cystectomy of endometriomas but recovered at 12 months compared with the first 6 months with unilateral endometrioma. Bilateral endometriomas, size of the cyst, and preoperative AMH levels might independently affect AMH levels at 12 months after surgery.

Dinoprostone Vaginal Insert for Induction of Labor in Women with Low-Risk Pregnancies: A Prospective Study.

Background: Induction of labor (IOL) is a technique to establish vaginal delivery when the risks for continuing the pregnancy for mother or baby are higher than the risks of delivery. It is usually performed in high-risk pregnancies, but can also be beneficial in low-risk populations, as shown in the ARRIVE trial. Objective: To evaluate the effectiveness and safety of slow-release vaginal dinoprostone (prostaglandin E2 10 mg) for labor induction in women with low-risk pregnancies. Methods: A prospective study was performed at Hanoi Obstetrics and Gynecology Hospital, Vietnam. We recruited women with low-risk pregnancies from 39 weeks + 0 days to 40 weeks + 6 days of gestation and an unfavorable cervix. Women who participated received 10 mg intravaginal slow-release dinoprostone (Propess) for induction of labor. Labor, deliveries, and post-partum management were performed according to the local protocol. Results: From September 2020 to March 2021, 102 low-risk women were eligible to participate in the study. Among these women, 67.6% had vaginal deliveries, 6.9% had postpartum bleeding, and 3.9% experienced tachysystole. All newborns were healthy, with good APGAR scores. None of the women needed respiratory support or intensive care unit admission. All other maternal or fetal complications were explored. The rate of cesarean section was 3.8 higher in nulliparous than multiparous women and 2.2 times higher in women who did not receive epidural analgesia than in those who did. The risk of cesarean section increased if the time between labor induction and active labor was greater than 12.5 hours. Conclusion: Slow-release dinoprostone insert is safe and effective for the induction of labor in low-risk pregnant women. The risk of cesarean section was elevated in nulliparous patients and those who did not receive epidural analgesia during labor. As the time from labor induction to active labor increased, the risk of cesarean section increased.

It doesn't always pay to be fit: success landscapes.

Landscapes play an important role in many areas of biology, in which biological lives are deeply entangled. Here we discuss a form of landscape in evolutionary biology which takes into account (1) initial growth rates, (2) mutation rates, (3) resource consumption by organisms, and (4) cyclic changes in the resources with time. The long-term equilibrium number of surviving organisms as a function of these four parameters forms what we call a success landscape, a landscape we would claim is qualitatively different from fitness landscapes which commonly do not include mutations or resource consumption/changes in mapping genomes to the final number of survivors. Although our analysis is purely theoretical, we believe the results have possibly strong connections to how we might treat diseases such as cancer in the future with a deeper understanding of the interplay between resource degradation, mutation, and uncontrolled cell growth.

Non-Human Primate Blood-Brain Barrier and In Vitro Brain Endothelium: From Transcriptome to the Establishment of a New Model.

The non-human primate (NHP)-brain endothelium constitutes an essential alternative to human in the prediction of molecule trafficking across the blood-brain barrier (BBB). This study presents a comparison between the NHP transcriptome of freshly isolated brain microcapillaries and in vitro-selected brain endothelial cells (BECs), focusing on important BBB features, namely tight junctions, receptors mediating transcytosis (RMT), ABC and SLC transporters, given its relevance as an alternative model for the molecule trafficking prediction across the BBB and identification of new brain-specific transport mechanisms. In vitro BECs conserved most of the BBB key elements for barrier integrity and control of molecular trafficking. The function of RMT via the transferrin receptor (TFRC) was characterized in this NHP-BBB model, where both human transferrin and anti-hTFRC antibody showed increased apical-to-basolateral passage in comparison to control molecules. In parallel, eventual BBB-related regional differences were investigated in seven-day in vitro-selected BECs from five brain structures: brainstem, cerebellum, cortex, hippocampus, and striatum. Our analysis retrieved few differences in the brain endothelium across brain regions, suggesting a rather homogeneous BBB function across the brain parenchyma. The presently established NHP-derived BBB model closely mimics the physiological BBB, thus representing a ready-to-use tool for assessment of the penetration of biotherapeutics into the human CNS.

Tetravalent Bispecific Tandem Antibodies Improve Brain Exposure and Efficacy in an Amyloid Transgenic Mouse Model.

Most antibodies display very low brain exposure due to the blood-brain barrier (BBB) preventing their entry into brain parenchyma. Transferrin receptor (TfR) has been used previously to ferry antibodies to the brain by using different formats of bispecific constructs. Tetravalent bispecific tandem immunoglobulin Gs (IgGs) (TBTIs) containing two paratopes for both TfR and protofibrillar forms of amyloid-beta (Aß) peptide were constructed and shown to display higher brain penetration than the parent anti-Aß antibody. Additional structure-based mutations on the TfR paratopes further increased brain exposure, with maximal enhancement up to 13-fold in wild-type mice and an additional 4-5-fold in transgenic (Tg) mice harboring amyloid plaques, the main target of our amyloid antibody. Parenchymal target engagement of extracellular amyloid plaques was demonstrated using in vivo and ex vivo fluorescence imaging as well as histological methods. The best candidates were selected for a chronic study in an amyloid precursor protein (APP) Tg mouse model showing efficacy at reducing brain amyloid load at a lower dose than the corresponding monospecific antibody. TBTIs represent a promising format for enhancing IgG brain penetration using a symmetrical construct and keeping bivalency of the payload antibody.

Complement protein levels and MBL2 polymorphisms are associated with dengue and disease severity.

The complement system may be crucial during dengue virus infection and progression to severe dengue. This study investigates the role of MBL2 genetic variants and levels of MBL in serum and complement proteins in Vietnamese dengue patients. MBL2 genotypes (- 550L/H, MBL2 codon 54), MBL2 diplotypes (XA/XO, YA/XO) and MBL2 haplotypes (LXPB, HXPA, XO) were associated with dengue in the study population. The levels of complement factors C2, C5, and C5a were higher in dengue and dengue with warning signs (DWS) patients compared to those in healthy controls, while factor D levels were decreased in dengue and DWS patients compared to the levels determined in healthy controls. C2 and C5a levels were associated with the levels of AST and ALT and with WBC counts. C9 levels were negatively correlated with ALT levels and WBC counts, and factor D levels were associated with AST and ALT levels and with platelet counts. In conclusions, MBL2 polymorphisms are associated with dengue in the Vietnamese study population. The levels of the complement proteins C2, C4b, C5, C5a, C9, factor D and factor I are modulated in dengue patients during the clinical course of dengue.

Emerging manufacturers engagements in the COVID -19 vaccine research, development and supply.

The World Health Organization declared the COVID-19 disease as a pandemic requiring a rapid response. Through online search, direct communication with network members and an internal survey, engagements of developing countries' vaccine manufacturers' network members in the research and development of COVID-19 vaccines and their capacities in the manufacturing, fill-finish and distribution of vaccines were assessed. Currently, 19 network members engaged in research and development of COVID-19 vaccines, using six principal technology platforms. In addition, an internal survey showed that the number of vaccines supplied collectively by 37 members, in 2018-19, was about 3.5 billion doses annually. Almost a third of network members having vaccines prequalified by the World Health Organization comply with international regulations and mechanisms to distribute vaccines across borders. The use of existing manufacturing, fill-finish and distribution capabilities can support an efficient roll-out of vaccines against COVID-19, while maintaining supply security of existing vaccines for on-going immunization programmes.

Proinflammatory Cytokines Are Modulated in Vietnamese Patients with Dengue Fever.

The clinical outcome of dengue is due to a complex interplay between dengue virus (DENV) and host immune factors, including complement and cytokine systems. Proinflammatory cytokines are mainly produced by monocytes in response to infectious pathogens. This study investigated the levels of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1 beta (IL-1ß), and IL-12 in Vietnamese patients with dengue, and their correlations with the clinical outcome of dengue infection in 156 patients clinically classified as dengue without warning signs (DWS-, n = 87), dengue with warning signs (DWS+, n = 62), and severe dengue (SD, n = 7) patients as well as in 60 healthy controls (HCs). Serum TNF-α, IL-1ß, and IL-12 levels were quantified by enzyme-linked immunosorbent assay (ELISA). The results showed that TNF-α, IL-1ß, and IL-12 levels were significantly increased in dengue patients compared with HCs (p < 0.0001). TNF-α levels were significantly correlated with white blood cells and platelet counts (rs = 0.52, 0.2; p < 0.0001, p = 0.018, respectively). IL-1ß levels were correlated with red blood cells counts and the levels of aspartate aminotransferase and alanine aminotransferase (rs = 0.23, 0.21, 0.23; p = 0.004, 0.012, 0.005, respectively). The results suggest that these three proinflammatory cytokines are associated with the clinical outcome of dengue and could play roles in the pathogenesis of the disease.

Association of FCN2 polymorphisms and Ficolin-2 levels with dengue fever in Vietnamese patients.

BACKGROUND AND OBJECTIVE: The human ficolin-2, encoded by FCN2, recognizes pathogen-associated acetylated residues on their cell surfaces and activates the lectin complement cascade. This study aimed to investigate the contribution of human ficolin-2 and the functional FCN2 genetic variants in dengue virus (DENV) infection and in clinical progression. METHODS: FCN2 genetic polymorphisms in the promoter, intron 7 and exon 8 were genotyped in 279 patients with dengue fever and in 200 healthy controls by direct Sanger sequencing. The ficolin-2 levels were measured in serum samples by ELISA and correlated with clinical data. RESULTS: The frequencies of +6031GG, +6220GG and +6424TT genotypes were significantly higher in dengue patients compared to healthy controls indicating an increased risk of dengue fever. The SNPs rs11103563 (+6031A/G), rs7872508 (+6220 T/G), and rs7851696 (+6424G/T) significantly regulated ficolin-2 levels in dengue patients (P < 0.0001). Ficolin-2 levels were increased in patients with dengue and Dengue with Warning Signs (DWS) compared to healthy controls (P < 0.0001 and P = 0.038, respectively). Ficolin-2 levels were significantly increased after 10-14 days of admission in both dengue and DWS patients and then slightly decreased after three weeks of discharge, indicating that ficolin-2 levels were modulated during the progression of dengue fever. In addition, ficolin-2 levels were negatively correlated with AST levels and positively correlated with platelet counts. CONCLUSIONS: FCN2 polymorphisms are associated with dengue fever in the Vietnamese population. Ficolin-2 levels are modulated during the progression of dengue fever and correlated with clinical parameters and thus may play a possible role in the pathogenesis of DENV infection.

A population of dust-enshrouded objects orbiting the Galactic black hole.

The central 0.1 parsecs of the Milky Way host a supermassive black hole identified with the position of the radio and infrared source Sagittarius A* (refs. 1,2), a cluster of young, massive stars (the S stars3) and various gaseous features4,5. Recently, two unusual objects have been found to be closely orbiting Sagittarius A*: the so-called G sources, G1 and G2. These objects are unresolved (having a size of the order of 100 astronomical units, except at periapse, where the tidal interaction with the black hole stretches them along the orbit) and they show both thermal dust emission and line emission from ionized gas6-10. G1 and G2 have generated attention because they appear to be tidally interacting with the supermassive Galactic black hole, possibly enhancing its accretion activity. No broad consensus has yet been reached concerning their nature: the G objects show the characteristics of gas and dust clouds but display the dynamical properties of stellar-mass objects. Here we report observations of four additional G objects, all lying within 0.04 parsecs of the black hole and forming a class that is probably unique to this environment. The widely varying orbits derived for the six G objects demonstrate that they were commonly but separately formed.

An assessment of the impact of climate change on the distribution of the grey-shanked douc Pygathrix cinerea using an ecological niche model.

Climate change can have many negative impacts on wildlife species, and species with narrow distributions are more likely to be significantly affected. In this study, we used ecological niche modeling for species (MaxEnt software) as well as species occurrence data and climate variables to assess the impacts of climate change on the distribution of the grey-shanked douc-an endemic and rare primate species of Vietnam. We used climate data at the current time and two future times (2050 and 2070). Climate data were generated for two climate scenarios RCP4.5 and RCP8.5, together with three climate models ACCESS1-0, GFDL-CM3, and MPI-ESM-LR. We predicted that the distribution of the grey-shanked douc would be sharply reduced by the effects of climate change. The species' suitable distribution range in the future tended to shift toward the center of their current range and to higher mountainous areas. A larger suitable area, in particular highly suitable areas to the north and west of its current potential distribution range, would become less suitable or even unsuitable in 2050 and 2070. Kon Cha Rang Nature Reserve and Kon Ka Kinh National Park should be given priority in conservation of the grey-shanked douc because they now support important populations of the species and are in the highly suitable area remaining for the species in the future. The establishment of a new protected area for grey-shanked douc conservation should be considered in Kon Plong District, Kom Tum Province, which will be the center of the species distribution range.

Neopterin levels and Kyn/Trp ratios were significantly increased in dengue virus patients and subsequently decreased after recovery.

OBJECTIVES: During dengue fever, a pronounced gamma-interferon immune response produces neopterin and promotes tryptophan degradation by the enzyme indoleamine-2,3-dioxygenase 1 (IDO-1). Activated IDO-1 is indicated by an increased kynurenine to tryptophan ratio (Kyn/Trp) in patients. METHODS: Plasma levels of neopterin, kynurenine, and tryptophan were measured in 72 hospitalized dengue virus (DENV) patients and 100 healthy individuals. Plasma levels of neopterin, kynurenine, and tryptophan were also measured prospectively in a second cohort of 13 DENV patients; on the day of hospitalization, on day 2-3 at discharge, and 7-10 days after discharge. DENV RNA positivity was determined by qualitative and quantitative methodologies. RESULTS: DENV RNA-positive patients presented significantly higher levels of neopterin (mean 36.5nmol/l) and Kyn/Trp ratios (mean 102µmol/mmol) compared to DENV RNA-negative individuals. A significant correlation between neopterin levels and Kyn/Trp ratios was observed in both DENV RNA-positive (Spearman's rho=0.37, p< 0.01) and DENV RNA-negative (Spearman's rho=0.89, p<0.001) patients. Kyn/Trp ratios were negatively correlated with platelet counts (Spearman's rho=-0.43, p<0.01) and positively correlated with liver enzymes: AST (Spearman's rho=0.68, p<0.01) and ALT (Spearman's rho=0.51, p<0.05). In addition, the follow-up data presented a significant decrease in neopterin levels and Kyn/Trp ratios within 10 days after hospital entry. CONCLUSIONS: Neopterin levels and Kyn/Trp ratios were significantly increased in DENV patients and subsequently decreased after recovery.

Vitamin D receptor ApaI polymorphism associated with progression of liver disease in Vietnamese patients chronically infected with hepatitis B virus.

BACKGROUND: Vitamin D derivatives and their receptor (VDR) are potent modulators of immune responses in various diseases including malignancies as well as in metabolic and infectious disorders. The impact of vitamin D receptor polymorphisms on clinical outcomes of hepatitis B virus (HBV) infection is not well understood. This study aims to investigate the potential role of VDR polymorphisms (TaqI, FokI, ApaI, and BsmI) in Vietnamese HBV infected patients and to correlate these polymorphisms with the progression of HBV-related liver disease. METHODS: Four hundred forty-three HBV infected patients of the three clinically well-defined subgroups chronic hepatitis B (CHB, n = 183), liver cirrhosis (LC, n = 89) and hepatocellular carcinoma (HCC, n = 171) and 238 healthy individuals (HC) were enrolled. VDR polymorphisms were genotyped by DNA sequencing and in-house validated ARMS assays. Logistic regression models were applied in order to determine the association of VDR polymorphisms with manifest HBV infection as well as with progression of related liver diseases mulin different genetic models. RESULTS: The VDR ApaI CA genotype was less frequent in HCC than in CHB patients in different genetic models (codominant model, OR = 0.5, 95%CI = 0.3-0.84, P = 0.004; dominant model, OR = 0.46, 95%CI = 0.27-0.76, P = 0.0023). In the recessive model, the genotype ApaI AA was found more frequently among HCC compared to CHB patients (OR = 2.56, 95%CI = 1.01-6.48, P = 0.04). Similarly, the ApaI CA genotype was less frequent in HCC than in non-HCC group codominant model, OR = 0.6, 95%CI = 0.4-0.98, dominant model, P = 0.04 and OR = 0.6, 95%CI = 0.38-0.90, P = 0.017). The ApaI genotypes CA and AA was significantly associated with higher levels of liver enzymes, bilirubin, and HBV DNA (P < 0.05). No association between TaqI, FokI and BsmI polymorphisms and any clinical outcome as well as liver disease progression was found. CONCLUSIONS: Among the four investigated VDR polymorphisms, ApaI is associated with clinical outcome and liver disease progression in Vietnamese HBV infected patients.

Relativistic redshift of the star S0-2 orbiting the Galactic Center supermassive black hole.

The general theory of relativity predicts that a star passing close to a supermassive black hole should exhibit a relativistic redshift. In this study, we used observations of the Galactic Center star S0-2 to test this prediction. We combined existing spectroscopic and astrometric measurements from 1995-2017, which cover S0-2's 16-year orbit, with measurements from March to September 2018, which cover three events during S0-2's closest approach to the black hole. We detected a combination of special relativistic and gravitational redshift, quantified using the redshift parameter ϒ. Our result, ϒ = 0.88 ± 0.17, is consistent with general relativity (ϒ = 1) and excludes a Newtonian model (ϒ = 0) with a statistical significance of 5σ.

A heterologous prime-boost strategy for immunization against Dengue virus combining the Tetra DIIIC subunit vaccine candidate with the TV005 live-attenuated tetravalent vaccine.

The development of live-attenuated vaccines against Dengue virus (DENV) has been problematic. Dengvaxia, licensed in several countries where DENV is endemic, has shown low efficacy profiles and there are safety concerns prohibiting its administration to children younger than 9 years old, and the live-attenuated tetravalent vaccine (LATV) developed by NIAID has proven too reactogenic during clinical trialing. In this work we examined whether the combination of TV005, a LATV-derived formulation, with Tetra DIIIC, a subunit vaccine candidate based on fusion proteins derived from structural proteins from all four DENV serotypes, can overcome the respective limitations of these two vaccine approaches. Rhesus macaques were first primed with one or two doses of Tetra DIIIC and then boosted with TV005, following the time course of the appearance of virus-binding and neutralizing antibodies, and evaluating protection by means of a challenge experiment with wild-type viruses. Although the two evaluated prime-boost regimes were equivalent to a single administration of TV005 in terms of the development of virus-binding and neutralizing antibodies as well as the protection against viral challenge, both regimes reduced vaccine viremia to undetectable levels. Thus, the combination of Tetra DIIIC with TV005 offers a potential solution to the reactogenicity problems, which have beset the development of the latter vaccine candidate.

Isolation and Characterization of a Variant Manganese Resistant Strain of Saccharomyces cerevisiae.

　Manganese contamination in water is one of the most serious problems in Southeast Asian countries, including Vietnam. Bioremediation using microorganisms, especially from the brewing yeast Saccharomyces cerevisiae, is expected to be a useful technique to remove manganese from contaminated water. Yeast strain S. cerevisiae BY4741 as the wild-type strain and some manganese-accumulating mutants bred from BY4741 were examined for cell growth and manganese accumulation in YPD liquid medium containing various concentrations of Mn2+.　Variants accumulating larger concentrations of manganese were isolated by the repeated screening of survivors in YPD media containing10mM Mn2+. Manganese was accumulated by the yeast cells during growth, but the growth of BY4741 was retarded with increasing Mn2+ concentrations and almost inhibited at 15mM Mn2+. One variant isolate, named IM3, showed no retardation of growth up to 15 mM Mn2+ and could absorb over 4-fold more manganese than the BY4741 strain. Effects of culture temperature and pH on the growth and manganese accumulation were analyzed for IM3. Maximum accumulation was shown at 30℃, pH 6.0 while the optimal growth was shown at 37℃, pH 5.0 - 7.0. Interestingly, IM3 could grow a little at pH 9.0 when manganese was added to the culture media, while it could not grow without the addition of manganese.