Collateral Damage Occurs When Using Photosensitizer Probes to Detect or Modulate Nucleic Acid Modifications.

Nucleic acids are chemically modified to fine-tune their properties for biological function. Chemical tools for selective tagging of base modifications enables new approaches; the photosensitizers riboflavin and anthraquinone were previously proposed to oxidize N6 -methyladenine (m6 A) or 5-methylcytosine (5mdC) selectively. Herein, riboflavin, anthraquinone, or Rose Bengal were allowed to react with the canonical nucleosides dA, dC, dG, and dT, and the modified bases 5mdC, m6 A, 8-oxoguanine (dOG), and 8-oxoadenine (dOA) to rank their reactivities. The nucleoside studies reveal that dOG is the most reactive and that the native nucleoside dG is higher or similar in reactivity to 5mdC or m6 A; competition in both single- and double-stranded DNA of dG vs. 5mdC or 6mdA for oxidant confirmed that dG is favorably oxidized. Thus, photosensitizers are promiscuous nucleic acid oxidants with poor chemoselectivity that will negatively impact attempts at targeted oxidation of modified nucleotides in cells.

Model Updating for Nam O Bridge Using Particle Swarm Optimization Algorithm and Genetic Algorithm.

Vibration-based structural health monitoring (SHM) for long-span bridges has become a dominant research topic in recent years. The Nam O Railway Bridge is a large-scale steel truss bridge located on the unique main rail track from the north to the south of Vietnam. An extensive vibration measurement campaign and model updating are extremely necessary to build a reliable model for health condition assessment and operational safety management of the bridge. The experimental measurements are carried out under ambient vibrations using piezoelectric sensors, and a finite element (FE) model is created in MATLAB to represent the physical behavior of the structure. By model updating, the discrepancies between the experimental and the numerical results are minimized. For the success of the model updating, the efficiency of the optimization algorithm is essential. Particle swarm optimization (PSO) algorithm and genetic algorithm (GA) are employed to update the unknown model parameters. The result shows that PSO not only provides a better accuracy between the numerical model and measurements, but also reduces the computational cost compared to GA. This study focuses on the stiffness conditions of typical joints of truss structures. According to the results, the assumption of semi-rigid joints (using rotational springs) can most accurately represent the dynamic characteristics of the truss bridge considered.

Identification of novel mutations in BCKDHB and DBT genes in Vietnamese patients with maple sirup urine disease.

BACKGROUND: Maple sirup urine disease (MSUD) is an autosomal recessive inherited metabolic disorder. The disease-causing mutations can affect the BCKDHA, BCKDHB, and DBT genes encoding for the E1α, E1ß, and E2 subunits of the multienzyme branched-chain α-keto acid dehydrogenase (BCKDH) complex. In the present study, novel pathogenic variants in BCKDHB and DBT genes were identified in three Vietnamese families with MSUD. METHODS: Three newborn patients from three unrelated Vietnamese families were diagnosed with MSUD at the Metabolic Clinic, National Hospital of Pediatrics. Blood samples of 11 relatives from two generations of the three families diagnosed with MSUD were analyzed using exome and Sanger sequencing analyses. RESULTS: Novel pathogenic variants in BCKDHB (c.1103C>T, c.989A>G, and c.704G>A), and DBT (c.263_265delAAG) genes were identified in three pediatric patients with MSUD. CONCLUSIONS: We have identified novel pathogenic variants in the MSUD-related genes in the pedigree of the three patient's families. Our findings expand the mutational spectrum of MSUD and provide the scientific basis for genetic counseling for the patient's families.

Colocalization of m6A and G-Quadruplex-Forming Sequences in Viral RNA (HIV, Zika, Hepatitis B, and SV40) Suggests Topological Control of Adenosine N 6-Methylation.

This Outlook calls attention to two seemingly disparate and emerging fields regarding viral genomics that may be correlated in a way previously overlooked. First, we describe identification of conserved potential G-quadruplex-forming sequences (PQSs) in viral genomes relevant to human health. Studies have demonstrated that PQSs are highly conserved and can fold to G-quadruplexes (G4s) to regulate viral processes. Key examples include G4s as a countermeasure to the host's immune system or G4-guided regulation of replication or transcription. Second, emerging data are discussed concerning the epitranscriptomic modification N 6-methyladenosine (m6A) in viral RNA installed by host proteins in a consensus sequence favoring 5'-GG(m6A)C-3'. The proposed pathways by which m6A is written, read, and erased in viral RNA genomes and the impact this has on viral replication are described. The structural reason why certain sites are selected for modification while others are not is still mysterious. Finally, we discuss our new observations regarding these previous sequencing data that identify m6A installation within the loops of two-tetrad PQSs in the RNA genomes of the Zika, HIV, hepatitis B, and SV40 viruses. We hypothesize that conserved viral PQSs can provide a framework (sequence and/or structural) for m6A installation. We also discuss literature sources suggesting that PQSs as sites of RNA modification could be a general phenomenon. We anticipate our observations will provide ample opportunities for exciting discoveries regarding the interplay between G4 structures and epitranscriptomic modifications of RNA.

Central Fibroblast Growth Factor 21 Browns White Fat via Sympathetic Action in Male Mice.

Fibroblast growth factor 21 (FGF21) has multiple metabolic actions, including the induction of browning in white adipose tissue. Although FGF21 stimulated browning results from a direct interaction between FGF21 and the adipocyte, browning is typically associated with activation of the sympathetic nervous system through cold exposure. We tested the hypothesis that FGF21 can act via the brain, to increase sympathetic activity and induce browning, independent of cell-autonomous actions. We administered FGF21 into the central nervous system via lateral ventricle infusion into male mice and found that the central treatment increased norepinephrine turnover in target tissues that include the inguinal white adipose tissue and brown adipose tissue. Central FGF21 stimulated browning as assessed by histology, expression of uncoupling protein 1, and the induction of gene expression associated with browning. These effects were markedly attenuated when mice were treated with a ß-blocker. Additionally, neither centrally nor peripherally administered FGF21 initiated browning in mice lacking ß-adrenoceptors, demonstrating that an intact adrenergic system is necessary for FGF21 action. These data indicate that FGF21 can signal in the brain to activate the sympathetic nervous system and induce adipose tissue thermogenesis.

Leprosy in French Polynesia. The possible impact of multidrug therapy on epidemiological trends.

In 1982, following the recommendations of a WHO study group, multidrug therapy (MDT) was introduced into French Polynesia to treat all patients suffering from active leprosy, and--only on request--those still on dapsone monotherapy. After 5 years, a clear-cut decrease of prevalence and mean annual detection rates for leprosy (except for detection rates among children aged less than 15 years, many of such cases being detected early by increased household contact training) has been observed. There was also a decrease in the proportion of newly detected cases with disabilities. During the 21-year period preceding the introduction of MDT into the control programme, mean annual detection rates for leprosy had remained stable, and this led to the consideration that such a decrease was due neither to the natural decline of the disease nor to the economic improvement of the country. Our results, together with the fact that, to date, the relapse rate was nil in the Polynesian patients put on MDT, strongly suggest that the implementation of MDT has resulted in a decrease of detection rates for leprosy which may be a consequence of a decrease in the transmission of the disease.

A comparative study of detection methods for evaluation of microfilaremia in lymphatic filariasis control programmes.

The evaluation of microfilaremia (mf) was performed in 96% of the population aged 15 years or more in a village of Moorea, one of the Society Islands in French Polynesia. Finger-prick and venous blood samples were collected simultaneously from 782 individuals in order to compare the results obtained by the standard blood film method and the membrane filtration technique. Of the 782 blood-sampled inhabitants 69 (8.8%) were found mf positive. 39 (5%) were mf positive by both methods and 30 were mf positive by the membrane filtration technique only. In these latter 30 carriers the geometric mean mf count was 19.7 mf/ml, significantly lower than that of 651.1 mf/ml in the 39 carriers positive by both techniques. Using the membrane filtration technique, the mf carrier prevalence rate increased from 1.9% in the youngest age group (15-19 years) to 16.9% in the oldest (< or = 60 years) while using the blood film method, it increased from 1.3% to 12.7%. Roughly, when using the membrane filtration technique, the mf carrier prevalence rate was 1.77 higher than that found using the blood film method, considering either the whole population or successive age-groups. Moreover, when using the blood film method in the 40 years and more age group, the mf carrier prevalence rate was 10%, a proportion similar to the 8.8% prevalence rate determined by the membrane filtration technique in the whole population. Further studies are planned to assess whether the last finding may be confirmed in other Polynesian populations.(ABSTRACT TRUNCATED AT 250 WORDS)

Periodicity of Wuchereria bancrofti var. pacifica filariasis in French Polynesia.

In 1992, a study on microfilaremia periodicity was carried out on 12 Wuchereria bancrofti carriers in the Marquesas islands. Blood samples were collected simultaneously every 4 hours during a 48 hour period by finger-prick and venipuncture for determination of microfilaremia by both blood film and membrane filtration technique methods, and for determination of antigenemia. The membrane filtration results showed no significant nycthemeral variations between the microfilaria densities at hours 16:00, 20:00, 24:00, 04:00, 08:00 and 12:00. Conversely, the blood film method showed a significant difference between the microfilaria densities: the microfilaremia was higher during the day (12:00-20:00 hours) than during the night (24:00-08:00 hours). As for antigenemia, using Og 4 C3 monoclonal antibody, there was no significant fluctuation during 48 hours. These results confirm that W. bancrofti var. pacifica is subperiodic and diurnal in French Polynesia. In particular, they substantiate the validity of examining venous blood by the membrane filtration technique as the judgment criterion of choice in therapeutic trials and of examining capillary blood during peak hours by the blood film method for evaluating the endemic level in a population.