Evolutionary analyses of the major variant surface antigen-encoding genes reveal population structure of Plasmodium falciparum within and between continents

Malaria remains a major public health problem in many countries. Unlike influenza and HIV, where diversity in immunodominant surface antigens is understood geographically to inform disease surveillance, relatively little is known about the global population structure of PfEMP1, the major variant surface antigen of the malaria parasite Plasmodium falciparum. The complexity of the var multigene family that encodes PfEMP1 and that diversifies by recombination, has so far precluded its use in malaria surveillance. Recent studies have demonstrated that cost-effective deep sequencing of the region of var genes encoding the PfEMP1 DBLα domain and subsequent classification of within host sequences at 96% identity to define unique DBLα types, can reveal structure and strain dynamics within countries. However, to date there has not been a comprehensive comparison of these DBLα types between countries. By leveraging a bioinformatic approach (jumping hidden Markov model) designed specifically for the analysis of recombination within var genes and applying it to a dataset of DBLα types from 10 countries, we are able to describe population structure of DBLα types at the global scale. The sensitivity of the approach allows for the comparison of the global dataset to ape samples of Plasmodium Laverania species. Our analyses show that the evolution of the parasite population emerging out of Africa underlies current patterns of DBLα type diversity. Most importantly, we can distinguish geographic population structure within Africa between Gabon and Ghana in West Africa and Uganda in East Africa. Our evolutionary findings have translational implications in the context of globalization. Firstly, DBLα type diversity can provide a simple diagnostic framework for geographic surveillance of the rapidly evolving transmission dynamics of P. falciparum. It can also inform efforts to understand the presence or absence of global, regional and local population immunity to major surface antigen variants. Additionally, we identify a number of highly conserved DBLα types that are present globally that may be of biological significance and warrant further characterization.     

SMARTp: A SMART design for nonsurgical treatments of chronic periodontitis with spatially referenced and nonrandomly missing skewed outcomes

This paper proposes dynamic treatment regimes (DTRs) as effective individualized treatment strategies for managing chronic periodontitis. The proposed DTRs are studied via SMARTp —a two-stage sequential multiple assignment randomized trial (SMART) design. For this design, we propose a statistical analysis plan and a novel cluster-level sample size calculation method that factors in typical features of periodontal responses such as non-Gaussianity, spatial clustering, and nonrandom missingness. Here, each patient is viewed as a cluster, and a tooth within a patient's mouth is viewed as an individual unit inside the cluster, with the tooth-level covariance structure described by a conditionally autoregressive structure. To accommodate possible skewness and tail behavior, the tooth-level clinical attachment level (CAL) response is assumed to be skew-t, with the nonrandomly missing structure captured via a shared parameter model corresponding to the missingness indicator. The proposed method considers mean comparison for the regimes with or without sharing an initial treatment, where the expected values and corresponding variances or covariance for the sample means of a pair of DTRs are derived by the inverse probability weighting and method of moments. Simulation studies are conducted to investigate the finite-sample performance of the proposed sample size formulas under a variety of outcome-generating scenarios. An R package SMARTp implementing our sample size formula is available at the Comprehensive R Archive Network for free download.     

Design and Synthesis of Selective Acetylcholinesterase Inhibitors: Arylisoxazole‐Phenylpiperazine Derivatives

In this work, a novel series of arylisoxazole‐phenylpiperazines were designed, synthesized, and evaluated toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Our results revealed that [5‐(2‐chlorophenyl)‐1,2‐oxazol‐3‐yl](4‐phenylpiperazin‐1‐yl)methanone ( 5c ) was the most potent AChE inhibitor with IC₅₀ of 21.85 μm . It should be noted that most of synthesized compounds showed no BChE inhibitory activity and [5‐(2‐fluorophenyl)‐1,2‐oxazol‐3‐yl](4‐phenylpiperazin‐1‐yl)methanone ( 5a ) was the most active anti‐BChE derivative (IC₅₀=51.66 μm ). Also, kinetic studies for the AChE and BChE inhibitory activity of compounds 5c and 5a confirmed that they have simultaneously bound to the catalytic site (CS) and peripheral anionic site (PAS) of both AChE and BChE. Furthermore, docking study of compound 5c showed desired interactions of that compound with amino acid residues located in the active and peripheral anionic sites. Compound 5c was also evaluated for its BACE1 inhibitory activity and demonstrated IC₅₀=76.78 μm . Finally, neuroprotectivity of compound 5c on Aβ‐treated neurotoxicity in PC12 cells depicted low activity.     

Synthesis and investigation of new Hesperadin analogues antitumor effects on HeLa cells

Hesperadin is one of the indolinones that was designed against the ATP-binding site of Aurora kinase. This molecule inhibits Aurora B kinase by phosphorylation of histone H3. In this study, new derivatives of Hesperadin containing an amide group in their structures were synthesized through sequential Ugi/palladium-catalyzed approach and in vitro antitumor activity of new compounds were evaluated by cell proliferation assay. The results show that compounds 6f, 6i, 6l, and 6o were dose-dependently inhibited in different concentrations, and IC50 values were between 35 and 43 nM. It seems that lipophilic substitution on the indolinone core with the ability to form additional hydrogen bond might lead to increased stability of structure and activity of new Hesperadin analogues.     

The effect of aflibercept and arsenic trioxide on the proliferation,migration and apoptosis of oral squamous cell carcinoma in vitro

Molecular Biology Reports - Aflibercept and arsenic trioxide drugs apply a cytotoxic effect on some human cancer cell lines. However, no more study has followed the effects of both drugs,...     

Modeling the adsorptive selectivity of carbon nanotubes for effective separation of CO2/N2 mixtures

Canonical Monte Carlo (CMC) simulations were carried out to investigate the behavior of CO₂ and N₂ mixtures upon adsorption on single walled carbon nanotubes (CNTs). In the simulation, all the particle–particle interactions between CO₂, N and C were modeled using Lennard-Jones (LJ) potential. To provide deep insight into the effect of pore width, temperature, pressure and bulk composition on the adsorption behavior of CO₂ /N₂ mixtures, five different CNTs [(6,6), (7,7), (8,8) (9,9) and (10,10) CNT] with diameters ranging from 0.807 to 1.35 nm, three temperatures (300 323 and 343 K), six pressures (0.15, 2, 4, 6, 8 and 10 MPa), and three bulk mole compositions of carbon dioxide (0.3 0.5 and 0.7) were tested. The results from all the simulation conditions investigated in this work show that CNTs preferentially adsorb carbon dioxide relative to nitrogen in a binary mixture. The results are consistent with the hypothesis that stronger interaction of one component with the nanotube surface results in a higher adsorption capacity compared to the other component. An optimized pore size of D = 8.07 nm corresponding to (6, 6) CNT, at T = 300 K and P = 0.15 MPa at a bulk mole composition of y_CO2 =0.3 was identified in which carbon nanotubes demonstrate the greatest selectivity for separation of carbon dioxide relative to nitrogen. In addition, it is worth pointing out that, under similar simulation conditions, CNTs exhibit higher selectivity compared to other carbon-based materials [carbon membrane polyimide (PI) and PI/multi-wall carbon nanotubes (MWCNTs)] for CO₂ adsorption. As a prototype, the selectivity of an equimolar mixture of CO₂ /N₂ for adsorption on (6, 6) CNTs at 300 K and 0.15 MPa reaches 9.68, which is considerably larger than that reported in carbon membrane. Therefore, it can be concluded that carbon nanotubes can act as a capable adsorbent for adsorption/desorption of CO₂ in comparison with other carbon-based materials in the literature.     

Exosomal noncoding RNAs: key players in glioblastoma drug resistance

Molecular and Cellular Biochemistry - Glioma, as one of the most severe human malignancies, is defined as the Central Nervous System’s (CNS) tumors. Glioblastoma (GBM) in this regard, is the...     

Synthesis and molecular structure of the all-trans- and the trans-cis-isomers of dichlorodimethyltin complexes of phosphoric triamides

Four new phosphoramidates with formula 4-RC₆H₄C(O)NHP(O)(NH(CH(CH₃)₂)₂, R = H (1), OCH₃ (2), CH₃ (3), Cl (4) and their diorganotin(IV) complexes with formula SnCl₂(CH₃)₂(X)₂, X = 1 (5), 2 (6), 3 (7) and 4 (8) were synthesized and characterized by NMR, IR spectroscopy and elemental analysis. The spectroscopic properties of complexes were compared with those corresponding ligands. The molecular structures for 5, 5·CH₃CN, 6·CH₃CN, 7 and 8 were established by X-ray diffraction analysis and shown that the tin atoms have a distorted octahedral coordination with trans-methyl groups. Two different all-trans and cis-trans isomers were obtained by changing the crystallization solvent system. The existence of CH₃CN in molecular packing of trans-cis isomers might be a packing factor governing the orientation of the ligands. Due to the presence of several hydrogen bond donors and acceptors on compounds, extended hydrogen-bonded networks were observed. The structure of 2 was also determined and possesses two crystallographically independent molecules in asymmetric unit. On forming complex 6·CH₃CN, the ligand 2 shows shortening of CO and P-N bond distances and increasing of PO bond length. Pseudopolymorphism of diorganotins in 5 and 5·CH₃CN is reported for the first time.