Pathophysiological Scenario of Hematopoietic Disorders: A Comparative Study of Aplastic Anemia,Myelodysplastic Syndrome and Leukemia in Experimental Animals

The conversion of physiology to pathophysiology in hematological disorders viz: aplastic anemia, myelodysplastic syndrome (MDS) and leukemia in murine models was the subject of study in the present programme. Peripheral blood hemogram, spleno-somatic index, bone marrow smear study, cytochemical staining of marrow, cell release kinetics study during marrow explants culture, hematopoietic niche assessment, chromosomal aberration study, plasma membrane stability study of marrow cells, lysosomal membrane and mitochondrial membrane stability study and innate immune parameters were performed in the aplastic anemia, leukemia and MDS mouse model. In bone marrow aplasia, peripheral blood pancytopenia, marrow hypocellularity, decreased marrow cellular viability, deterioration of bone marrow hematopoiesis as well as hematopoietic microenvironment and extramedullary hematopoiesis were noticed. In addition, disruption of mitochondrial and lysosomal membrane integrity along with reduction of innate immune parameters were found in the hematopoietic suppressed condition. Surprisingly, no noticeable chromosomal aberration was found in the aplastic condition. Ineffective marrow hematopoiesis together with the disruption of hematopoietic microenvironment was observed in MDS. Also, extramedullary hematopoiesis, increased marrow cellular death, chromosomal aberration and loss of innate immunity were the common events. During leukemia, the number of functionally and structurally immature cells in the peripheral blood and bone marrow was increased together with malignant conversion of hematopoietic cells in the presence of malignancy supportive stromal microenvironment. Chromosomal aberration, decrease of cell mediated immunity with least mitochondrial apoptotic damage were also found in leukemic condition as well.     

Factors influencing the habitat choice of pangolins (Manis spp.) in low land of Nepal

Pangolins in the genus Manis are nocturnal, burrowing, insectivorous mammals listed as Critically Endangered or Endangered by the International Union for Conservation of Nature. Two species of pangolins are found in Nepal: the Chinese pangolin (Manis pentadactyla) and Indian pangolin (Manis crassicaudata). Despite having high conservation priority, little attention has been given to conservation interventions of both species of pangolins found in the Terai region (low land) of Nepal. The present study assesses habitat use and factors affecting the habitat choice of pangolins in low land (Terai), Nepal, focusing on Amritdharapani Community Forest of Chitwan district. Pangolin burrows were used as the indirect signs, and opportunistic sampling method was used to record the burrows. After the identification of all occurrence sites (burrows) in the field, random points were generated excluding the points where burrows were recorded for sampling of nonoccurrence sites. A total of thirty‐nine burrows were observed at elevations ranging from 301 to 413 masl. Burrows were frequently associated with northwest aspects, gentle slope (15°–20°), moderate canopy cover (51%–75%), red‐colored soil, and acidic soils with pH 6.5–7. The burrows were most common in areas with weak human disturbance (i.e., 1,500–1,700 m from settlements), 800–1,200 m from roads, and within 300 m from a water source and within 20 m from the nearest termitarium. Distance to settlement, distance to road, soil pH, and canopy cover were found to affect the habitat choice of pangolins in the study area.     

6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]thiazoles: Facile synthesis and comparative appraisal against tuberculosis and neglected tropical diseases

As part of a quest for backups to the antitubercular drug pretomanid (PA-824), we investigated the unexplored 6-nitro-2,3-dihydroimidazo[2,1-b][1,3]-thiazoles and related -oxazoles. The nitroimidazothiazoles were prepared in high yield from 2-bromo-4-nitroimidazole via heating with substituted thiiranes and diisopropylethylamine. Equivalent examples of these two structural classes provided broadly comparable MICs, with 2-methyl substitution and extended aryloxymethyl side chains preferred; albeit, S-oxidised thiazoles were ineffective for tuberculosis. Favourable microsomal stability data for a biaryl thiazole (45) led to its assessment in an acute Mycobacterium tuberculosis mouse model, alongside the corresponding oxazole (48), but the latter proved to be more efficacious. In vitro screening against kinetoplastid diseases revealed that nitroimidazothiazoles were inactive versus leishmaniasis but showed interesting activity, superior to that of the nitroimidazooxazoles, against Chagas disease. Overall, “thio-delamanid” (49) is regarded as the best lead.     

Differential reduction of reactive oxygen species by human tissue-specific mesenchymal stem cells from different donors under oxidative stress

Clinical trials using human Mesenchymal Stem Cells (MSCs) have shown promising results in the treatment of various diseases. Different tissue sources, such as bone marrow, adipose tissue, dental pulp and umbilical cord, are being routinely used in regenerative medicine. MSCs are known to reduce increased oxidative stress levels in pathophysiological conditions. Differences in the ability of MSCs from different donors and tissues to ameliorate oxidative damage have not been reported yet. In this study, for the first time, we investigated the differences in the reactive oxygen species (ROS) reduction abilities of tissue-specific MSCs to mitigate cellular damage in oxidative stress. Hepatic Stellate cells (LX-2) and cardiomyocytes were treated with Antimycin A (AMA) to induce oxidative stress and tissue specific MSCs were co-cultured to study the reduction in ROS levels. We found that both donor’s age and source of tissue affected the ability of MSCs to reduce increased ROS levels in damaged cells. In addition, the abilities of same MSCs differed in LX-2 and cardiomyocytes in terms of magnitude of reduction of ROS, suggesting that the type of recipient cells should be kept in consideration when using MSCs in regenerative medicine for treatment purposes.     

CXCL-16, IL-17, and bone morphogenetic protein 2 (BMP-2) are associated with overweight and obesity conditions in middle-aged and elderly women

Background

The current concept of overweight/obesity is most likely related to a combination of increased caloric intake and decreased energy expenditure. Widespread inflammation, associated with both conditions, appears to contribute to the development of some obesity-related comorbidities. Interventions that directly or indirectly target individuals at high risk of developing obesity have been largely proposed because of the increasing number of overweight/obese cases worldwide. The aim of the present study was to assess CXCL16, IL-17, and BMP-2 plasma factors in middle-aged and elderly women and relate them to an overweight or obese status. In total, 117 women were selected and grouped as eutrophic, overweight, and obese, according to anthropometric parameters. Analyses of anthropometric and circulating biochemical parameters were followed by plasma immunoassays for CXCL-16, IL-17, and BMP-2.

Results

Plasma mediators increased in all overweight and obese individuals, with the exception of BMP-2 in the elderly group, whereas CXCL16 levels were shown to differentiate overweight and obese individuals. Overweight and/or obese middle-aged and elderly individuals presented with high LDL, triglycerides, and glycemia levels. Anthropometric parameters indicating increased-cardiovascular risk were positively correlated with CXCL-16, BMP-2, and IL-17 levels in overweight and obese middle-aged and elderly individuals.

Conclusion

This study provides evidence that CXCL-16, IL-17, and BMP-2 are potential plasma indicators of inflammatory status in middle-aged and elderly women; therefore, further investigation of obesity-related comorbidities is recommended. CXCL16, in particular, could be a potential marker for middle-aged and elderly individuals transitioning from eutrophic to overweight body types, which represents an asymptomatic and dangerous condition.

     

Nitrogen‐Doped CNx/CNTs Heteroelectrocatalysts for Highly Efficient Dye‐Sensitized Solar Cells

The use of polydopamine as a nitrogen containing precursor to generate catalytically active nitrogen‐doped carbon (CN_x) materials on carbon nanotubes (CNTs) is reported. These N‐doped CN_x/CNT materials display excellent electrocatalytic activity toward the reduction of triiodide electrolyte in dye‐sensitized solar cells (DSSCs). Further, the influence of various synthesis parameters on the catalytic performance of CN_x/CNTs is investigated in detail. The best performing device fabricated with the CN_x/CNTs material delivers power conversion efficiency of 7.3%, which is comparable or slightly higher than that of Pt (7.1%) counter electrode‐based DSSC. These CN_x/CNTs materials show great potential to address the issues associated with the Pt electrocatalyst including the high cost and scarcity.     

Intra- and Intergenomic variation of Ploidy and Clonality characterize <Emphasis Type="Italic">Phytophthora capsici</Emphasis> on <Emphasis Type="Italic">Capsicum</Emphasis> sp. in Taiwan

Phytophthora capsici is a devastating disease of pepper (Capsicum sp.) in Taiwan causing complete loss of commercial fields. The objective of this study was to characterize genetic diversity for 38 newly collected isolates and three historical isolates. Analysis of data includes whole genome sequence for two new isolates and for two isolates collected previously in 1987 and 1995. In addition, 63 single nucleotide polymorphism loci were genotyped using targeted-sequencing, revealing 27 unique genotypes. Genotypes fell into three genetic groups: two of the groups contain 90% (n = 33) of the 2016 isolates, are triploid (or higher), are exclusively the A2 mating type and appear to be two distinct clonal lineages. The isolates from 2016 that grouped with the historical isolates are diploid and the A1 mating type. Whole genome sequence revealed that ploidy varies by linkage group, and it appears the A2 clonal lineages may have switched mating type due to increased ploidy. Most of the isolates were recently race-typed on a set of differential C. annuum, and although there was no direct correlation between virulence and ploidy, many of the triploid isolates were less virulent as compared to the historical diploid isolates. The implications for breeding resistant pepper and conducting population analyses are discussed.     

Hydrolytically degradable hyaluronic acid hydrogels with controlled temporal structures

Polysaccharides are being processed into biomaterials for numerous biological applications due to their native source in numerous tissues and biological functions. For instance, hyaluronic acid (HA) is found abundantly in the body, interacts with cells through surface receptors, and can regulate cellular behavior (e.g., proliferation, migration). HA was previously modified with reactive groups to form hydrogels that are degraded by hyaluronidases, either added exogenously or produced by cells. However, these hydrogels may be inhibitory and their applications are limited if the appropriate enzymes are not present. Here, for the first time, we synthesized HA macromers and hydrogels that are both hydrolytically (via ester group hydrolysis) and enzymatically degradable. The hydrogel degradation and growth factor release was tailored through the hydrogel cross-linking density (i.e., macromer concentration) and copolymerization with purely enzymatically degradable macromers. When mesenchymal stem cells (MSCs) were encapsulated in the hydrogels, cellular organization and tissue distribution was influenced by the copolymer concentration. Importantly, the distribution of released extracellular matrix molecules (e.g., chondroitin sulfate) was improved with increasing amounts of the hydrolytically degradable component. Overall, this new macromer allows for enhanced control over the structural evolution of the HA hydrogels toward applications as biomaterials.     

Antitumor studies. Part 5: Synthesis, antitumor activity, and molecular docking study of 5-(monosubstituted amino)-2-deoxo-2-phenyl-5-deazaflavins

Various novel 5-(monosubstituted amino)-2-deoxo-2-phenyl-5-deazaflavins derivatives have been synthesized by direct coupling of 5-deazaflavins and N-alkyl or aryl amines. The antitumor activities against human tumor cell lines CCRF-HSB-2 and KB cells have been investigated in vitro and many compounds showed promising potential antitumor activities with less cytotoxicities. AutoDock molecular docking into PTK (PDB code: 1t46) has been done for lead optimization of these compounds as potential PTK inhibitors. Some of the synthesized 5-(monosubstituted amino)-2-deoxo-2-phenyl-5-deazaflavins at the 5-position exhibited reasonable binding affinities into PTK with the hydrogen bond through their C(5)-NH moiety.     

The genome of the thermoacidophilic red microalga <Emphasis Type="Italic">Galdieria sulphuraria</Emphasis> encodes a small family of secreted class III peroxidases that might be involved in cell wall modification

We report the identification of a small family of secreted class III plant peroxidases (Prx) from the genome of the unicellular thermoacidophilic red alga Galdieria sulphuraria (Cyanidiaceae). Apart from two class I ascorbate peroxidases and one cytochrome c peroxidase, the red algal genome encodes four class III plant peroxidases, thus complementing the short list of algal cell wall peroxidases (Passardi et al. in Genomics 89:567–579, 2007). We have characterized the family gene structure, analyzed the extracellular space and cell wall fraction of G. sulphuraria for the presence of peroxidase activity and used shotgun proteomics to identify candidate extracellular peroxidases. For a detailed enzymatic characterization, we have purified a secreted peroxidase (GsPrx04) from the cell-free medium using hydrophobic interaction chromatography. The enzyme proved heat and acid-stable and exhibited an apparent molecular mass of 40 kDa. Comparative genomics between endolithically growing G. sulphuraria and a close relative, the obligatory aquatic, cell wall-less Cyanidioschyzon merolae, revealed that class III peroxidases only occur in the terrestrial microalga, thus supporting the key function of these enzymes in the process of land colonization. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. Nucleotide sequence database accession numbers: GsuAPX01 (EF589723), GsuAPX02 (EF589721), GsuCcP01 (EF589722), GsPrx01 (EF589724), GsPrx02 (EF589725), GsPrx03 (EF589726), and GsPrx04 (EF589727). The nomenclature of peroxidases has been adapted to PeroxiBase ().