Analogs of the marine alkaloid makaluvamines: synthesis, topoisomerase II inhibition, and anticancer activity

Twelve analogs of makaluvamines have been synthesized. These compounds were evaluated for their ability to inhibit the enzyme topoisomerase II. Five compounds were shown to inhibit topoisomerase catalytic activity comparable to two known topoisomerase II targeting control drugs, etoposide and m-AMSA. Their cytotoxicity against human colon cancer cell line HCT-116 and human breast cancer cell lines MCF-7 and MDA-MB-468 has been evaluated. Four makaluvamine analogs exhibited better IC(50) values against HCT-116 as compared to control drug etoposide. One analog exhibited better IC(50) value against HCT-116 as compared to m-AMSA. All 12 of the makaluvamine analogs exhibited better IC(50) values against MCF-7 and MDA-MB-468 as compared to etoposide as well as m-AMSA.     

Genomic analysis of Indian strains of Salmonella enterica subsp. enterica serovar Typhi indicates novel genetic repertoire for pathogenicity and adaptations

Molecular Biology Reports - In the era of emerging antibiotic resistance, Salmonella enterica subsp. enterica serovar Typhi the causative agent of typhoid, is a threat for healthcare systems in...     

Analysis of spatial distribution of genetic diversity and validation of Indian foxtail millet core collection

Foxtail millet [Setaria italica (L.) P. Beauv.] is an important small millet, grown as a short duration, drought tolerant crop across the world. This crop can be grown on wide ranges of soil conditions and has an immense potential for food and fodder in rainfed and arid regions of the India. In the present study, 31 primer pairs (27 SSR and 4 EST-SSR) were used to analyse the genetic diversity in 223 core collection accessions. Analysis resulted in detection of a total of 136 alleles with an average of 4.38 alleles per locus. Among these 136 alleles, 22 were rare, 70 were common and 44 were frequent. The PIC value ranged from 0.01 to 0.86 with an average of 0.31. The average number of observed alleles ranged from 2.0 (northern hills of India accessions) to 4.06 (exotic) with an average of 2.72. The mean Shannon’s Information Index ranged from 0.44 (northern hills of India) to 0.69 (exotic) with an average of 0.52. Pair-wise Fst values indicated little to moderate genetic differentiation among the group of accessions. UPGMA clustering grouped the accessions into two major groups while analysis for population substructure indicated presence of four subpopulations. However there was no statistically well supported grouping of the accessions based on eco-geographic specificities. The core collection designated here represented substantial genetic diversity at molecular level, hence may be a good source of diversity for use in foxtail improvement programs in the region.     

Few‐Layer Black Phosphorus Nanosheets as Electrocatalysts for Highly Efficient Oxygen Evolution Reaction

Black phosphorus (BP) is a new rediscovered layered material, which has attracted enormous interests in the field of electrocatalysis. Recent investigations reveal that bulk BP is a promising electrocatalyst for oxygen evolution reactions (OER), whereas its bulk crystal structure restricts sufficient active sites for achieving highly efficient OER catalytic performances. Toward this end, few‐layer BP nanosheets prepared by facile liquid exfoliation are applied as electrocatalysts and exhibit preferable electrocatalytic OER activity in association with structural robustness; subsequently, the dependence of current density and applied bias potential on the concentration of OH^? has also been uncovered. Most importantly, we are aware that reduction in the thickness of BP nanosheets would generate extra active sites from the ultrathin planar structure and complimenting to the electrocatalytic activities. It is further anticipated that the current work might provide further implementation about the OER performance of BP nanosheets, thereby, offering extendable availabilities for BP‐based electrocatalysts in constructing high‐performance OER devices.     

A highly efficient retroviral vector allows detection of the transforming activity of the human c-fps/fes proto-oncogene.

We have constructed an efficient new retroviral vector containing strong promoting elements derived from the Friend murine leukemia virus (F-MuLV) long terminal repeat (LTR) and have used the vector to demonstrate that overexpression of human c-fps/fes can transform established mouse cells. When a c-fps/fes cDNA was cloned into the vector, this viral DNA and the recovered virus induced very high levels of the c-fps/fes product NCP92 and tumorigenic transformation of NIH 3T3 cells. Compared with an isogenic vector under control of a Moloney MuLV-derived LTR, the vector driven by the F-MuLV LTR induced 3- to 10-times-higher levels of expression of c-fps/fes, a higher level of phosphotyrosine in cellular proteins, and a virus whose transforming activity was 2 orders of magnitude greater. We conclude (i) that normal c-fps/fes can induce morphologic transformation and that its transforming activity is a function of the level of expression of NCP92 and (ii) that the vector based on the F-MuLV LTR is more efficient than the vector driven by a Moloney MuLV LTR in inducing high levels of expression and measurable biological activity.     

Resistance Evolution against Host-directed Antiviral Agents: Buffalopox Virus Switches to Use p38-ϒ under Long-term Selective Pressure of an Inhibitor Targeting p38-α

Host-dependency factors have increasingly been targeted to minimize antiviral drug resistance. In this study, we have demonstrated that inhibition of p38 mitogen-activated protein kinase (a cellular protein) suppresses buffalopox virus (BPXV) protein synthesis by targeting p38-MNK1-eIF4E signaling pathway. In order to provide insights into the evolution of drug resistance, we selected resistant mutants by long-term sequential passages (P; n = 60) in the presence of p38 inhibitor (SB239063). The P60-SB239063 virus exhibited significant resistance to SB239063 as compared to the P60-Control virus. To provide mechanistic insights on the acquisition of resistance by BPXV-P60-SB239063, we generated p38-α and p38-ϒ (isoforms of p38) knockout Vero cells by CRISPR/Cas9-mediated genome editing. It was demonstrated that unlike the wild type (WT) virus which is dependent on p38-α isoform, the resistant virus (BPXV-P60-SB239063) switches over to use p38-ϒ so as to efficiently replicate in the target cells. This is a rare evidence wherein a virus was shown to bypass the dependency on a critical cellular factor under selective pressure of a drug.     

Quantitative trait loci mapping reveals pleiotropic effect for grain iron and zinc concentrations in wheat

Malnutrition because of the deficiency of minerals such as iron (Fe) and zinc (Zn) afflicts over 2 billion people worldwide. Wheat is a major staple crop, providing 20% of dietary energy and protein consumption worldwide. Breeding wheat with elevated levels of grain Zn and Fe concentrations (GZn and GFe) represents a significant opportunity to increase the intake of these micronutrients for the resource poor people who depend on it as a major source of dietary energy. Synthetic hexaploid wheats (SHWs) have large genetic variation for GZn and GFe, which can be exploited for developing wheat varieties with higher concentrations of these minerals. The objective of this study was to localise genomic regions associated with GZn and GFe, thousand kernel weight (TKW) and test weight (TW) in a mapping population derived from the cross of Seri M82 and the SHW CWI76364. Major quantitative trait loci (QTL) on chromosome 4BS were detected for GZn and GFe; the QTL explained up to 19.6% of the total phenotypic variation for GZn and showed pleiotropic effects on GFe. This indicates that simultaneous improvement of GZn and GFe is feasible. Three and five QTL for TW and TKW were detected, respectively. One of the QTL for TKW was also located on chromosome 4BS. Positive correlations between plant height and GZn/GFe were observed. The 4BS QTL is of great interest for breeding biofortified wheat by means of marker‐assisted selection.     

Attrition of TCR Vα7.2+ CD161++ MAIT Cells in HIV-Tuberculosis Co-Infection Is Associated with Elevated Levels of PD-1 Expression

Mucosal-associated invariant T (MAIT) cells are evolutionarily conserved antimicrobial MR1-restricted CD8⁺ T cells co-expressing the semi-invariant TCR Vα7.2, and are numerous in the blood and mucosal tissues of humans. MAIT cells appear to undergo exhaustion in chronic viral infections. However, their role in human immunodeficiency virus type 1 (HIV-1) mono-infection and HIV/tuberculosis (TB) co-infection have seldom been elaborately investigated. We conducted a cross-sectional study to investigate the frequencies and phenotypes of CD161⁺⁺CD8⁺ T cells among anti-retroviral therapy (ART)/anti-TB therapy (ATT) treatment-naïve HIV/TB co-infected, ART/TB treated HIV/TB co-infected, ART naïve HIV-infected, ART-treated HIV-infected patients, and HIV negative healthy controls (HCs) by flow cytometry. Our data revealed that the frequency of MAIT cells was severely depleted in HIV mono- and HIV/TB co-infections. Further, PD-1 expression on MAIT cells was significantly increased in HIV mono- and HIV-TB co-infected patients. The frequency of MAIT cells did not show any significant increase despite the initiation of ART and/or ATT. Majority of the MAIT cells in HCs showed a significant increase in CCR6 expression as compared to HIV/TB co-infections. No marked difference was seen with expressions of chemokine co-receptor CCR5 and CD103 among the study groups. Decrease of CCR6 expression appears to explain why HIV-infected patients display weakened mucosal immune responses.     

Molecular identification and in vitro screening of antagonistic bacteria from agricultural byproduct compost: Effect of compost on development and photosynthetic efficiency of tomato plant

The dynamics of mesophilic and thermophilic bacterial population of compost was studied. The bacteria population in the compost ranged from 10⁹ to 10⁵ CFU g^?1 and was found to be maximum during mesophilic phase, and then decreased during the thermophilic, the cooling and maturation phases. Assessment of culturable bacteria by 16S rDNA revealed phylogenetic lineage of different polymorphic class bacilli, γ, β-proteobacteria and actinobacteria. Bacterial isolates produced extracellular enzymes: proteases, cellulase, xylanase, pectinase, tannase and amylase. Among them, mesophilic bacteria exhibited xylanolytic (81.25 %) and cellulolytic (63 %) activity. Thermophilic bacteria showed cellulolytic (75 %) and xylanolytic (66.6 %) activity, but a few isolates also produced tannase and pectinase. All bacterial isolates were observed to cause inhibition of three isolates of Bacillus pumilus and one isolate each of Staphylococcus sciuri and Kocuria sp. The physiological effect of compost on shoot length, leaf size and fruit maturation of tomato have been evaluated; the compost (75 g/pot) improved these parameters as compared to known compost (SOM). The efficacy of compost and SOM on photochemistry of tomato leaves was studied, based on imaging-PAM of the chlorophyll fluorescence parameters. F_v/F_m and electron transport rate (ETR) were increased significantly in compost (75 g) amended pot within 30 days of growth. Likewise, highest Y (II) of photosystem II (PS II) yield was found in compost (75 g) pot in 15 days. The findings of this study proved that the compost comprising of various bacteria involved in degradation of substrates was found to be beneficial for enhancement of tomato growth and development.     

Production of ganoderic acid by Ganoderma lucidum RCKB-2010 and its therapeutic potential

The newly isolated basidiomycetous fungus, identified as Ganoderma lucidum RCKB-2010 was tested for production of ganoderic acid (GA) under submerged fermentation conditions. Production of GA under liquid static cultivation condition was found to be 2,755.88 mg L^?1 on the 25th day of incubation, whereas under shaking cultivation conditions the maximum production of GA was observed to be 373.75 mg L^?1. ¹H NMR analysis revealed clearly that the fungal extracts possessed a lanostane skeleton, confirming the presence of GA. Interestingly, GA was found to have potential to inhibit the proliferation of HeLa cells and U87 human glioma cells in a dose dependent manner. In addition, GA was also found to possess antibacterial activity, exhibiting a minimal inhibitory concentration of 0.25 mg mL^?1 against standard strains of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Staphylococcus epidermidis. GA produced in the present study holds potential as a potent anticancer agent.