Correction to: SIGLECs and their contribution to tuberculosis Due to an oversight an error with respect to SNP number and associated polymorphism was crept in the abstract of the original version. The corrected version of the same should read as follows.

Exploration of biological phenomena of below-background natural radiation Abstract Worldwide, humans are exposed to a mean background radiation dose of about 2.4 mSv per year. Natural background radiation is a constant and ubiquitous environmental factor affecting all living things on this planet, and organisms have evolved in the presence of the natural radiation since the first forms of life appeared on Earth. However, its role in biology is still not completely understood. Here, we summarize the interesting biological responses in organism at below-background radiation and highlight recent development of the studies with molecular based analyses. To date, deprivation of natural background radiation has been carried out with shielding chambers or by conducting experiments in underground laboratories. In recent decades some research groups have reported changes to growth-related biological endpoints in microorganisms and mammalian cells under low-background radiation conditions. Moreover, new technologies, such as DNA microarray and next-generation sequencing, have begun to shed fresh light on the molecular mechanisms of these biological phenomena. Although there is no consistent explanation for the mechanisms so far, such studies might provide clues toward an understanding of the biological responses to natural background radiation.

Genetics and tyrosine kinase inhibitors of chronic myeloid leukemia Abstract Chronic myeloid leukemia (CML) is caused by a reciprocal translocation between 9q34 and 22q11, which produces a chimeric BCR-ABL oncogene located on the Philadelphia chromosome i.e. rearranged 22. The fusion gene implicates in the overexpression of tyrosine kinase through binding with ATP in signal transduction. Therefore, targeted drug development aimed at inhibitors of tyrosine kinase (TKI) and formulated imatinib, which resulted in miraculous disease free survival in majority of the CML patients. However, drug-resistance remained a problem due mainly to emergence of missense point mutations in and around the BCR-ABL kinase domain. Loss of its sensitivity to leukemic stem cells guided development of altered TKIs such as dasatinib, nilotinib, bosutinib and ponatinib—each having specific sensitivity to different amino acid residues (T315I, Y253F/H, E255K/V, M351T, G250E, F359C/V, H396R/P, M244V, E355G, F317L, M237I, Q252H/R, D276G, L248V, F486S), have been implicated in ~ 85% of CML. At chromosomal level, trisomy 8, isochromosome 17q, amplification of the Philadelphia chromosome, additional translocations and complex karyotype are described in TKI-resistant CML. Therefore, mutational events at kinase domain and additional chromosome abnormalities could be considered for development and initiation of TKI-therapy, and cross-talk of complex mutations could lead to formulation of personalized TKI.

Potential facet for prenatal arsenic exposure paradigm: linking endocrine disruption and epigenetics Abstract Environmental exposure to toxicants/heavy metals during critical periods of development can influence changes in embryo and germline of the offspring; and later on affect the disease susceptibility in adults. Exposures to toxic metals or endocrine disruptors are particularly harmful during fetal development. Arsenic, a well-known toxic metalloid and reproductive toxicant is one the major concern because of its adverse and delayed health effects. Considering the complex and numerous adverse health effects of prenatal arsenic exposure, it is very difficult to identify the one single mechanism for arsenic-induced toxicity. This is further complicated due to biphasic response reported where arsenic has very different effects at low and high doses particularly during early life exposure scenario. In this review, we are focusing on prenatal arsenic exposure and its lifelong adverse effects, and their association with endocrine disruption and epigenetic changes. We provide evidence that developmental arsenic exposure alters the functional fetal epigenome in a tissue-specific manner by alterations in DNA methylation patterns, histone modifications and changes in micro RNA. Arsenic as an endocrine disruptor also affects the reproductive potential of the organism. These adverse effects of arsenic could manifest directly through classical hormone imprinting or through irreversible epigenetic modulation. Thus, understanding the association of epigenetic changes and endocrine disruption by prenatal arsenic exposure may help unravel the crucial mechanism for the development of disease later in life.

SIGLECs and their contribution to tuberculosis Abstract Multiple host genes determine susceptibility or resistance to tuberculosis. In an exome-wide association study conducted among tuberculosis patients and their exposed but clinically asymptomatic household contacts, we found that the SNP rs61104666 located in the fifth exon of SIGLEC15 gene is associated with the disease. No other variant in SIGLEC15 has been reported previously to be associated with tuberculosis. The associated polymorphism results in a synonymous change (E292E) and therefore is unlikely to be involved in disease pathogenesis. Bioinformatic analysis of epigenetic marks in the genomic region reveals an enhancer mark present in lung and blood, downstream to the SIGLEC15 gene may harbor candidate causal SNPs which are in strong LD with the index SNP. This region overlaps with the 3′UTR region of the neighboring gene EPG5. EPG5 has role in autophagy, a phenomenon relevant to clearing of the infection. The region also harbors DNAse I sensitive sites with SNPs of low RegulomeDB score indicative of potential transcription binding sites. All these evidences suggest further exploration of the enhancer region to understand its role in disease manifestation.

Cancer stem cell fate determination: a nuclear phenomenon Abstract Cancer stem cells (CSCs) are a subset of cells within the tumor bulk, with a potential to undergo self-renewal, differentiation, proliferation and metastasis. Cumulative evidences suggest that mainly CSCs are responsible for tumor recurrences and resistance towards chemo- and radiotherapy. Unlike non-stem cancer cells, CSCs can undergo self-renewal and differentiation through asymmetric cell division (ACD) similar to normal stem cells. Asymmetric division results in two daughter cells: a structural and functional copy of the mother cell (CSC) and another one destined to undergo differentiation, non-cancer stem cell. Apart from the involvement of various polarity-determining factors, transcription factors and epigenetic regulators, micro-RNAs also play a crucial role in cell-fate decision making. Eventually, two daughter cells with distinct fates are produced with an unequal inheritance of differentiation-linked fate determinants, centrosomes and other stemness associated factors. Violation of the mechanisms leading to ACD will compromise the generation of both new CSCs and progenitor cells within the tumor. Thus, manipulation of asymmetric division of CSCs may introduce new strategies for dual targeting of CSCs and the tumor bulk. In this review, we discuss how CSCs play a critical role in almost all the events of tumorigenesis. Apart from that, we also delineate how these CSCs exploit the phenomenon of ACD during cancer relapses or tumor recurrences to regenerate the entire tumor. Therefore, in a nutshell this review highlights the therapeutic relevance of CSCs for successful elimination of cancer and suggests a novel improvisation in CSC-targeting by perturbing its ACD mechanisms.

Protective and therapeutic efficacy of pomegranate extracts in combination with 2-methoxyestradiol (2-ME) on S-180 ascitic tumour cells Abstract Pomegranate (PG), an edible fruit, is used for medicinal purposes. Pomegranate extracts (PGEs) exhibit antiproliferative and antineoplastic activities. Our earlier studies showed that, aqueous extracts of PG inhibit the rate of cell proliferation in tumour cells with steady decrease of mitotic index and sperm head abnormality. 2-Methoxyestradiol (2-ME), an antineoplastic and antiangiogenic agent has been widely used in preclinical research for cancer therapy. Given the importance of PGE, our studies have been extended to evaluate the anticancer and apoptotic activity of PGE and 2-ME in combination on Sarcoma-180 ascitic tumour bearing mice. To evaluate the efficacy and safety of combined effect of PGE and 2-ME on in vivo Sarcoma-180 tumour bearing mice, we have undertaken different tests to measure growth potentialities of the tumour. Our results revealed that combined effects of PGE and 2-ME significantly reduce the cell population of the tumour and elevation of the life span of the host with less toxic side effects.

A review on fluoride induced organotoxicity and genotoxicity in mammals and zebrafish Abstract Fluorine is a highly reactive electronegative element and naturally found in a combined form with other elements. In water, it remains as fluoride. It can be present in soil and air also. Beside the natural abundance, anthropogenic activities e.g. use of pesticides, fertilizers, sewage, coal burning etc. can increase the fluoride concentration in the environment. According to the World Health Organization, Permissible limit of fluoride in drinking water is 1.5 ppm (mg/L). When presence of fluoride in drinking water is within the permissible limit, it exerts beneficial effects on teeth, preventing dental caries; while, chronic exposure of fluoride beyond the permissible limit causes mild to severe form of dental and skeletal fluorosis. Apart from these hard tissues, chronic fluoride exposure beyond the permissible limit causes detrimental effect on soft tissues e.g. liver, kidney, spleen, gastrointestinal tract, reproductive organ etc. Studies also indicate that fluoride induces significantly genotoxic effect both in vivo and in vitro. Although various techniques have been developed for defluoridation of water but each one has limitations. Unfortunately, till date, there is no effective strategy of fluorosis treatment. In order to develop an effective therapeutic strategy, thorough understandings on the molecular mechanism of fluoride induced toxicity should be unravelled. This review enlightens both beneficial and toxic effects of fluoride emphasizing its molecular mechanism of action.

Comparative phylogenetics of some species of Ophioglossum L. (Ophioglossaceae: Pteridophyta) in India with comments on evolutionary significance of high palaeoploidy and rare morphological traits Abstract The genomic constitution of the genus Ophioglossum is complicated because of its being geologically ancient and of long evolutionary history. A lot of plants of the same and different species resemble each other as well as show significant differences among morphological characters among themselves. Many of the new species described have exhibited several unknown features not observed in any species of the genus so far. In this paper, we wish to emphasize that mere observations on shape and size of trophophyll (leaf) and rhizome, should not be taken reliably in delimiting different species of the genus Ophioglossum because of several variations already reported for many species. Preference should be given to exine ornamentation of spores as emphasized by the present study. Detailed observations on exine ornamentation of spores under SEM have offered precious and distinctive features; semi-tuberculate, beaded strings, and stripped exines are a few forms of spore ornamentations offering clear distinction among species. Long chains of circulate-alete (round alete) spores, sometimes linear tetrads as described hereunder in Ophioglossum aletum are novel features exclusively confined to this species. Comparative chromosome profiles of many species described earlier do not offer any significant support to the identity except in O. eliminatum, which has the lowest chromosome count (n = 90). This appears that since almost all species possess intraspecific polyploidy, the intragenomic variability must be loaded with interspecific hybridization contents including chromosomal aberrations. Quite possibly, this may be one of the reasons that homologous chromosomes rarely form trivalents and multivalents during early meiotic stages, despite the fact that palaeoautoploidy must have resulted in copying homologous chromosomes. In recent years, repeated phylogenetic analysis of chloroplast rbcL have revealed that many species in India appear to be offshoots of a vulgatum clade which are likely to be the hybridization products involving O. costatum, O. vulgatum, O. reticulatum, and also including of other interspecific hybridizations. It is remarkable to mention that some of the new taxa published by us, viz. O. eliminatum, O. indicum, O. aletum and O. chalonerii (unpublished), explicitly show distinct phylogenetic relationship maintaining independent genomic identity. Furthermore, each new species shows some rare uniquely confined trait not possessed by any other species of the genus. These morphological traits also suggest that the plants may be expressing extremely rare genic-combinations which might have been brought forth due to autopolyploidy and/or allopolyploidy (hybridizations) during the past few decades. Obviously, we will need a multidisciplinary approach (morphological, anatomical, biochemical) in order to identify different species of Ophioglossum with new and unusual genomic identity and also to understand possible evolutionary mechanisms undergoing within the genome.

Adaptation and diversification of venomous snake proteins Abstract According to the World Health Organization, approximately 1.8–2.7 million people worldwide suffer from venomous snake bites each year and at least 138,000 of these incidents are fatal. Whereas, snakebite envenoming poses a serious threat to public health, yet the snake venom toxins endow several pharmacological effects, including presynaptic neurotoxicity, myotoxicity, and cardiotoxicity, as well as anticoagulant, hemolytic, hemorrhagic, edema-inducing, and platelet aggregation-inhibiting effects. Duplication and mutation of the genes encoding these toxins play an important role in generating molecular diversity. Curiously, venomous snakes are not lethal to the viper itself because the viper’s resistance against its own venom. However, endogenous inhibitor proteins evolutionarily acquired by venomous snakes to protect themselves have not yet been fully characterised because it is unclear how to inhibit for target toxin due to the lack of information including mutation analysis and the three-dimensional structures of the inhibitors. This review provides an overview of endogenous inhibitors of venomous snake as regulation systems for the toxin proteins. Recently, we isolated some inhibitors targeting different toxins from the sera of the Japanese vipers. We investigated the evolution of these endogenous inhibitors, which have been significantly influenced by positive selection. Directional mutagenesis, where mutation hotspots are found in genes encoding molecular surface proteins and functional domains of these proteins, acts as a diversifying mechanism for the exquisite biological targeting necessary to protect the host from its own venom.