2′-OH of mRNA are critical for the binding of its codons at the 40S ribosomal P site but not at the mRNA entry site

The roles of 2′-OH groups in the binding of mRNA to human ribosomes were studied using site-directed cross-linking. We found that both mRNA and mDNA analogues bearing a cross-linker can modify ribosomal proteins (rps) S3e and S2e at the mRNA entry site independently on tRNA presence, but only mRNA analogues were capable of a tRNA^Phe-dependent binding to human ribosomes and cross-linking to rpS26e in the mRNA binding centre. Thus, 2′-OH groups of mRNA are unimportant for binding at the entry site but they are crucial for codon-anticodon interactions at the P site, implying the existence of mRNA-ribosome contacts that do not occur in bacteria.     

Race,Ethnicity and Ancestry in Unrelated Transplant Matching for the National Marrow Donor Program: A Comparison of Multiple Forms of Self-Identification with Genetics

We conducted a nationwide study comparing self-identification to genetic ancestry classifications in a large cohort (n = 1752) from the National Marrow Donor Program. We sought to determine how various measures of self-identification intersect with genetic ancestry, with the aim of improving matching algorithms for unrelated bone marrow transplant. Multiple dimensions of self-identification, including race/ethnicity and geographic ancestry were compared to classifications based on ancestry informative markers (AIMs), and the human leukocyte antigen (HLA) genes, which are required for transplant matching. Nearly 20% of responses were inconsistent between reporting race/ethnicity versus geographic ancestry. Despite strong concordance between AIMs and HLA, no measure of self-identification shows complete correspondence with genetic ancestry. In certain cases geographic ancestry reporting matches genetic ancestry not reflected in race/ethnicity identification, but in other cases geographic ancestries show little correspondence to genetic measures, with important differences by gender. However, when respondents assign ancestry to grandparents, we observe sub-groups of individuals with well- defined genetic ancestries, including important differences in HLA frequencies, with implications for transplant matching. While we advocate for tailored questioning to improve accuracy of ancestry ascertainment, collection of donor grandparents’ information will improve the chances of finding matches for many patients, particularly for mixed-ancestry individuals.     

Recent methods of drought stress tolerance in plants

In the climate change scenario the drought has been diagnosed as major stress affecting crop productivity. This review demonstrates some recent findings on the amelioration of drought stress. Nanoparticles, synthetic growth regulators viz. Trinexapac-ethyl, and Biochar addition helps to economize the water budget of plants, enhances the bioavailability of water and nutrients as well as overcomes drought induced osmotic and oxidative stresses. Besides ABA, SA and JA are also involved in inducing tolerance to drought stress through modulation of physiological and biochemical processes in plants. Plant growth promoting rhizobacteria (PGPR) offer new opportunities in agricultural biotechnology. These beneficial microorganisms colonize the rhizosphere/endo-rhizosphere of plants and impart drought tolerance by improving root architechture, enhancing water use efficiency, producing exopolysaccharides, phytohormones viz, ABA, SA and IAA and volatile compounds. Further PGPR also play positive role in combating osmotic and oxidative stresses induced by drought stress through enhancing the accumulation of osmolytes, antioxidants and upregulation or down regulation of stress responsive genes. In transgenic plants stress inducible genes enhanced abiotic stress tolerance by encoding key enzymes regulating biosynthesis of compatible solutes. The role of genes/cDNAs encoding proteins involved in regulating other genes/proteins, signal transduction process and strategies to improve drought stress tolerance have also been discussed.     

Deformed Wing Virus Implicated in Overwintering Honeybee Colony Losses

The worldwide decline in honeybee colonies during the past 50 years has often been linked to the spread of the parasitic mite Varroa destructor and its interaction with certain honeybee viruses. Recently in the United States, dramatic honeybee losses (colony collapse disorder) have been reported; however, there remains no clear explanation for these colony losses, with parasitic mites, viruses, bacteria, and fungal diseases all being proposed as possible candidates. Common characteristics that most failing colonies share is a lack of overt disease symptoms and the disappearance of workers from what appears to be normally functioning colonies. In this study, we used quantitative PCR to monitor the presence of three honeybee viruses, deformed wing virus (DWV), acute bee paralysis virus (ABPV), and black queen cell virus (BQCV), during a 1-year period in 15 asymptomatic, varroa mite-positive honeybee colonies in Southern England, and 3 asymptomatic colonies confirmed to be varroa mite free. All colonies with varroa mites underwent control treatments to ensure that mite populations remained low throughout the study. Despite this, multiple virus infections were detected, yet a significant correlation was observed only between DWV viral load and overwintering colony losses. The long-held view has been that DWV is relatively harmless to the overall health status of honeybee colonies unless it is in association with severe varroa mite infestations. Our findings suggest that DWV can potentially act independently of varroa mites to bring about colony losses. Therefore, DWV may be a major factor in overwintering colony losses.Deformed wing virus (DWV), acute bee paralysis virus (ABPV), and black queen cell virus (BQCV) are single-stranded positive-sense RNA viruses of the order Picornavirales and are regularly detected in honeybee populations in the United Kingdom (1). ABPV has been assigned to the family Dicistroviridae and is known to follow a classic acute-type infection strategy since relatively low loads (10³ to 10⁶ viruses per honeybee) can rapidly translate into overt symptoms of paralysis and ultimately death for the honeybee, depending on the mode of transmission (6, 33). ABPV shares >92% sequence homology with other members of the family Dicistroviridae, Kashmir bee virus and Israeli acute paralysis virus, across the eight conserved domains of the RNA-dependent RNA polymerase gene, and it has been proposed that these viruses have recently diverged and are variants of each other (7). Advances in the study of this proposed ABPV complex is revealing the significant impact these viruses may have on honeybee colonies on a global scale. For example, a recent study in the United States has observed a correlation between Israeli acute paralysis virus and colony collapse disorder (17). That said, other agents, including bacteria and microsporidia, have also been proposed as important factors in the onset of colony loss (25, 27).BQCV is similar to ABPV in that it, too, follows a typical acute infection strategy. This virus is known to infect honeybee queen cell larvae, causing the larvae to discolor and die (5). It has been shown to be associated with the microsporidian Nosema apis (4) although whether N. apis has a direct role in the transmission of this virus still needs to be determined. Both ABPV and BQCV have been detected in worker honeybees and pupae (38), and the viruses are transmitted orally, via food and feeding activities (14). BQCV has also been detected in queen honeybees (13), suggesting that vertical transmission is also important for this virus. Both BQCV (12) and ABPV (38) have been detected within the varroa mite; however, only ABPV (9) has been shown to be vectored by varroa mites and has been found associated with dead colonies infested with varroa mites in Germany, Russia, and the United States (1). Later modeling work (33) indicated that very large (10,000+) mite populations are required to kill a colony since it is difficult for ABPV to become established among the bee population due to its high virulence.DWV is currently designated as a member of the unassigned genus Iflavirus within the order Picornavirales. It is generally considered as less virulent than ABPV or Kashmir bee virus, but it is known to cause overt symptoms of wing deformities in developing honeybees, resulting in emerging honeybees that are unable to fly and die shortly (5). It is also speculated that a cloud of DWV sequence variants exists that have evolved from a common ancestor. This is due to the high sequence similarities DWV isolates share with Kakugo virus and Varroa destructor virus within the RNA-dependent RNA polymerase gene, yet differences in virus epidemiology and pathological effects distinguish them from each other (29). DWV has been detected in worker honeybees, pupae, larvae, drones, and queens (15, 18, 20) as well as within the varroa mite (38, 43) and more recently the mite Tropilaelaps mercedesae (21), implying a range of horizontal and vertical transmission routes. Despite their global occurrence, it is generally accepted that DWVs play a secondary role in the causes of honeybee disease compared to their parasitic and bacterial counterparts as the viruses routinely reside at low levels in colonies, with symptomatic infections being rare (5). Moreover, multiple variants with differing infection strategies can account for a lack of discernible symptoms.Whether these viruses follow a persistent, latent, inapparent, or progressive infection strategy still remains unclear. Persistent (often called chronic) infections imply that the rate of infection within a host is in balance with the reproduction rate of the infected cell type or host itself. This is achieved through a combination of changing virus replication and host immune responses. Latent infections occur when the virus lies dormant within the host (replication inactive) until activation by defined stimuli. Progressive infections are caused by viruses that enter the host cell and replicate undetected for many cellular generations over many years before manifesting overt or acute symptoms. These three infection strategies all evade the host immune system, which results in the inability of the host to fully expel the virus, and this inability is often lethal. Inapparent (often referred to as covert) infections are indicative of a highly evolved relationship between the virus and natural host. Moreover, these infections are distinct in that the natural host can eventually clear itself from this short-term infection (19). Infections of DWV are often described as inapparent (15); however, Yue et al. (44) have suggested that a distinction should be made between “true inapparent” and their newly defined “covert infection” based on the long-term nature of DWV infection in honeybee colonies and on the nature of its transmission. This conclusion is congruent with current knowledge that traditional serological screening methods for DWV have limitations in their sensitivity (20). Therefore, the presence and duration of DWV within colonies have often been underestimated using serological assays as the overt symptoms of the deformed wing phenotype (>10¹¹ virions per honeybee) are short-lived. Advances in virus detection methodologies have enabled the development of more sensitive techniques, such as PCR, and this has demonstrated that DWV persists for longer periods within colonies (38). However, based on the current research evidence, a case could be made that DWV actually follows the classic persistent infection strategy.DWV is thought to have an intricate relationship with varroa mites such that immunosuppression of the honeybee pupae by the mites results in increased DWV amplification when the honeybees are exposed to other pathogens (42). It has additionally been shown that the number of mites parasitizing honeybee pupae is positively correlated with the probability of their developing malformed wings (10). Other findings indicate that DWV replication within the mite and subsequent transmission to developing honeybees lead to the increased likelihood of the bees'' emerging with wing deformities (24, 43). Taken together, the expectation is that DWV-associated colony collapse would typically occur in the presence of a large (>2,000) varroa mite infestation carrying high levels of DWV and with a high proportion of deformed honeybees. While the effect of varroa mite-induced DWV disease is well recognized, i.e., wing deformities coupled with downregulation of immunity-related genes and antimicrobial peptides (36, 42) and impaired learning behavior (28), the impact of non-varroa mite-vectored DWV within asymptomatic honeybees still needs to be realized. Moreover, it was recently reported that varroa mite-free bumblebees that tested positive for DWV actually showed symptoms of DWV infection (23). Even though these bumblebees were in close proximity to DWV-infected and varroa mite-infested honeybee colonies, it is evidence that the dependency of DWV on varroa mite vectoring for a symptomatic infection (manifested as classic wing deformities or other symptoms) may not be as critical as previously thought.The purpose of this study was to investigate asymptomatic viral dynamics within husbanded honeybee colonies over an annual cycle. We set out to observe the relationship, if any, between virus infections, varroa mite parasitism and vectoring, honeybee colony health, and colony longevity. For the first time, a quantitative analysis of three picorna-like honeybee viruses over the course of a year was undertaken for DWV, ABPV, and BQCV.     

MET and PI3K/mTOR as a Potential Combinatorial Therapeutic Target in Malignant Pleural Mesothelioma

Malignant pleural mesothelioma (MPM) is an aggressive disease with a poor prognosis. Studies have shown that both MET and its key downstream intracellular signaling partners, PI3K and mTOR, are overexpressed in MPM. Here we determined the combinatorial therapeutic efficacy of a new generation small molecule inhibitor of MET, ARQ 197, and dual PI3K/mTOR inhibitors NVP-BEZ235 and GDC-0980 in mesothelioma cell and mouse xenograft models. Cell viability results show that mesothelioma cell lines were sensitive to ARQ 197, NVP-BEZ235 and GDC-0980 inhibitors. The combined use of ARQ 197 with either NVP-BEZ235 or GDC-0980, was synergistic (CI<1). Significant delay in wound healing was observed with ARQ 197 (p<0.001) with no added advantage of combining it with either NVP-BEZ235 or GDC-0980. ARQ 197 alone mainly induced apoptosis (20±2.36%) that was preceded by suppression of MAPK activity, while all the three suppressed cell cycle progression. Both GDC-0980 and NVP-BEZ235 strongly inhibited activities of PI3K and mTOR as evidenced from the phosphorylation status of AKT and S6 kinase. The above observation was further substantiated by the finding that a majority of the MPM archival samples tested revealed highly active AKT. While the single use of ARQ 197 and GDC-0980 inhibited significantly the growth of MPM xenografts (p<0.05, p<0.001 respectively) in mice, the combination of the above two drugs was highly synergistic (p<0.001). Our results suggest that the combined use of ARQ 197/NVP-BEZ235 and ARQ 197/GDC-0980 is far more effective than the use of the drugs singly in suppressing MPM tumor growth and motility and therefore merit further translational studies.     

Metal pollution in water environment and the associated human health risk from drinking water: A case study of Sukinda chromite mine,India

Sukinda is one of the most polluted regions of the globe due to chromium pollution. The study sheds light into the heavy metal pollution around the mining area and its effect on the health of the resident populace. The Cr(VI) was in the range of 0.027–2.48 mg/L in surface water and BDL–1.35 mg/L in the groundwater. Multivariate analysis revealed that mining activity was the main source of TCr, Cr(VI), and Zn in the surface water that warrants attention. Heavy metal evaluation index showed high levels of Fe, Mn, and Cr in groundwater that can pose serious threat to the exposed population. Cancer and non-cancer risk of Cr(VI) was higher than other metals in groundwater. The results revealed that the total cancer risk was 1.21E-03 and 1.05E-03 in adults and children, respectively, which exceeded the USEPA acceptable cancer health risk. High health risk was observed through oral intake of water, while both cancer and non-cancer risks were negligible through dermal contact. This study strongly advocates proper periodic assessment of drinking as well as surface water in the area and regulation to restrict the use of contaminated water for daily use.