Pleistocene rapid uplift of the Himalayan frontal ranges recorded in the Kathmandu and Siwalik basins

Core-drilling project carried out in the southern margin of the Kathmandu Basin revealed that muddy debris flow deposits dammed up the Proto-Bagmati river to form the Paleo-Kathmandu Lake during the Jaramillo subchron from 1.07 to 0.97 Ma. Subsequent deposition of the alluvial fanglomerate, derived from the uplifting Mahabharat Range to the south, raised the dam deepening the lake-water. After 1 Ma, in the southern part of the basin, palaeo-current directions changed from southward to northward and deposition of gneissose and granitic detritus are replaced by meta-sediments derived from the Mahabharat Range.During the same time, at about 1 Ma, the boulder conglomerates were deposited on top of the Siwalik Group as piggy-back basins in front of an intra-basinal high, along the Main Dung Thrust in Nepal and NW India. Onset of movement of the Main Dung Thrust is dated back to 3 to 2.4 Ma [Mugnier, J.L., Huyge, P., Leturmy, P., Jouanne, F., 2003, Episodicity and rates of thrust-sheet motion in the Himalayas, Western Nepal. Am. Assoc. Petrol. Geol., Mem. 82, 1-24]. The Main Frontal Thrust is most active at present suggesting that imbricated structure of the Siwalik Group was formed by convergence of the Indian plate during the last 3 myr. The accretionary wedge of the Siwalik Group, stacked beneath the Main Boundary Thrust, might have started to jack up the frontal range of the Lesser Himalaya since 1 Ma.Coeval uplift and erosion of the frontal range of the Lesser Himalaya and the intra-basinal high in the Siwalik since 1 Ma are possible causes of an abrupt increase in both sedimentation rate and grain size of detrital quartz, and changes in composition of clay minerals, recorded in the sediments of the Bengal Deep Sea Fan at 0.9 Ma.     

Discovering Relations Between Mind,Brain, and Mental Disorders Using Topic Mapping

Neuroimaging research has largely focused on the identification of associations between brain activation and specific mental functions. Here we show that data mining techniques applied to a large database of neuroimaging results can be used to identify the conceptual structure of mental functions and their mapping to brain systems. This analysis confirms many current ideas regarding the neural organization of cognition, but also provides some new insights into the roles of particular brain systems in mental function. We further show that the same methods can be used to identify the relations between mental disorders. Finally, we show that these two approaches can be combined to empirically identify novel relations between mental disorders and mental functions via their common involvement of particular brain networks. This approach has the potential to discover novel endophenotypes for neuropsychiatric disorders and to better characterize the structure of these disorders and the relations between them.     

Synonymous codon usage in forty staphylococcal phages identifies the factors controlling codon usage variation and the phages suitable for phage therapy

The immergence and dissemination of multidrug-resistant strains of Staphylococcus aureus in recent years have expedited the research on the discovery of novel anti-staphylococcal agents promptly. Bacteriophages have long been showing tremendous potentialities in curing the infections caused by various pathogenic bacteria including S. aureus. Thus far, only a few virulent bacteriophages, which do not carry any toxin-encoding gene but are capable of eradicating staphylococcal infections, were reported. Based on the codon usage analysis of sixteen S. aureus phages, previously three phages were suggested to be useful as the anti-staphylococcal agents. To search for additional S. aureus phages suitable for phage therapy, relative synonymous codon usage bias has been investigated in the protein-coding genes of forty new staphylococcal phages. All phages appeared to carry A and T ending codons. Several factors such as mutational pressure, translational selection and gene length seemed to be responsible for the codon usage variation in the phages. Codon usage indeed varied phage to phage. Of the phages, phages G1, Twort, 66 and Sap-2 may be extremely lytic in nature as majority of their genes possess high translational efficiency, indicating that these phages may be employed in curing staphylococcal infections.     

Modeled structure of trypanothione reductase of Leishmania infantum

Trypanothione reductase is an important target enzyme for structure-based drug design against Leishmania. We used homology modeling to construct a three-dimensional structure of the trypanothione reductase (TR) of Leishmania infantum. The structure shows acceptable Ramachandran statistics and a remarkably different active site from glutathione reductase(GR). Thus, a specific inhibitor against TR can be designed without interfering with host (human) GR activity.     

A Nonquiescent “Idling” Population State in Drug-Treated,BRAF-Mutated Melanoma

Targeted therapy is an effective standard of care in BRAF-mutated malignant melanoma. However, the duration of tumor remission varies unpredictably among patients, and relapse is almost inevitable. Here, we examine the responses of several BRAF-mutated melanoma cell lines (including isogenic subclones) to BRAF inhibitors. We observe complex response dynamics across cell lines, with short-term responses (<100 h) varying from cell line to cell line. In the long term, however, we observe equilibration of all drug-treated populations into a nonquiescent state characterized by a balanced rate of death and division, which we term the “idling” state, and to our knowledge, this state has not been previously reported. Using mathematical modeling, we propose that the observed population-level dynamics are the result of cells transitioning between basins of attraction within a drug-modified phenotypic landscape. Each basin is associated with a drug-induced proliferation rate, a recently introduced metric of an antiproliferative drug effect. The idling population state represents a new dynamic equilibrium in which cells are distributed across the landscape such that the population achieves zero net growth. By fitting our model to experimental drug-response data, we infer the phenotypic landscapes of all considered melanoma cell lines and provide a unifying view of how BRAF-mutated melanomas respond to BRAF inhibition. We hypothesize that the residual disease observed in patients after targeted therapy is composed of a significant number of idling cells. Thus, defining molecular determinants of the phenotypic landscape that idling populations occupy may lead to “targeted landscaping” therapies based on rational modification of the landscape to favor basins with greater drug susceptibility.     

Structural Evolution of the Emerging 2014-2015 GII.17 Noroviruses

Recent reports suggest that human genogroup II genotype 17 (GII.17) noroviruses are increasing in prevalence. We analyzed the evolutionary changes of three GII.17 capsid protruding (P) domains. We found that the GII.17 P domains had little cross-reactivity with antisera raised against the dominant GII.4 strains. X-ray structural analysis of GII.17 P domains from 2002 to 2014 and 2015 suggested that surface-exposed substitutions on the uppermost part of the P domain might have generated a novel 2014-2015 GII.17 variant.     

Structural Basis for Norovirus Inhibition by Human Milk Oligosaccharides

Histo-blood group antigens (HBGAs) are important binding factors for norovirus infections. We show that two human milk oligosaccharides, 2′-fucosyllactose (2′FL) and 3-fucosyllactose (3FL), could block norovirus from binding to surrogate HBGA samples. We found that 2′FL and 3FL bound at the equivalent HBGA pockets on the norovirus capsid using X-ray crystallography. Our data revealed that 2′FL and 3FL structurally mimic HBGAs. These results suggest that 2′FL and 3FL might act as naturally occurring decoys in humans.