CHARMM at 45: Enhancements in Accessibility, Functionality, and Speed

Since its inception nearly a half century ago, CHARMM has been playing a central role in computational biochemistry and biophysics. Commensurate with the developments in experimental research and advances in computer hardware, the range of methods and applicability of CHARMM have also grown. This review summarizes major developments that occurred after 2009 when the last review of CHARMM was published. They include the following: new faster simulation engines, accessible user interfaces for convenient workflows, and a vast array of simulation and analysis methods that encompass quantum mechanical, atomistic, and coarse-grained levels, as well as extensive coverage of force fields. In addition to providing the current snapshot of the CHARMM development, this review may serve as a starting point for exploring relevant theories and computational methods for tackling contemporary and emerging problems in biomolecular systems. CHARMM is freely available for academic and nonprofit research at https://academiccharmm.org/program

Biocompatibility of Graphene Oxide

Herein, we report the effects of graphene oxides on human fibroblast cells and mice with the aim of investigating graphene oxides' biocompatibility. The graphene oxides were prepared by the modified Hummers method and characterized by high-resolution transmission electron microscope and atomic force microscopy. The human fibroblast cells were cultured with different doses of graphene oxides for day 1 to day 5. Thirty mice divided into three test groups (low, middle, high dose) and one control group were injected with 0.1, 0.25, and 0.4 mg graphene oxides, respectively, and were raised for 1 day, 7 days, and 30 days, respectively. Results showed that the water-soluble graphene oxides were successfully prepared; graphene oxides with dose less than 20 μg/mL did not exhibit toxicity to human fibroblast cells, and the dose of more than 50 μg/mL exhibits obvious cytotoxicity such as decreasing cell adhesion, inducing cell apoptosis, entering into lysosomes, mitochondrion, endoplasm, and cell nucleus. Graphene oxides under low dose (0.1 mg) and middle dose (0.25 mg) did not exhibit obvious toxicity to mice and under high dose (0.4 mg) exhibited chronic toxicity, such as 4/9 mice death and lung granuloma formation, mainly located in lung, liver, spleen, and kidney, almost could not be cleaned by kidney. In conclusion, graphene oxides exhibit dose-dependent toxicity to cells and animals, such as inducing cell apoptosis and lung granuloma formation, and cannot be cleaned by kidney. When graphene oxides are explored for in vivo applications in animal or human body, its biocompatibility must be considered

Mapping QTLs for blight resistance and morpho-phenological traits in inter-species hybrid families of chestnut (Castanea spp.)

Chestnut blight (caused by Cryphonectria parasitica), together with Phytophthora root rot (caused by Phytophthora cinnamomi), has nearly extirpated American chestnut (Castanea dentata) from its native range. In contrast to the susceptibility of American chestnut, many Chinese chestnut (C. mollissima) genotypes are resistant to blight. In this research, we performed a series of genome-wide association studies for blight resistance originating from three unrelated Chinese chestnut trees (Mahogany, Nanking and M16) and a Quantitative Trait Locus (QTL) study on a Mahogany-derived inter-species F2 family. We evaluated trees for resistance to blight after artificial inoculation with two fungal strains and scored nine morpho-phenological traits that are the hallmarks of species differentiation between American and Chinese chestnuts. Results support a moderately complex genetic architecture for blight resistance, as 31 QTLs were found on 12 chromosomes across all studies. Additionally, although most morpho-phenological trait QTLs overlap or are adjacent to blight resistance QTLs, they tend to aggregate in a few genomic regions. Finally, comparison between QTL intervals for blight resistance and those previously published for Phytophthora root rot resistance, revealed five common disease resistance regions on chromosomes 1, 5, and 11. Our results suggest that it will be difficult, but still possible to eliminate Chinese chestnut alleles for the morpho-phenological traits while achieving relatively high blight resistance in a backcross hybrid tree. We see potential for a breeding scheme that utilizes marker-assisted selection early for relatively large effect QTLs followed by genome selection in later generations for smaller effect genomic regions

Population structure and genetic diversity of native and invasive populations of Solanum rostratum (Solanaceae)

Aims: We investigate native and introduced populations of Solanum rostratum, an annual, self-compatible plant that has been introduced around the globe. This study is the first to compare the genetic diversity of Solanum rostratum between native and introduced populations. We aim to (1) determine the level of genetic diversity across the studied regions; (2) explore the likely origins of invasive populations in China; and (3) investigate whether there is the evidence of multiple introductions into China. Methods: We genotyped 329 individuals at 10 microsatellite loci to determine the levels of genetic diversity and to investigate population structure of native and introduced populations of S. rostratum. We studied five populations in each of three regions across two continents: Mexico, the U.S.A. and China. Important Findings: We found the highest genetic diversity among Mexican populations of S. rostratum. Genetic diversity was significantly lower in Chinese and U.S.A. populations, but we found no regional difference in inbreeding coefficients (FIS) or population differentiation (FST). Population structure analyses indicate that Chinese and U.S.A. populations are more closely related to each other than to sampled Mexican populations, revealing that introduced populations in China share an origin with the sampled U.S.A. populations. The distinctiveness between some introduced populations indicates multiple introductions of S. rostratum into China

Climate warming and decreasing total column ozone over the Tibetan Plateau during winter and spring

The long-term trends of the total column ozone (TCO) over the Tibetan Plateau (TP) and factors responsible for the trends are analysed in this study using various observations and a chemistry–climate model (CCM). The results indicate that the total column ozone low (TOL) over the TP during winter and spring is deepening over the recent decade, which is opposite to the recovery signal in annual mean TCO over the TP after mid-1990s. The TOL intensity is increasing at a rate of 1.4 DU/decade and the TOL area is extending with 50,000 km2/decade during winter for the period 1979–2009. The enhanced transport of ozone-poor air into the stratosphere and elevated tropopause due to the rapid and significant warming over the TP during winter reduce ozone concentrations in the upper troposphere and lower stratosphere and hence lead to the deepening of the TOL. Based on the analysis of the multiple regression model, the thermal dynamical processes associated with the TP warming accounts for more than 50% of TCO decline during winter for the period 1979–2009. The solar variations during 1995–2009 further enlarge ozone decreases over the TP in the past decade. According to the CCM simulations, the increases in NOx emissions in East Asia and global tropospheric N2O mixing ratio for the period 1979–2009 contribute to no more than 20% reductions in TCO during this period

Genetic variants in FGFR2 and FGFR4 genes and skin cancer risk in the Nurses' Health Study

<p>Abstract</p> <p>Background</p> <p>The human fibroblast growth factor (FGF) and its receptor (FGFR) play an important role in tumorigenesis. Deregulation of the <it>FGFR2 </it>gene has been identified in a number of cancer sites. Overexpression of the <it>FGFR4 </it>protein has been linked to cutaneous melanoma progression. Previous studies reported associations between genetic variants in the <it>FGFR2 </it>and <it>FGFR4 </it>genes and development of various cancers.</p> <p>Methods</p> <p>We evaluated the associations of four genetic variants in the <it>FGFR2 </it>gene highly related to breast cancer risk and the three common tag-SNPs in the <it>FGFR4 </it>gene with skin cancer risk in a nested case-control study of Caucasians within the Nurses' Health Study (NHS) among 218 melanoma cases, 285 squamous cell carcinoma (SCC) cases, 300 basal cell carcinoma (BCC) cases, and 870 controls.</p> <p>Results</p> <p>We found no evidence for associations between these seven genetic variants and the risks of melanoma and nonmelanocytic skin cancer.</p> <p>Conclusion</p> <p>Given the power of this study, we did not detect any contribution of genetic variants in the <it>FGFR2 </it>or <it>FGFR4 </it>genes to inherited predisposition to skin cancer among Caucasian women.</p

Constraints on anomalous QGC's in e+e−e^{+}e^{-} interactions from 183 to 209 GeV

The acoplanar photon pairs produced in the reaction e(+) e(-) - → vvyy are analysed in the 700 pb(-1) of data collected by the ALEPH detector at centre-of-mass energies between 183 and 209 GeV. No deviation from the Standard Model predictions is seen in any of the distributions examined. The resulting 95% C.L. limits set on anomalous QGCs, a(0)(Z), a(c)(Z), a(0)(W) and a(c)(W), are -0.012 lt a(0)(Z)/Lambda(2) lt +0.019 GeV-2, -0.041 lt a(c)(Z)/Lambda(2) lt +0.044 GeV-2, -0.060 lt a(0)(W)/Lambda(2) lt +0.055 GeV-2, -0.099 lt a(c)(W)/Lambda(2) lt +0.093 GeV-2, where Lambda is the energy scale of the new physics responsible for the anomalous couplings

Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma

Primary open-angle glaucoma (POAG), characterized by retinal ganglion cell death, is a leading cause of irreversible blindness worldwide. However, its molecular and cellular causes are not well understood. Elevated intraocular pressure (IOP) is a major risk factor, but many patients have normal IOP. Colocalization and Mendelian randomization analysis of &gt;240 POAG and IOP genome-wide association study (GWAS) loci and overlapping expression and splicing quantitative trait loci (e/sQTLs) in 49 GTEx tissues and retina prioritizes causal genes for 60% of loci. These genes are enriched in pathways implicated in extracellular matrix organization, cell adhesion, and vascular development. Analysis of single-nucleus RNA-seq of glaucoma-relevant eye tissues reveals that the POAG and IOP colocalizing genes and genome-wide associations are enriched in specific cell types in the aqueous outflow pathways, retina, optic nerve head, peripapillary sclera, and choroid. This study nominates IOP-dependent and independent regulatory mechanisms, genes, and cell types that may contribute to POAG pathogenesis.</p

Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma

Primary open-angle glaucoma (POAG), characterized by retinal ganglion cell death, is a leading cause of irreversible blindness worldwide. However, its molecular and cellular causes are not well understood. Elevated intraocular pressure (IOP) is a major risk factor, but many patients have normal IOP. Colocalization and Mendelian randomization analysis of &gt;240 POAG and IOP genome-wide association study (GWAS) loci and overlapping expression and splicing quantitative trait loci (e/sQTLs) in 49 GTEx tissues and retina prioritizes causal genes for 60% of loci. These genes are enriched in pathways implicated in extracellular matrix organization, cell adhesion, and vascular development. Analysis of single-nucleus RNA-seq of glaucoma-relevant eye tissues reveals that the POAG and IOP colocalizing genes and genome-wide associations are enriched in specific cell types in the aqueous outflow pathways, retina, optic nerve head, peripapillary sclera, and choroid. This study nominates IOP-dependent and independent regulatory mechanisms, genes, and cell types that may contribute to POAG pathogenesis.</p

First measurement of the BSB_S meson mass

If simplified, every information retrieval problem can be solved when the information need implied by its expression has been identified. We are interested in the criteria used in realising a good information retrieval problem expression. We have listed these criteria through some principles and maxims which first characterized the communication between two persons are applied. We choose to use the gricean maxims because they are the most favoured for this type of situation. Secondly, we have tried to identify some others principles that can be used to realise a good information retrieval problem expression. The principles by Grice can not resolve all forms of error associated with this particular form of communication. In our work, we defined three other principles namely: adhesion principle, reformulation principle, memorization principle. We give some examples of situations where the principles we have formulated are not applicable and the consequences. We present the possible applications of our new model: MIRABEL, which can help in the description of information retrieval problem from. It also compels its user to use essential good expression principle implicitly