136 research outputs found
Modelling the Effects of Disease-Associated Single Amino Acid Variants and Rescuing the Effects by Small Molecules
Single nucleotide polymorphism (SNP) is a variation of a single nucleotide in the genome. Some of these variations can cause a change of single amino acid in the corresponding protein, resulting in single amino acid variation (SAV). SAVs can lead to profound alterations of the corresponding biological processes and thus can be associated with many human diseases. This dissertation focuses on integration of existing and development of new computational approaches to model the effects of SAVs with the goal to reveal molecular mechanism of human diseases. Since proton transfer and pKa shifts are frequently attributed to disease causality, the proton transfers in the protein-nucleic acid interactions are investigated and along with development of a new computational approach to predict the SAV’s effect on the protein-DNA binding affinity. The SAVs in four proteins: Lysine-specific demethylase 5C (KDM5C), Spermine Synthase (SpmSyn), 7-Dehydrocholesterol reductase (DHCR7) and methyl CpG binding protein 2 (MeCP2) are extensively studied using numerous computational approaches to reveal molecular details of disease-associated effects. In case of MeCP2 protein, the effects of the most commonly occurring disease-causing mutation, R133C, was targeted by structure-based virtual screening to identify the small molecules potentially to rescue the malfunctioning R133C mutant
Influence of stirring speed on SiC particles distribution in A356 liquid
A straight-blade mechanical stirrer was designed to stir A356-3.5vol%SiCp liquid in a cylindrical crucible with the capability of systematically investigating the influence of rotating speed of stirrer on the distribution of SiC particles in A356 liquid. The experimental results show that the vertical distribution of SiC particles in A356 liquid can be uniform when the rotating speed of stirrer is 200 rpm, but the radial distribution of SiC particles in A356 liquid is always nonhomogeneous regardless of the rotating speed of stirrer. The radial centrifugalization ratio of SiC particles in A356 liquid between the center and the periphery of crucible increases with the rotating speed of stirrer. The results were explained in the light of SiC particles motion subject to a combination of stirring and centrifugal effect
E-hooks provide guidance and a soft landing for the microtubule binding domain of dynein
Macromolecular binding is a complex process that involves sensing and approaching the binding partner, adopting the proper orientation, and performing the physical binding. We computationally investigated the role of E-hooks, which are intrinsically disordered regions (IDRs) at the C-terminus of tubulin, on dynein microtubule binding domain (MTBD) binding to the microtubule as a function of the distance between the MTBD and its binding site on the microtubule. Our results demonstrated that the contacts between E-hooks and the MTBD are dynamical; multiple negatively charted patches of amino acids on the E-hooks grab and release the same positively charged patches on the MTBD as it approaches the microtubule. Even when the distance between the MTBD and the microtubule was greater than the E-hook length, the E-hooks sensed and guided MTBD via long-range electrostatic interactions in our simulations. Moreover, we found that E-hooks exerted electrostatic forces on the MTBD that were distance dependent; the force pulls the MTBD toward the microtubule at long distances but opposes binding at short distances. This mechanism provides a “soft-landing” for the MTBD as it binds to the microtubule. Finally, our analysis of the conformational states of E-hooks in presence and absence of the MTBD indicates that the binding process is a mixture of the induced-fit and lock-and-key macromolecular binding hypotheses. Overall, this novel binding mechanism is termed “guided-soft-binding” and could have broad-reaching impacts on the understanding of how IDRs dock to structured proteins
Detail Enhancement for Infrared Images Based on Propagated Image Filter
For displaying high-dynamic-range images acquired by thermal camera systems, 14-bit raw infrared data should map into 8-bit gray values. This paper presents a new method for detail enhancement of infrared images to display the image with a relatively satisfied contrast and brightness, rich detail information, and no artifacts caused by the image processing. We first adopt a propagated image filter to smooth the input image and separate the image into the base layer and the detail layer. Then, we refine the base layer by using modified histogram projection for compressing. Meanwhile, the adaptive weights derived from the layer decomposition processing are used as the strict gain control for the detail layer. The final display result is obtained by recombining the two modified layers. Experimental results on both cooled and uncooled infrared data verify that the proposed method outperforms the method based on log-power histogram modification and bilateral filter-based detail enhancement in both detail enhancement and visual effect
Forces and Disease: Electrostatic force differences caused by mutations in kinesin motor domains can distinguish between disease-causing and non-disease-causing mutations
The ability to predict if a given mutation is disease-causing or not has enormous potential to impact human health. Typically, these predictions are made by assessing the effects of mutation on macromolecular stability and amino acid conservation. Here we report a novel feature: the electrostatic component of the force acting between a kinesin motor domain and tubulin. We demonstrate that changes in the electrostatic component of the binding force are able to discriminate between disease-causing and non-disease-causing mutations found in human kinesin motor domains using the receiver operating characteristic (ROC). Because diseases may originate from multiple effects not related to kinesin-microtubule binding, the prediction rate of 0.843 area under the ROC plot due to the change in magnitude of the electrostatic force alone is remarkable. These results reflect the dependence of kinesin’s function on motility along the microtubule, which suggests a precise balance of microtubule binding forces is required
Effect of Radix Platycodonis and Radix Cyathulae in Xuefu Zhuyu Tang on tissuedistribution of paeoniflorin in blood-stasis mice by HPLC: Experimentalevidence on Shi ingredients in traditional formula compatibility
Xuefu Zhuyu Tang (XFZY), a famous formula in traditional Chinese medicine, has been demonstrated to show goodtherapeutic effects on diseases caused by blood stasis syndrome. Two of its eleven herbs, Radix Platycodonis and RadixCyathulae, have been considered as Shi ingredients in the hierarchy of traditional formula compatibility and provenpossessing synergistic properties that strengthen the formula's potency of activating blood circulation and resolving bloodstagnation. However, its mechanism is still not clearly elucidated. In our previous study, we observed their effects onpaeoniflorin pharmacokinetics of XFZY in rats. In this study, we continued by detecting and comparing their effect on thetissue distribution of paeoniflorin after oral administration of XFZY and its three variants (XFZY without RadixPlatycodonis or/and Radix Cyathulae) in blood-stasis mice via HPLC assay. The results indicated that combining usage ofRadix Platycodonis and Radix Cyathula increased the distribution of paeoniflorin in the lung and kidney and introduced thepaeoniflorin into the liver, spleen and heart. It might explain their synergistic properties that strengthen the formula's effectof invigorating blood and dissolving stasis and provide experimental evidence to understand the pharmacological effects ofShi herbs in the hierarchy of traditional formula compatibility
Neurologic Abnormalities in Workers of a 1-Bromopropane Factory
We reported recently that 1-bromopropane (1-BP; n-propylbromide, CAS Registry no. 106-94-5), an alternative to ozone-depleting solvents, is neurotoxic and exhibits reproductive toxicity in rats. The four most recent case reports suggested possible neurotoxicity of 1-BP in workers. The aim of the present study was to establish the neurologic effects of 1-BP in workers and examine the relationship with exposure levels. We surveyed 27 female workers in a 1-BP production factory and compared 23 of them with 23 age-matched workers in a beer factory as controls. The workers were interviewed and examined by neurologic, electrophysiologic, hematologic, biochemical, neurobehavioral, and postural sway tests. 1-BP exposure levels were estimated with passive samplers. Tests with a tuning fork showed diminished vibration sensation of the foot in 15 workers exposed to 1-BP but in none of the controls. 1-BP factory workers showed significantly longer distal latency in the tibial nerve than did the controls but no significant changes in motor nerve conduction velocity. Workers also displayed lower values in sensory nerve conduction velocity in the sural nerve, backward recalled digits, Benton visual memory test scores, pursuit aiming test scores, and five items of the Profile of Mood States (POMS) test (tension, depression, anxiety, fatigue, and confusion) compared with controls matched for age and education. Workers hired after May 1999, who were exposed to 1-BP only (workers hired before 1999 could have also been exposed to 2-BP), showed similar changes in vibration sense, distal latency, Benton test scores, and depression and fatigue in the POMS test. Time-weighted average exposure levels in the workers were 0.34–49.19 ppm. Exposure to 1-BP could adversely affect peripheral nerves or/and the central nervous system
A New Method to Improve Running Economy and Maximal Aerobic Power in Athletes: Endurance Training With Periodic Carbon Monoxide Inhalation
Background: Altitude training stimulates erythropoietin hormone (EPO) release and increases blood hemoglobin (Hb) mass, which may result in improved oxygen (O-2) transport capacity. It was hypothesized in the present study that periodic inhalation of carbon monoxide (CO) might elicit similar physiological adaptations compared to altitude training.Methods: Twelve male college student athletes, who were well-trained soccer players, participated. They performed a 4-week treadmill-training program, five times a week. Participants were randomly assigned into an experimental group with inhaling CO (INCO) (1 mL/kg body weight for 2 min) in O-2 (4 L) before all training sessions and a control group without inhaling CO (NOCO). CO and EPO concentrations in venous blood were first measured acutely at the 1st, 2nd, 4th, 6th, and 8th hour after INCO, and total hemoglobin mass (tHb), running economy and VO(2)max were measured before and after the 4 weeks training intervention.Results: HbCO% increased from 0.7 to 4.4% (P Conclusion: Acutely, EPO increased sharply post CO inhalation, peaking at 4 h post inhalation. 4-weeks of training with CO inhalation before exercise sessions improved tHb and VO(2)max as well as running economy, suggesting that moderate CO inhalation could be a new method to improve the endurance performance in athletes.</div
Detection of new pioneer transcription factors as cell-type specific nucleosome binders
Wrapping of DNA into nucleosomes restricts DNA accessibility and the recognition of binding motifs by transcription factors. A certain class of transcription factors, so-called pioneer transcription factors, can specifically recognize their binding sites on nucleosomal DNA, initiate local chromatin opening and facilitate the binding of co-factors in a cell-type-specific manner. For the vast majority of human pioneer transcription factors, the locations of their binding sites, mechanisms of binding and regulation remain unknown. We have developed a computational method to predict the cell-type-specific ability of transcription factors to bind nucleosomes by integrating ChIP-seq, MNaseq-seq and DNase-seq data with the details of nucleosome structure. We have achieved classification accuracy with AUC=0.94 in discriminating pioneer factors from canonical transcription factors and predicted 32 potential pioneer transcription factors as nucleosome binders in embryonic cell differentiation. Lastly, we systemically analyzed the interaction modes between various pioneer factors and detected several clusters of distinctive binding sites on nucleosomal DNA
DMSP-producing bacteria are more abundant in the surface microlayer than subsurface seawater of the East China Sea
Microbial production and catabolism of dimethylsulfoniopropionate (DMSP), generating the climatically active gases dimethyl sulfide (DMS) and methanethiol (MeSH), have key roles in global carbon and sulfur cycling, chemotaxis, and atmospheric chemistry. Microorganisms in the sea surface microlayer (SML), the interface between seawater and atmosphere, likely play an important role in the generation of DMS and MeSH and their exchange to the atmosphere, but little is known about these SML microorganisms. Here, we investigated the differences between bacterial community structure and the distribution and transcription profiles of the key bacterial DMSP synthesis (dsyB and mmtN) and catabolic (dmdA and dddP) genes in East China Sea SML and subsurface seawater (SSW) samples. Per equivalent volume, bacteria were far more abundant (~ 7.5-fold) in SML than SSW, as were those genera predicted to produce DMSP. Indeed, dsyB (~ 7-fold) and mmtN (~ 4-fold), robust reporters for bacterial DMSP production, were also far more abundant in SML than SSW. In addition, the SML had higher dsyB transcripts (~ 3-fold) than SSW samples, which may contribute to the significantly higher DMSP level observed in SML compared with SSW. Furthermore, the abundance of bacteria with dmdA and their transcription were higher in SML than SSW samples. Bacteria with dddP and transcripts were also prominent, but less than dmdA and presented at similar levels in both layers. These data indicate that the SML might be an important hotspot for bacterial DMSP production as well as generating the climatically active gases DMS and MeSH, a portion of which are likely transferred to the atmosphere
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