scholarly journals Design to Data for mutants of β-glucosidase B from Paenibacillus polymyxa: I45K, A357S, I20A, I20V, and I20E

2020 ◽  
Author(s):  
Jennie A. Luong ◽  
Ashley Vater ◽  
Justin B. Siegel
Keyword(s):  
Hydrogen Bonding ◽  
Paenibacillus Polymyxa ◽  
Modeling Tools ◽  
Data Set ◽  
Synthetic Genes ◽  
E Coli ◽  
Generative Modeling ◽  
Expression Kinetic ◽  
Enzyme Functionality ◽  
The Relationship

ABSTRACTThe relatively small size and scope of most current datasets of biophysical mutation effects in enzymes limit the ability to develop data-driven algorithms enabling accurate generative modeling tools for designing novel enzyme function. Here, the Michaelis-Menten constants (kcat, KM, and kcat/KM) and thermal stability (TM) of five new mutations of β-glucosidase B from Paenibacillus polymyxa (BglB) are characterized. Foldit software was used to create molecular models of the mutants, for which synthetic genes were constructed and the corresponding proteins produced and purified from E. coli. It was found that mutations that disrupted pre-existing hydrogen bonds near the active site had reduced expression in contrast to mutations at the same site that did not affect native hydrogen bonding. This is consistent with previous results showing the relationship between hydrogen bonding and enzyme functionality. These mutants contribute to a growing data set of >100 mutants that have been characterized for expression, kinetic, and thermal properties

scholarly journals Pharmacological Basis of β-Lactamase Inhibitor Therapeutics: Tazobactam in Combination with Ceftolozane

2013 ◽  
Vol 57 (12) ◽  
pp. 5924-5930 ◽  
Author(s):  
Brian VanScoy ◽  
Rodrigo E. Mendes ◽  
Jennifer McCauley ◽  
Sujata M. Bhavnani ◽  
Catharine C. Bulik ◽  
...  
Keyword(s):  
Threshold Concentration ◽  
Genetically Engineered ◽  
Clinical Isolates ◽  
Enzyme Expression ◽  
Data Set ◽  
Content Type ◽  
E Coli ◽  
Resistance Determinants ◽  
The Relationship

ABSTRACTWe recently investigated the pharmacokinetics-pharmacodynamics (PK-PD) of tazobactam in combination with ceftolozane against an isogenic CTX-M-15-producingEscherichia colitriplet set, genetically engineered to transcribe different levels ofblaCTX-M-15. The percentage of the dosing interval that tazobactam concentrations remained above a threshold (%Time>threshold) was identified as the PK-PD exposure measure that was most closely associated with efficacy. Moreover, the tazobactam concentration was dependent upon the enzyme transcription level. Given that the aforementioned strains were genetically engineered to transcribe a single β-lactamase enzyme and that clinical isolates typically produce multiple β-lactamase enzymes with various transcription levels, it is likely that the tazobactam threshold concentration is isolate/enzyme dependent. Our first objective was to characterize the relationship between the tazobactam %Time>threshold in combination with ceftolozane and efficacy using clinical isolates in anin vitroPK-PD infection model. Our second objective was to identify a translational relationship that would allow for the comodeling across clinical isolates. The initial challenge panel included four well-characterized β-lactamase-producingE. colistrains with variable enzyme expression and other resistance determinants. As evidenced byr2values of ranging from 0.90 to 0.99 for each clinical isolate, the observed data were well described by fitted functions describing the relationship between the tazobactam %Time>threshold and change in log10CFU from baseline; however, the data from the four isolates did not comodel well. The threshold concentration identified for each isolate ranged from 0.5 to 4 mg/liter. We identified an enabling translational relationship for the tazobactam threshold that allowed comodeling of all four clinical isolates, which was the product of the individual isolate's ceftolozane-tazobactam MIC value and 0.5. As evidenced by anr2value of 0.90, the transformed data were well described by a fitted function describing the relationship between tazobactam %Time>threshold and change in log10CFU from baseline. Due to these findings, the challenge panel was expanded to include three well-characterized β-lactamase-producingKlebsiella pneumoniaestrains with variable enzyme expression and other resistance determinants. The translational relationship for the tazobactam threshold that allowed for the comodeling of the fourE. coliisolates performed well for the expanded data set (seven isolates in total; fourE. coliand threeK. pneumoniae), as evidenced by anr2value of 0.84. This simple translational relationship is especially useful as it is directly linked toin vitrosusceptibility test results, which are used to guide the clinician's choice of drug and dosing regimen.

The relationship between health effects in triathletes and microbiological quality of freshwater

1995 ◽  
Vol 31 (5-6) ◽  
pp. 19-26 ◽  
Author(s):  
G. J. Medema ◽  
I. A. van Asperen ◽  
J. M. Klokman-Houweling ◽  
A. Nooitgedagt ◽  
M. J. W. van de Laar ◽  
...  
Keyword(s):  
Water Quality ◽  
Geometric Mean ◽  
Microbiological Quality ◽  
Quality Parameters ◽  
Health Complaints ◽  
E Coli ◽  
Thermotolerant Coliforms ◽  
Microbiological Water Quality ◽  
The Relationship ◽  
Faecal Streptococci

This pilot study was carried out to determine the relationship between microbiological water quality parameters and the occurrence of health complaints among triathletes. Data were collected at an Olympic distance triathlon (n=314) and a run-bike-run (n=81; controls for exposure to fresh water). At the time of the triathlon, the concentrations of Escherichia coli , thermotolerant coliforms, faecal streptococci, entero- and reoviruses, F-specific RNA phages, Salmonella, Campylobacter, Aeromonas, Plesiomonas shigelloides, Pseudomonas aeruginosa and Staphylococcus aureus were examined over the swimming course. Information on the occurrence of health complaints during the competition and in the week thereafter was collected through a written questionnaire. The results show that triathletes and run-bike-runners are comparable with respect to factors other than water exposure (age, sex, training history, physical stress, lower intestinal health complaints during the competition) that may influence the occurrence of health complaints in the week after the competition. Triathletes and run-bike-runners reported gastro-intestinal (7.7% vs 2.5%), respiratory (5.5% vs 3.7%), skin/mucosal (2.6% vs 1.2%), general (3.5% vs 1.2%) and total symptoms (14.8% vs 7.4%) in the week after the event. The health risks for triathletes for all symptom groups are not significantly higher than for run-bike-runners. The geometric mean concentration of faecal indicator bacteria is relatively low: E. coli 170/100 ml; faecal streptococci 13/100 ml, enteroviruses were present at concentrations of 0.1/l. The group of triathletes was homogeneusly and relatively intensely exposed to water; they all swam in the same body of water at the same time and 75% reported to have swallowed freshwater. It was concluded that this study design is suitable to study the relationship between health complaints and microbiological water quality. In the summers of 1993 and 1994, a study will be carried out concerning several run-bike-runs and triathlons in freshwaters of different quality.

The effect of type of water supply on water quality in a developing community in South Africa

1997 ◽  
Vol 35 (11-12) ◽  
pp. 35-40 ◽  
Author(s):  
B. Genthe ◽  
N. Strauss ◽  
J. Seager ◽  
C. Vundule ◽  
F. Maforah ◽  
...  
Keyword(s):  
Water Quality ◽  
Water Supply ◽  
Cross Sectional Study ◽  
Cross Sectional ◽  
E Coli ◽  
Guideline Values ◽  
Developing Communities ◽  
Quality Guideline ◽  
And Control ◽  
The Relationship

Efforts to provide water to developing communities in South Africa have resulted in various types of water supplies being used. This study examined the relationship between the type of water supply and the quality of water used. Source (communal taps, private outdoor and indoor taps) and point-of-use water samples were examined for heterotrophic plate counts (HPC), total and faecal coliforms, E. coli, and coliphages. Ten percent of samples were also analysed for enteric viruses, Giardia and Cryptosporidium. Approximately 320 households were included in a case-control study. In addition, a cross-sectional study was conducted. Both studies examined the relationship between different types of water facilities and diarrhoea among pre-school children. The source water was of good microbial quality, but water quality was found to have deteriorated significantly after handling and storage in both case and control households, exceeding drinking water quality guideline values by 1-6 orders of magnitude. Coliphage counts were low for all water samples tested. Enteric viruses and Cryptosporidium oocysts were not detected. Giardia cysts were detected on one occasion in case and control in-house samples. Comparisons of whether in-house water, after handling and storage, complied with water quality guideline values demonstrated households using communal taps to have significantly poorer quality than households using private outdoor or indoor taps for HPC and E. coli (χ2 = 14.9, P = 0.001; χ2 = 6.6, P = 0.04 respectively). A similar trend (although not statistically significant) was observed for the other microbial indicators. The cross-sectional study demonstrated an apparent decrease in health risk associated with private outdoor taps in comparison to communal taps. This study suggests that a private outdoor tap is the minimum level of water supply in order to ensure the supply of safe water to developing communities.

Structure Guided Molecular Docking Assisted Alignment Dependent 3DQSAR Study on Steroidal Aromatase Inhibitors (SAIs) as Anti-breast Cancer Agents

2019 ◽  
Vol 16 (7) ◽  
pp. 808-817 ◽  
Author(s):  
Laxmi Banjare ◽  
Sant Kumar Verma ◽  
Akhlesh Kumar Jain ◽  
Suresh Thareja
Keyword(s):  
Breast Cancer ◽  
Molecular Docking ◽  
Aromatase Inhibitors ◽  
Direct Synthesis ◽  
3D Qsar ◽  
Chemotherapeutic Agents ◽  
Modeling Tools ◽  
Data Set ◽  
Wide Range ◽  
Steroidal Aromatase Inhibitors

Background: In spite of the availability of various treatment approaches including surgery, radiotherapy, and hormonal therapy, the steroidal aromatase inhibitors (SAIs) play a significant role as chemotherapeutic agents for the treatment of estrogen-dependent breast cancer with the benefit of reduced risk of recurrence. However, due to greater toxicity and side effects associated with currently available anti-breast cancer agents, there is emergent requirement to develop target-specific AIs with safer anti-breast cancer profile. Methods: It is challenging task to design target-specific and less toxic SAIs, though the molecular modeling tools viz. molecular docking simulations and QSAR have been continuing for more than two decades for the fast and efficient designing of novel, selective, potent and safe molecules against various biological targets to fight the number of dreaded diseases/disorders. In order to design novel and selective SAIs, structure guided molecular docking assisted alignment dependent 3D-QSAR studies was performed on a data set comprises of 22 molecules bearing steroidal scaffold with wide range of aromatase inhibitory activity. Results: 3D-QSAR model developed using molecular weighted (MW) extent alignment approach showed good statistical quality and predictive ability when compared to model developed using moments of inertia (MI) alignment approach. Conclusion: The explored binding interactions and generated pharmacophoric features (steric and electrostatic) of steroidal molecules could be exploited for further design, direct synthesis and development of new potential safer SAIs, that can be effective to reduce the mortality and morbidity associated with breast cancer.

PSVI-8 Meta-regression Analysis to Determine the Relationship Between Growing Pig Body Weight and Variation

2021 ◽  
Vol 99 (Supplement_1) ◽  
pp. 218-219
Author(s):  
Andres Fernando T Russi ◽  
Mike D Tokach ◽  
Jason C Woodworth ◽  
Joel M DeRouchey ◽  
Robert D Goodband ◽  
...  
Keyword(s):  
Body Weight ◽  
Regression Analysis ◽  
Sample Size ◽  
Polynomial Regression ◽  
Data Sets ◽  
Regression Equations ◽  
Prediction Equations ◽  
Data Set ◽  
Rate Of Increase ◽  
The Relationship

Abstract The swine industry has been constantly evolving to select animals with improved performance traits and to minimize variation in body weight (BW) in order to meet packer specifications. Therefore, understanding variation presents an opportunity for producers to find strategies that could help reduce, manage, or deal with variation of pigs in a barn. A systematic review and meta-analysis was conducted by collecting data from multiple studies and available data sets in order to develop prediction equations for coefficient of variation (CV) and standard deviation (SD) as a function of BW. Information regarding BW variation from 16 papers was recorded to provide approximately 204 data points. Together, these data included 117,268 individually weighed pigs with a sample size that ranged from 104 to 4,108 pigs. A random-effects model with study used as a random effect was developed. Observations were weighted using sample size as an estimate for precision on the analysis, where larger data sets accounted for increased accuracy in the model. Regression equations were developed using the nlme package of R to determine the relationship between BW and its variation. Polynomial regression analysis was conducted separately for each variation measurement. When CV was reported in the data set, SD was calculated and vice versa. The resulting prediction equations were: CV (%) = 20.04 – 0.135 × (BW) + 0.00043 × (BW)2, R2=0.79; SD = 0.41 + 0.150 × (BW) - 0.00041 × (BW)2, R2 = 0.95. These equations suggest that there is evidence for a decreasing quadratic relationship between mean CV of a population and BW of pigs whereby the rate of decrease is smaller as mean pig BW increases from birth to market. Conversely, the rate of increase of SD of a population of pigs is smaller as mean pig BW increases from birth to market.

scholarly journals Exploring the taxonomical and functional profile of As Burgas hot spring focusing on thermostable β-galactosidases

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
María-Eugenia DeCastro ◽  
Michael P. Doane ◽  
Elizabeth Ann Dinsdale ◽  
Esther Rodríguez-Belmonte ◽  
María-Isabel González-Siso
Keyword(s):  
Microbial Community ◽  
Hot Spring ◽  
Functional Characterization ◽  
Tca Cycle ◽  
Maximal Activity ◽  
Sulfur Cycle ◽  
E Coli ◽  
Complex Microbial Community ◽  
Relationship Of ◽  
The Relationship

AbstractIn the present study we investigate the microbial community inhabiting As Burgas geothermal spring, located in Ourense (Galicia, Spain). The approximately 23 Gbp of Illumina sequences generated for each replicate revealed a complex microbial community dominated by Bacteria in which Proteobacteria and Aquificae were the two prevalent phyla. An association between the two most prevalent genera, Thermus and Hydrogenobacter, was suggested by the relationship of their metabolism. The high relative abundance of sequences involved in the Calvin–Benson cycle and the reductive TCA cycle unveils the dominance of an autotrophic population. Important pathways from the nitrogen and sulfur cycle are potentially taking place in As Burgas hot spring. In the assembled reads, two complete ORFs matching GH2 beta-galactosidases were found. To assess their functional characterization, the two ORFs were cloned and overexpressed in E. coli. The pTsbg enzyme had activity towards o-Nitrophenyl-β-d-galactopyranoside (ONPG) and p-Nitrophenyl-β-d-fucopyranoside, with high thermal stability and showing maximal activity at 85 °C and pH 6, nevertheless the enzyme failed to hydrolyze lactose. The other enzyme, Tsbg, was unable to hydrolyze even ONPG or lactose. This finding highlights the challenge of finding novel active enzymes based only on their sequence.

Railroad Integration and Uneven Development on the European Periphery, 1870–1910

2021 ◽  
Vol 45 (2) ◽  
pp. 261-289
Author(s):  
Eduard J. Alvarez-Palau ◽  
Alfonso Díez-Minguela ◽  
Jordi Martí-Henneberg
Keyword(s):  
Economic Development ◽  
Positive Impact ◽  
Data Set ◽  
Per Capita Gdp ◽  
Catching Up ◽  
Nation States ◽  
Railroad Network ◽  
Per Capita ◽  
European Periphery ◽  
The Relationship

AbstractThis study explores the relationship between railroad integration and regional development on the European periphery between 1870 and 1910, based on a regional data set including 291 spatial units. Railroad integration is proxied by railroad density, while per capita GDP is used as an indicator of economic development. The period under study is of particular relevance as it has been associated with the second wave of railroad construction in Europe and also coincides with the industrialization of most of the continent. Overall, we found that railroads had a significant and positive impact on the growth of per capita GDP across Europe. The magnitude of this relationship appears to be relatively modest, but the results obtained are robust with respect to a number of different specifications. From a geographical perspective, we found that railroads had a significantly greater influence on regions located in countries on the northern periphery of Europe than in other outlying areas. They also helped the economies of these areas to begin the process of catching up with the continent’s industrialized core. In contrast, the regions on the southern periphery showed lower levels of economic growth, with this exacerbating the preexisting divergence in economic development. The expansion of the railroad network in them was unable to homogenize the diffusion of economic development and tended to further benefit the regions that were already industrialized. In most of the cases, the capital effect was magnified, and this contributed to the consolidation of newly created nation-states.

scholarly journals Cryo-EM structure of mycobacterial cytochrome bd reveals two oxygen access channels

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Weiwei Wang ◽  
Yan Gao ◽  
Yanting Tang ◽  
Xiaoting Zhou ◽  
Yuezheng Lai ◽  
...  
Keyword(s):  
Rational Design ◽  
Pathogenic Bacteria ◽  
Structural Topology ◽  
Antimicrobial Drugs ◽  
E Coli ◽  
Cytochrome Bd ◽  
Cryo Electron Microscopy ◽  
Functional Mechanisms ◽  
The Relationship ◽  
Potential Oxygen

AbstractCytochromes bd are ubiquitous amongst prokaryotes including many human-pathogenic bacteria. Such complexes are targets for the development of antimicrobial drugs. However, an understanding of the relationship between the structure and functional mechanisms of these oxidases is incomplete. Here, we have determined the 2.8 Å structure of Mycobacterium smegmatis cytochrome bd by single-particle cryo-electron microscopy. This bd oxidase consists of two subunits CydA and CydB, that adopt a pseudo two-fold symmetrical arrangement. The structural topology of its Q-loop domain, whose function is to bind the substrate, quinol, is significantly different compared to the C-terminal region reported for cytochromes bd from Geobacillus thermodenitrificans (G. th) and Escherichia coli (E. coli). In addition, we have identified two potential oxygen access channels in the structure and shown that similar tunnels also exist in G. th and E. coli cytochromes bd. This study provides insights to develop a framework for the rational design of antituberculosis compounds that block the oxygen access channels of this oxidase.

scholarly journals RESTING HEART RATE MODERATES THE RELATIONSHIP BETWEEN NEUROPSYCHIATRIC SYMPTOMS, MCI, AND ALZHEIMER’S DISEASE

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S641-S641
Author(s):  
Shanna L Burke
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Heart Rate ◽  
Relative Risk ◽  
Neuropsychiatric Symptoms ◽  
Cognitive Status ◽  
Resting Heart Rate ◽  
Data Set ◽  
Increased Risk ◽  
The Relationship

Abstract Little is known about how resting heart rate moderates the relationship between neuropsychiatric symptoms and cognitive status. This study examined the relative risk of NPS on increasingly severe cognitive statuses and examined the extent to which resting heart rate moderates this relationship. A secondary analysis of the National Alzheimer’s Coordinating Center Uniform Data Set was undertaken, using observations from participants with normal cognition at baseline (13,470). The relative risk of diagnosis with a more severe cognitive status at a future visit was examined using log-binomial regression for each neuropsychiatric symptom. The moderating effect of resting heart rate among those who are later diagnosed with mild cognitive impairment (MCI) or Alzheimer’s disease (AD) was assessed. Delusions, hallucinations, agitation, depression, anxiety, elation, apathy, disinhibition, irritability, motor disturbance, nighttime behaviors, and appetite disturbance were all significantly associated (p<.001) with an increased risk of AD, and a reduced risk of MCI. Resting heart rate increased the risk of AD but reduced the relative risk of MCI. Depression significantly interacted with resting heart rate to increase the relative risk of MCI (RR: 1.07 (95% CI: 1.00-1.01), p<.001), but not AD. Neuropsychiatric symptoms increase the relative risk of AD but not MCI, which may mean that the deleterious effect of NPS is delayed until later and more severe stages of the disease course. Resting heart rate increases the relative risk of MCI among those with depression. Practitioners considering early intervention in neuropsychiatric symptomology may consider the downstream benefits of treatment considering the long-term effects of NPS.

scholarly journals Spatial pattern and genetic diversity estimates are linked in stochastic models of population differentiation

2000 ◽  
Vol 23 (3) ◽  
pp. 541-544 ◽  
Author(s):  
José Alexandre Felizola Diniz-Filho ◽  
Mariana Pires de Campos Telles
Keyword(s):  
Genetic Diversity ◽  
Spatial Pattern ◽  
Stochastic Models ◽  
Population Differentiation ◽  
Real Data ◽  
Population Heterogeneity ◽  
Data Set ◽  
Mantel’S Test ◽  
The Relationship ◽  
Diversity Estimates

In the present study, we used both simulations and real data set analyses to show that, under stochastic processes of population differentiation, the concepts of spatial heterogeneity and spatial pattern overlap. In these processes, the proportion of variation among and within a population (measured by G ST and 1 - G ST, respectively) is correlated with the slope and intercept of a Mantel's test relating genetic and geographic distances. Beyond the conceptual interest, the inspection of the relationship between population heterogeneity and spatial pattern can be used to test departures from stochasticity in the study of population differentiation.

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