A novel medium size lactam ring analoges as antibacterial agents

A novel series of medium size (S)-3-alkyl-3,4,6,7-tetrahydro-1H-benzo[e][1,4]diazonine-2,5-dione (6a-f) analogues were synthesized from (E)-3-(2-nitrophenyl)acrylicacid (2) reacting with various amino acid esters using Di-isopropyl Carbodiimide as a coupling agent. The final cyclization is carried out by using reagent 1-Ethyl-3(3- dimethylaminopropyl) Carbodiimide Hydrochloride. The synthesized compounds have been supported by Mass, 1H-NMR and 13C-NMR. Further antibacterial studies were conducted, where some molecules are noticed with potent activity, especially molecule 6d shown highest activity which was also supported by molecular docking studies. All final molecules were docked with enzyme peptide deformylase to determine the probable binding conformation

DNA-Induced Unfolding of the Thyroid Hormone Receptor a A/B Domain through Allostery

The A/B domains of nuclear receptors such as thyroid receptor a (TRa) are considered to be conformationally flexible and can potentially adopt multiple structural conformations. We used intrinsic tryptophan fluorescence quenching and circular dichroism spectroscopy to characterize the unfolding of this A/B domain upon DNA binding to the contiguous DNA binding domain (DBD). We propose that this allosteric change in A/B domain conformation can allow it to make the multiple interactions with distinct molecular factors of the transcriptional preinitiation complex. We further suggest that by influencing the affinity of the DBD for DNA, A/B domain can fine-tune the recognition of promotor DNA by TRa

Allosteric Modulators of Steroid Hormone Receptors : Structural Dynamics and Gene Regulation

Peer reviewedPublisher PD

Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p 10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group

Efficiency Based Comparison of Project Delivery Methods: Efficiency Based Comparison of Project Delivery Methods

Public Private Partnerships (PPP) are the future of infrastructure project delivery. Majority of the PPPs have been successful except a few over the past decade. The reasons for their failure are well documented by researchers. The misconceptions about PPPs make it increasingly difficult to pursue projects using PPP delivery system. One of the root causes of the misconceptions is from the ambiguities arising from qualitative data and assessments. To overcome this issue, efficiency-based comparison of project delivery methods utilizing Data Envelopment Analysis (DEA) for decision making is presented through this paper. Proposed approach uses qualitative ratings and harnesses the integral utility of the ratings obtained while conducting objective assessment of qualitative data. California’s Presidio Parkway Project is used for case study analysis and the data is varied to create three hypothetical scenarios to determine sensitivity of the model. Results from case study are consistent with actual project implementation and the sensitivity analyses result are found to be consistent

Beam couplings and phase conjugate effects in reflection and transmission in BaTiO<SUB>3</SUB>

The details of experiments showing the effects of self-pumped phase conjugation on reflection and on transmission in barium titanate crystal are given. The specular reflection and the second-surface reflection of an extraordinary polarized beam, incident on the face of the crystal parallel to itsc-axis, get reduced in intensity as the phase conjugation develops. It has been found that parts of the self-pumped phase conjugate beam emerge out of the crystal as additional transmission beams. They grow in intensity as the phase conjugation develops. Other measurements which combine coherent or incoherent coupling beams are presented and used to explain the observations

A Comprehensive Reliability Methodology for Assessing Risk of Reusing Failed Hardware Without Corrective Actions with and Without Redundancy

This paper deals with the development of a reliability methodology to assess the consequences of using hardware, without failure analysis or corrective action, that has previously demonstrated that it did not perform per specification. The subject of this paper arose from the need to provide a detailed probabilistic analysis to calculate the change in probability of failures with respect to the base or non-failed hardware. The methodology used for the analysis is primarily based on principles of Monte Carlo simulation. The random variables in the analysis are: Maximum Time of Operation (MTO) and operation Time of each Unit (OTU) The failure of a unit is considered to happen if (OTU) is less than MTO for the Normal Operational Period (NOP) in which this unit is used. NOP as a whole uses a total of 4 units. Two cases are considered. in the first specialized scenario, the failure of any operation or system failure is considered to happen if any of the units used during the NOP fail. in the second specialized scenario, the failure of any operation or system failure is considered to happen only if any two of the units used during the MOP fail together. The probability of failure of the units and the system as a whole is determined for 3 kinds of systems - Perfect System, Imperfect System 1 and Imperfect System 2. in a Perfect System, the operation time of the failed unit is the same as that of the MTO. In an Imperfect System 1, the operation time of the failed unit is assumed as 1 percent of the MTO. In an Imperfect System 2, the operation time of the failed unit is assumed as zero. in addition, simulated operation time of failed units is assumed as 10 percent of the corresponding units before zero value. Monte Carlo simulation analysis is used for this study. Necessary software has been developed as part of this study to perform the reliability calculations. The results of the analysis showed that the predicted change in failure probability (P(sub F)) for the previously failed units is as high as 49 percent above the baseline (perfect system) for the worst case. The predicted change in system P(sub F) for the previously failed units is as high as 36% for single unit failure without any redundancy. For redundant systems, with dual unit failure, the predicted change in P(sub F) for the previously failed units is as high as 16%. These results will help management to make decisions regarding the consequences of using previously failed units without adequate failure analysis or corrective action