Exploring bat-inspired cyclic tryptophan diketopiperazines as ABCB1 Inhibitors.

Chemotherapy-induced drug resistance remains a major cause of cancer recurrence and patient mortality. ATP binding cassette subfamily B member 1 (ABCB1) transporter overexpression in tumors contributes to resistance, yet current ABCB1 inhibitors have been unsuccessful in clinical trials. To address this challenge, we propose a new strategy using tryptophan as a lead molecule for developing ABCB1 inhibitors. Our idea stems from our studies on bat cells, as bats have low cancer incidences and high ABCB1 expression. We hypothesized that potential ABCB1 substrates in bats could act as competitive inhibitors in humans. By molecular simulations of ABCB1-substrate interactions, we generated a benzylated Cyclo-tryptophan (C3N-Dbn-Trp2) that inhibits ABCB1 activity with efficacy comparable to or better than the classical inhibitor, verapamil. C3N-Dbn-Trp2 restored chemotherapy sensitivity in drug-resistant human cancer cells with no adverse effect on cell proliferation. Our unique approach presents a promising lead toward developing effective ABCB1 inhibitors to treat drug-resistant cancers.

A Comparative Study of the Perceptual Sensitivity of Topological Visualizations to Feature Variations.

Color maps are a commonly used visualization technique in which data are mapped to optical properties, e.g., color or opacity. Color maps, however, do not explicitly convey structures (e.g., positions and scale of features) within data. Topology-based visualizations reveal and explicitly communicate structures underlying data. Although our understanding of what types of features are captured by topological visualizations is good, our understanding of people's perception of those features is not. This paper evaluates the sensitivity of topology-based isocontour, Reeb graph, and persistence diagram visualizations compared to a reference color map visualization for synthetically generated scalar fields on 2-manifold triangular meshes embedded in 3D. In particular, we built and ran a human-subject study that evaluated the perception of data features characterized by Gaussian signals and measured how effectively each visualization technique portrays variations of data features arising from the position and amplitude variation of a mixture of Gaussians. For positional feature variations, the results showed that only the Reeb graph visualization had high sensitivity. For amplitude feature variations, persistence diagrams and color maps demonstrated the highest sensitivity, whereas isocontours showed only weak sensitivity. These results take an important step toward understanding which topology-based tools are best for various data and task scenarios and their effectiveness in conveying topological variations as compared to conventional color mapping.

Readout-Segmented Echoplanar (RESOLVE) Diffusion-Weighted Imaging on 3T MRI in Detection of Cholesteatoma-Our Experience.

Background Several research studies have demonstrated the utility of diffusion-weighted imaging (DWI) in detecting middle ear cholesteatomas, especially with the non-echoplanar imaging (non-EPI) DWI technique. REadout Segmentation Of Long Variable Echo trains (RESOLVE), a multishot-EPI DWI, has better spatial resolution at a thinner section acquisition with reduced image distortion compared to the single-shot-EPI DWI technique. Purpose In this study, we evaluated the diagnostic ability of RESOLVE -DWI in middle ear cholesteatomas with surgical and histopathological support. Patients and Methods Fifty patients with clinical suspicion of primary cholesteatoma or postoperative recurrence were subjected to routine sequences and RESOLVE-DWI on magnetic resonance imaging (MRI). Thirty-eight patients had unilateral disease, while 12 patients had bilateral disease. The bilateral temporal bones of 50 patients were evaluated on MRI. The results attained by RESOLVE-DWI were correlated with intraoperative and histopathological findings. Results RESOLVE-DWI truly detected 55 of the 58 surgically proven cholesteatomas. RESOLVE-DWI could not detect three cholesteatoma lesions due to their small size and falsely diagnosed one case each of impacted wax and non-cholesteatomatous otitis media as cholesteatoma. With a 95% confidence interval, RESOLVE-DWI showed 94.8% sensitivity, 95.2% specificity, 96% positive predictive value, 93% negative predictive value, and 95% diagnostic accuracy in cholesteatoma detection. Conclusion RESOLVE-DWI is a sensitive and specific DWI technique for detecting middle ear cholesteatoma. However, RESOLVE-DWI has limitations in the diagnosis of small (<3 mm) cholesteatomas.

Quantifying and Visualizing Uncertainty for Source Localization in Electrocardiographic Imaging.

Electrocardiographic imaging (ECGI) presents a clinical opportunity to noninvasively understand the sources of arrhythmias for individual patients. To help increase the effectiveness of ECGI, we provide new ways to visualize associated measurement and modeling errors. In this paper, we study source localization uncertainty in two steps: First, we perform Monte Carlo simulations of a simple inverse ECGI source localization model with error sampling to understand the variations in ECGI solutions. Second, we present multiple visualization techniques, including confidence maps, level-sets, and topology-based visualizations, to better understand uncertainty in source localization. Our approach offers a new way to study uncertainty in the ECGI pipeline.

Unveiling an indole alkaloid diketopiperazine biosynthetic pathway that features a unique stereoisomerase and multifunctional methyltransferase.

The 2,5-diketopiperazines are a prominent class of bioactive molecules. The nocardioazines are actinomycete natural products that feature a pyrroloindoline diketopiperazine scaffold composed of two D-tryptophan residues functionalized by N- and C-methylation, prenylation, and diannulation. Here we identify and characterize the nocardioazine B biosynthetic pathway from marine Nocardiopsis sp. CMB-M0232 by using heterologous biotransformations, in vitro biochemical assays, and macromolecular modeling. Assembly of the cyclo-L-Trp-L-Trp diketopiperazine precursor is catalyzed by a cyclodipeptide synthase. A separate genomic locus encodes tailoring of this precursor and includes an aspartate/glutamate racemase homolog as an unusual D/L isomerase acting upon diketopiperazine substrates, a phytoene synthase-like prenyltransferase as the catalyst of indole alkaloid diketopiperazine prenylation, and a rare dual function methyltransferase as the catalyst of both N- and C-methylation as the final steps of nocardioazine B biosynthesis. The biosynthetic paradigms revealed herein showcase Nature's molecular ingenuity and lay the foundation for diketopiperazine diversification via biocatalytic approaches.

Fiber Uncertainty Visualization for Bivariate Data With Parametric and Nonparametric Noise Models.

Visualization and analysis of multivariate data and their uncertainty are top research challenges in data visualization. Constructing fiber surfaces is a popular technique for multivariate data visualization that generalizes the idea of level-set visualization for univariate data to multivariate data. In this paper, we present a statistical framework to quantify positional probabilities of fibers extracted from uncertain bivariate fields. Specifically, we extend the state-of-the-art Gaussian models of uncertainty for bivariate data to other parametric distributions (e.g., uniform and Epanechnikov) and more general nonparametric probability distributions (e.g., histograms and kernel density estimation) and derive corresponding spatial probabilities of fibers. In our proposed framework, we leverage Green's theorem for closed-form computation of fiber probabilities when bivariate data are assumed to have independent parametric and nonparametric noise. Additionally, we present a nonparametric approach combined with numerical integration to study the positional probability of fibers when bivariate data are assumed to have correlated noise. For uncertainty analysis, we visualize the derived probability volumes for fibers via volume rendering and extracting level sets based on probability thresholds. We present the utility of our proposed techniques via experiments on synthetic and simulation datasets.

Hematological and biochemical reference intervals of wild-caught and inhouse adult Indian rhesus macaques (Macaca mulatta).

BACKGROUND: Nonhuman primates are used for research purposes such as studying diseases and drug discovery and development programs. Various clinical pathology parameters are used as biomarkers of disease conditions in biomedical research. Detailed reports of these parameters are not available for Indian-origin rhesus macaques. To meet the increasing need for information, we conducted this study on 121 adult Indian rhesus macaques (57 wild-sourced and 64 inhouse animals, aged 3-7 years). A total of 18 hematology and 18 biochemistry parameters were evaluated and reported in this study. Data from these parameters were statistically evaluated for significance amongst inhouse and wild-born animals and for differences amongst sexes. The reference range was calculated according to C28-A3 guidelines for reporting reference intervals of clinical laboratory parameters. RESULTS: Source of the animals and sex appeared to have statistically significant effects on reference values and range. Wild-born animals reported higher WBC, platelets, neutrophils, RBC, hemoglobin, HCT, MCV, and total protein values in comparison to inhouse monkeys. Sex-based differences were observed for parameters such as RBCs, hemoglobin, HCT, creatinine, calcium, phosphorus, albumin, and total protein amongst others. CONCLUSIONS: Through this study, we have established a comprehensive data set of reference values and intervals for certain hematological and biochemical parameters which will help researchers in planning, conducting, and interpreting various aspects of biomedical research employing Indian-origin rhesus monkeys.

MRI Findings in Case of Post-COVID-19 Vaccination Rhabdomyolysis: A Rare Postvaccination Adverse Effect.

In the era of this pandemic, without any proper and efficacious availability of antiviral agents against the novel coronavirus disease 2019 (COVID-19), vaccines have come as a hope for humankind. Although adverse reactions are common after getting the COVID-19 vaccine, serious or life-threatening side effects are very uncommon in these new emergency-approved vaccines. In this case report, we describe an unusual case of adverse reaction in a patient who received the COVID-19 vaccination. The patient who received the COVID-19 vaccination presented with progressive right lower limb pain and swelling, which further progressed to bilateral shoulder pain and swelling. Ultrasonography, Doppler, and magnetic resonance imaging of right lower limb were done for the patient.

Biomimetic Total Synthesis of (+)-Nocardioazine B and Analogs.

Nocardioazines A and B are prenylated, bioactive pyrroloindoline natural products, isolated from Nocardiopsis, with a desymmetrized cyclo-d-Trp-d-Trp DKP core. Based on our deeper biosynthetic understanding, a biomimetic total synthesis of (+)-nocardioazine B is accomplished in merely seven steps and 23.2% overall yield. This pathway accesses regio- and stereoselectively C3-isoprenylated analogs of (+)-nocardioazine B, using the same number of steps and in similar efficiency. The successful strategy mandated that the biomimetic C3-prenylation step be executed early. The use of an unprotected carboxylic acid of Trp led to high diastereoselectivity toward formation of key intermediates exo-12a, exo-12b, and exo-12c (>19:1). Evidence shows that N1-methylation causes the prenylation reaction to bifurcate away to result in a C2-normal-prenylated isomer. Nocardioazine A, possessing an isoprenoidal-epoxide bridge, inhibits P-glycoprotein (P-gp)-mediated membrane efflux, in multidrug-resistant mammalian colon cancer cells. As several P-gp inhibitors have failed due to their toxicity effects, endogenous amino-acid-derived noncytotoxic inhibitors (from the nocardioazine core) are worthy leads toward a rejuvenated strategy against resistant carcinomas. This total synthesis provides direct access to Trp-derived isoprenylated DKP natural products and their derivatives.

Uncertainty Visualization of 2D Morse Complex Ensembles Using Statistical Summary Maps.

Morse complexes are gradient-based topological descriptors with close connections to Morse theory. They are widely applicable in scientific visualization as they serve as important abstractions for gaining insights into the topology of scalar fields. Data uncertainty inherent to scalar fields due to randomness in their acquisition and processing, however, limits our understanding of Morse complexes as structural abstractions. We, therefore, explore uncertainty visualization of an ensemble of 2D Morse complexes that arises from scalar fields coupled with data uncertainty. We propose several statistical summary maps as new entities for quantifying structural variations and visualizing positional uncertainties of Morse complexes in ensembles. Specifically, we introduce three types of statistical summary maps - the probabilistic map, the significance map, and the survival map - to characterize the uncertain behaviors of gradient flows. We demonstrate the utility of our proposed approach using wind, flow, and ocean eddy simulation datasets.

Hematological and biochemical reference intervals of wild‑caught and inhouse adult Indian rhesus macaques (Macaca mulatta) / 한국실험동물학회지

Background@#Nonhuman primates are used for research purposes such as studying diseases and drug discovery and development programs. Various clinical pathology parameters are used as biomarkers of disease conditions in biomedical research. Detailed reports of these parameters are not available for Indian-origin rhesus macaques. To meet the increasing need for information, we conducted this study on 121 adult Indian rhesus macaques (57 wild-sourced and 64 inhouse animals, aged 3–7 years). A total of 18 hematology and 18 biochemistry parameters were evaluated and reported in this study. Data from these parameters were statistically evaluated for significance amongst inhouse and wild-born animals and for differences amongst sexes. The reference range was calculated according to C28-A3 guidelines for reporting reference intervals of clinical laboratory parameters. @*Results@#Source of the animals and sex appeared to have statistically significant effects on reference values and range. Wild-born animals reported higher WBC, platelets, neutrophils, RBC, hemoglobin, HCT, MCV, and total protein values in comparison to inhouse monkeys. Sex-based differences were observed for parameters such as RBCs, hemoglobin, HCT, creatinine, calcium, phosphorus, albumin, and total protein amongst others. @*Conclusions@#Through this study, we have established a comprehensive data set of reference values and intervals for certain hematological and biochemical parameters which will help researchers in planning, conducting, and interpreting various aspects of biomedical research employing Indian-origin rhesus monkeys.

Systemic retinal biomarkers.

PURPOSE OF REVIEW: Systemic retinal biomarkers are biomarkers identified in the retina and related to evaluation and management of systemic disease. This review summarizes the background, categories and key findings from this body of research as well as potential applications to clinical care. RECENT FINDINGS: Potential systemic retinal biomarkers for cardiovascular disease, kidney disease and neurodegenerative disease were identified using regression analysis as well as more sophisticated image processing techniques. Deep learning techniques were used in a number of studies predicting diseases including anaemia and chronic kidney disease. A virtual coronary artery calcium score performed well against other competing traditional models of event prediction. SUMMARY: Systemic retinal biomarker research has progressed rapidly using regression studies with clearly identified biomarkers such as retinal microvascular patterns, as well as using deep learning models. Future systemic retinal biomarker research may be able to boost performance using larger data sets, the addition of meta-data and higher resolution image inputs.

Bioinspired Brønsted Acid-Promoted Regioselective Tryptophan Isoprenylations.

Tryptophan-containing isoprenoid indole alkaloid natural products are well known for their intricate structural architectures and significant biological activities. Nature employs dimethylallyl tryptophan synthases (DMATSs) or aromatic indole prenyltransferases (iPTs) to catalyze regio- and stereoselective prenylation of l-Trp. Regioselective synthetic routes that isoprenylate cyclo-Trp-Trp in a 2,5-diketopiperazine (DKP) core, in a desymmetrizing manner, are nonexistent and are highly desirable. Herein, we present an elaborate report on Brønsted acid-promoted regioselective tryptophan isoprenylation strategy, applicable to both the monomeric amino acid and its dimeric l-Trp DKP. This report outlines a method that regio- and stereoselectively increases sp3 centers of a privileged bioactive core. We report on conditions involving screening of Brønsted acids, their conjugate base as salt, solvent, temperature, and various substrates with diverse side chains. Furthermore, we extensively delineate effects on regio- and stereoselection of isoprenylation and their stereochemical confirmation via NMR experiments. Regioselectively, the C3-position undergoes normal-isoprenylation or benzylation and forms exo-ring-fused pyrroloindolines selectively. Through appropriate prenyl group migrations, we report access to the bioactive tryprostatin alkaloids, and by C3-normal-farnesylation, we access anticancer drimentines as direct targets of this method. The optimized strategy affords iso-tryprostatin B-type products and predrimentine C with 58 and 55% yields, respectively. The current work has several similarities to biosynthesis, such as-reactions can be performed on unprotected substrates, conditions that enable Brønsted acid promotion, and they are easy to perform under ambient conditions, without the need for stoichiometric levels of any transition metal or expensive ligands.

Direct Volume Rendering with Nonparametric Models of Uncertainty.

We present a nonparametric statistical framework for the quantification, analysis, and propagation of data uncertainty in direct volume rendering (DVR). The state-of-the-art statistical DVR framework allows for preserving the transfer function (TF) of the ground truth function when visualizing uncertain data; however, the existing framework is restricted to parametric models of uncertainty. In this paper, we address the limitations of the existing DVR framework by extending the DVR framework for nonparametric distributions. We exploit the quantile interpolation technique to derive probability distributions representing uncertainty in viewing-ray sample intensities in closed form, which allows for accurate and efficient computation. We evaluate our proposed nonparametric statistical models through qualitative and quantitative comparisons with the mean-field and parametric statistical models, such as uniform and Gaussian, as well as Gaussian mixtures. In addition, we present an extension of the state-of-the-art rendering parametric framework to 2D TFs for improved DVR classifications. We show the applicability of our uncertainty quantification framework to ensemble, downsampled, and bivariate versions of scalar field datasets.

Tracheostomy: Experience at Tertiary Hospital.

An attempt was made to find indications of tracheostomy procedure and its complications in the modern era of medicine with refined surgical techniques at a tertiary hospital. A retrospective study of 240 patients, who had undergone tracheostomy, was done during the period from January 2013 to April 2017 at Govt. Medical College Hospital. Various details of all participants such as age and sex of patients, detailed history of the current disease, and detailed information about tracheostomy and complications were recorded. In the present study, the most common indication for tracheostomy was prolonged ventilation due to Organophosphorus poisoning and Snake bite. The complication rate for tracheostomy procedure was 11.5%. The most common complication was tubal occlusion (7.5%) followed by Granulations around stoma (2.5%), Tracheal stenosis (1.25%), tracheoesophageal fistula (0.4%). No death was occurred during the tracheostomy procedure. The morbidity and mortality due to tracheostomy are reduced definitely. Tracheostomy Complications can be prevented by refined surgical techniques, use of high volume low pressure cuffed tracheostomy tubes and attentive post-operative nursing care. Yet complications of tracheomalacia and tracheal stenosis call for further improvement.

A statistical framework for quantification and visualisation of positional uncertainty in deep brain stimulation electrodes.

Deep brain stimulation (DBS) is an established therapy for treating patients with movement disorders such as Parkinson's disease. Patient-specific computational modelling and visualisation have been shown to play a key role in surgical and therapeutic decisions for DBS. The computational models use brain imaging, such as magnetic resonance (MR) and computed tomography (CT), to determine the DBS electrode positions within the patient's head. The finite resolution of brain imaging, however, introduces uncertainty in electrode positions. The DBS stimulation settings for optimal patient response are sensitive to the relative positioning of DBS electrodes to a specific neural substrate (white/grey matter). In our contribution, we study positional uncertainty in the DBS electrodes for imaging with finite resolution. In a three-step approach, we first derive a closed-form mathematical model characterising the geometry of the DBS electrodes. Second, we devise a statistical framework for quantifying the uncertainty in the positional attributes of the DBS electrodes, namely the direction of longitudinal axis and the contact-centre positions at subvoxel levels. The statistical framework leverages the analytical model derived in step one and a Bayesian probabilistic model for uncertainty quantification. Finally, the uncertainty in contact-centre positions is interactively visualised through volume rendering and isosurfacing techniques. We demonstrate the efficacy of our contribution through experiments on synthetic and real datasets. We show that the spatial variations in true electrode positions are significant for finite resolution imaging, and interactive visualisation can be instrumental in exploring probabilistic positional variations in the DBS lead.

Multicomponent synthesis of pyroglutamic acid derivatives via Knoevenagel-Michael-hydrolysis-lactamization-decarboxylation (KMHL-D) sequence.

A novel and practical method for the synthesis of 3-substituted pyroglutamic acid derivatives is described. One pot multicomponent reaction of Meldrum's acid, aldehyde and Schiff's base followed an unprecedented chemoselective Knoevenagel-Michael-hydrolysis-lactamization domino sequence to afford 4-carboxy 3-substituted pyroglutamic acid derivatives under mild conditions. A carboxy intermediate formed appears to accelerate its own formation. The generality of the synthesis is exemplified by the use of a wide variety of aldehydes including enolizable aliphatic aldehydes, while substrates are stable under reaction conditions.

An Adverse Effect of Higher Catalyst Loading and Longer Reaction Time on Enantioselectivity in an Organocatalytic Multicomponent Reaction.

An enantioselective organocatalytic multicomponent reaction of aldehydes, ketones, and Meldrum's acid has been developed. A cinchona-based primary amine (1 mol %) catalyses the multicomponent reaction via the formation of the Knoevenagel product and a chiral enamine to form enantiopure δ-keto Meldrum's acids in a tandem catalytic pathway. An adverse effect of higher catalyst loading and longer reaction time on enantioselectivity was studied. This mild protocol provides an easy access to enantiopure carboxylic acids, esters and amides and the method is scalable on a gram quantity. DFT calculations were carried out on the proposed reaction mechanism and they were in close agreement with the experimental results.